Pharmacology Book

Garry’s Notes on

Clinical Pharmacology and Therapeutics

2005

Copyright Garry KJ Pettet 2005

http://www.igarry.com

[email protected]

PREFACE ...............................................................................................1

DRUG DEVELOPMENT............................................................................2

ADVERSE DRUG REACTIONS.................................................................5

DRUG INTERACTIONS...........................................................................7

PHARMACODYNAMICS/PHARMACOKINETICS......................................9

PRESCRIBING IN RENAL / LIVER DISEASE........................................12

RHEUMATOLOGY.................................................................................16

GASTROENTEROLOGY.........................................................................21

ANTIVIRALS........................................................................................26

ASTHMA / COPD .................................................................................29

ANALGESICS .......................................................................................34

THE FAILING HEART ...........................................................................37

ENDOCRINOLOGY ...............................................................................45

LIPIDS ................................................................................................56

CLOTTING ...........................................................................................59

MOOD DISORDERS..............................................................................67

ANTI-ARRHYTHMIC DRUGS ................................................................73

HYPERTENSION ..................................................................................80

ANTIBIOTIC THERAPY........................................................................82

ANTIBIOTICS......................................................................................85



[email protected]

DIABETES............................................................................................94

EPILEPSY ............................................................................................99

MULTIPLE SCLEROSIS ......................................................................106

PARKINSON’S DISEASE ....................................................................107

DRUG-INDUCED MOVEMENT DISORDERS ........................................112

MYASTHENIA GRAVIS.......................................................................114

DIURETICS........................................................................................116

MUSCLE RELAXANTS.........................................................................119

ANTI-EMETICS ..................................................................................121

THE EYE ............................................................................................124

ANTIPSYCHOTICS (NEUROLEPTICS)................................................127

DRUGS IN THE ELDERLY, YOUNG OR PREGNANT .............................131

CYTOTOXIC CHEMOTHERAPY ...........................................................134



[email protected]

1

Preface I have written these notes as I found it very difficult to find a good single text to use for my CPT revision. I used the following textbooks in writing these notes:

- British National Formulary (BNF 47 March 2004) - Clinical medicine 5th edition (Kumar, Clark) - Hands-on-guide to clinical pharmacology (Chatu, Milson & Tofield) - Medical pharmacology at a glance 4th edition (Neal) - Oxford handbook of clinical medicine 6th edition (Longmore, Wilkinson

& Rajagopalan) - Pharmacology 4th edition (Rang, Dale, Ritter)

I have made sure that everything that has been mentioned in our lectures is in these notes. We must thank the following lecturers, as some of their material may well be in these notes:

- Dr Chris Bench - Dr Neil Chapman - Dr Anton Emmanuel - Dr Michael Feher - Dr Alun Hughes - Prof Sebastian Johnston - Prof John MacDermot - Dr Janice Main - Dr Vias Markides - Dr Jamil Mayet - Dr Andrew Rice - Dr Stephen Robinson - Dr Mike Schachter - Dr Tom Sensky - Prof Peter Sever - Dr Colin Tench - Dr Simon Thom - Dr Roxaneh Zamegar

I would also like to thank Dr Wajid Hussain for proofreading the section on anti-arrhythmics. Although every effort has been made to ensure the accuracy of these notes, I take not responsibility for errors within (but please let me know as I have to revise from these as well!).

Garry Pettet



[email protected]

2

Drug development

Surrogate markers: • A biological measurement which substitutes for the therapeutic end-

point • Examples:

o BP and stroke o Cholesterol and coronary disease

• Characteristics of a “good” surrogate: o Biological feasibility o Dose-related response to intervention o Easy to measure o Reproducible o Specific / sensitive o High predictive value o Acceptable by experts / regulatory authorities

Types of clinical trials:

• Open: o Subject and researcher know what they are getting

• Single-blind: o The subjects do not know what they are getting

• Double-blind: o No one knows what they are getting (during the trial)

• PROBE: o Prospective o Randomised o Open-labelled o Blinded o End-point o This is used for large, complex studies with several treatments.

It is an open trial where those who analyse the results do not know who got what treatment

The phases of a clinical trial:

• Phase 1: o Healthy volunteers (not for cancer / HIV trials) o Few subjects (< 50) o Looks at pharmacokinetics / pharmacodynamic activity / safety

• Phase 2: o Patients with the target disease o More subjects (100 – 200) o Usually single-blind trials o Looks again at pharmacokinetics / safety (note, these may be

different than in healthy volunteers)



[email protected]

3

• Phase 3: o Patients o Much larger (> 1000) o Usually double-blind or PROBE o May be parallel or crossover o Multi-centre o May use either “hard” (e.g. MI) or “surrogate” end-points

• Phase 4: o Post-marketing o Surveillance for:

Adverse drug reactions Rare side-effects Drug interactions

Parallel vs crossover studies:

• Parallel study:

o Most randomised controlled trials (RCTs) are parallel • Crossover study:

o Need fewer subjects o Should normally be used in chronic stable diseases and the

interventions should have a rapid onset and short duration o Beware of order effects:

Carry-over effects Period effects:

• Changes in the patient’s disease over time Power:

• Is the study large enough to answer the study’s question? • Type 1 error (α):

o Chance of finding 2 treatments are different when they are not o Usually:

α = 0.05 (i.e. p < 0.05) • Type 2 error (β):

o Chance of finding 2 treatments are equal when they are not o Usually:

γ = 0.1 or 0.2 (arbitrary) • Power = 1 - β (i.e. 80 – 90% usually) • The higher we set β (i.e. the greater our power) the more expensive

the trial becomes as we need more subjects

A

B

A

B



[email protected]

4

“Intention to treat” vs “per protocol” analysis: • Intention to treat:

o Ignore whether the subjects actually take the medication (i.e. just assume they did)

• Per protocol: o Only analyse data from subjects who actually took the

medication



[email protected]

5

Adverse drug reactions

Significance: • 3 – 40% of inpatient admissions • Affects 10 – 20% of hospital patients • 4th most common cause of death in US hospital patients • Up to 30 – 60% are preventable

Types of adverse drug reaction (ADR):

• Type 1: o “Predictable” reactions o Common o Dose-related o A consequence of the known pharmacology of the drug

• Type 2: o “Idiosyncratic” reactions o Rare o Usually not dose-related o Allergies o Pharmacogenetic variations

Classification of ADRs:

• Augmented pharmacological effect • Bizarre • Chronic • Delayed • End-of-treatment

Determinants of ADRs:

• Drug: o Pharmacodynamics o Pharmacokinetics o Dose o Formulation o Route of administration

• Patient: o Age o Co-morbidity o Organ dysfunction o Genetic predisposition

• Environment: o Mistakes



[email protected]

6

Allergies vs psuedoallergies: • Allergies:

o Type I (anaphylaxis): Penicillins Contrast media (anaphylactoid)

o Type II (cytotoxic antibodies – blood dyscrasias): Haemolytic anaemia:

• Methyldopa • Penicillin • Sulphonamides

Agranulocytosis: • Carbimazole • Clozapine

Thrombocytopenia: • Quinidine • Heparin

o Type III (immune complex formation): Penicillin Sulphonamides

o Type IV (cell mediated): Topical antibiotics

• Pseudoallergies: o Looks like an allergies but is not immune-mediated o Examples:

Aspirin - bronchospasm ACE inhibitors – cough

Long-term ADRs:

• Withdrawal: o Opiates o Benzodiazepines o Corticosteroids

• Rebound: o Clonidine o β-blockers

• Adaptive: o Neuroleptics



[email protected]

7

Drug interactions

Liver enzyme inducers (cytochrome P450):

• Carbamazepine • Phenobarbitone • Phenytoin • Rifampicin

Liver enzyme inhibitors (cytochrome P450):

• Cimetidine • Ciprofloxacin • Grapefruit juice • Macrolide antibiotics:

o Erythromycin • Omeprazole

Important drugs metabolised by the liver (cytochrome P450):

• Carbamazepine • Digoxin • Combined oral contraceptive (COC) pill • Phenytoin • Theophylline • Warfarin

Some important drugs interacting with warfarin:

• Drugs increasing the effect of warfarin: o Alcohol o Amiodarone o Antibiotics (many – reduced vitamin K absorption) o Cimetidine o Omeprazole o Simvastatin

• Drugs decreasing the effect of warfarin: o Carbamazepine o COC pill o Rifampicin

Interactions with diuretics:

• General: o Potentiate:

ACE inhibitors Lithium

o Metabolic: Hypokalaemia enhances digoxin efficacy β-blockers potentiate hypokalaemic effects of diuretics



[email protected]

8

• Loop: o Increased risk of ototoxicity with the aminoglycosides

• Potassium-sparing: o Risk of hyperkalaemia with ACE inhibitors

Drugs affecting gastric emptying and hence drug absorption:

• Increase emptying: o Metoclopramide

• Decrease emptying: o Atropine

Impairment of drug excretion:

• Probenicid: o Competes with Penicillins for renal tubular excretion, leads to

increased concentration of penicillins (can be beneficial)



[email protected]

9

Pharmacodynamics/pharmacokinetics

Half-life (t1/2): • The time taken for the concentration of drug in plasma (or blood) to

fall to half it’s original value • Drugs with a short t1/2 may have a long duration of action:

o So-called “cell-trapping” o E.g. omeprazole

Volume of distribution (Vd):

• This is the apparent volume into which the drug is distributed

Vd = dose / (initial apparent plasma concentration)

• Is used to calculate the clearance of a drug • Is high for lipid-soluble drugs • Is low for water-soluble drugs • Values of Vd:

o < 5L drug retained within the vascular system o < 15L drug is restricted to the extracellular fluid (ECF) o > 15L indicates the drug is distributed throughout the

total body water

Clearance: • The volume of plasma (or blood) cleared of drug per unit time • Depends on drug lipid solubility • Clearance (but not t1/2) provides an indication of the ability of the liver

and kidneys to dispose of the drug First vs zero order kinetics:

• First-order kinetics: o A metabolic process that depends on the drug concentration at

any given time is called a first-order process o I.e. a non-saturable process

• Zero-order kinetics: o If any enzyme system responsible for drug metabolism becomes

saturated, then the rate of elimination proceeds at a constant rate and is unaffected by an increase in the concentration of the drug

o I.e. a saturable process o Examples include:

Phenytoin Ethanol

o The importance of zero-order is that you could double the dose, but the plasma concentration would not double (may increase to an enormous extent)



[email protected]

10

Bioavailability: • The proportion of administered drug reaching the systemic circulation • IV drugs have 100% bioavailability • Drugs with high bioavailability:

o Ciprofloxacin (near 100%) • Drugs with high bioavailability:

o Bisphosphonates (~15%) First-pass metabolism:

• Also known as pre-systemic metabolism • This is drug metabolism that occurs before the drug reaches the

system circulation • Occurs in the liver and gut wall • Some drugs undergo extensive first-pass metabolism:

o Levodopa o Lignocaine o Morphine o Nitrates (e.g. GTN) o Propranolol o Verapamil

• Is generally a nuisance for two reasons: o A larger does is needed when it is given orally o Marked individual variations occur

Post-systemic metabolism:

• The main purpose is to increase water-solubility of the drug • Phase I:

o Three types of reaction: Oxidation:

• Most important are the P450 enzymes • Xanthine oxidase metabolises 6-mercaptopurine • Monoamine oxidase inactivates 5-HT, NA, tyramine

Reduction / Hydrolysis o Usually produces a more reactive compound that will be acted

on by phase II components o May activate a prodrug – examples:

Levodopa dopamine Enalapril enalaprilat Azathioprine 6-mercaptopurine

• Phase II: o Conjugation of a drug or phase I metabolite with an

endogenous substance to form a more polar, easily excreted, compound

o May be either: Glucuronidation Sulphation Acetylation (does not alter water-solubility) Glutathione



[email protected]

11

Loading doses: • In practice, a steady state concentration is effectively achieved after

three plasma half-times • Faster attainment of the steady state is achieved by starting with a

larger dose – a loading dose Therapeutic drug monitoring:

• Why? o To investigate lack of drug efficacy o Possible poor compliance o Suspected toxicity o Prevention of toxicity

• Type of drugs: o Narrow therapeutic index (TI) o Uncertain dose / concentration relationship o Defined plasma concentrations with no active metabolites

• Examples: o Not warfarin (this measures the INR, not drug concentration!) o Antibiotics (aminoglycosides, vancomycin) o Anticonvulsants (carbamazepine, phenytoin) o Aminophylline / theophylline o Cyclosporin A o Digoxin o Lithium



[email protected]

12

Prescribing in renal / liver disease

Important drugs whose elimination is affected by renal impairment

• Half-lives are approximate ranges when renal impairment present • Amoxicillin (t1/2 2 – 14 hours):

o Applies to most penicillins o Toxic effects:

Seizures (especially in meningitis) Rashes are more common in renal impairment

• Atenolol (t1/2 6 – 100 hours): o Contraindicated in:

Asthmatics Severe heart failure Peripheral vascular disease

o Toxic effects: Bradycardia Confusion Hypotension

• Captopril (t1/2 2 – 14 hours): o Toxic effects:

⇓ GFR Angioedema Cough:

• Probably due to a direct effect on sensory afferents • Not bradykinin

GI disturbances Hypotension Taste disturbances

• Digoxin (t1/2 36 – 90 hours): o Requires therapeutic drug monitoring (TDM) o Toxic effects:

Dysrhythmias (VT, heart block) Gynaecomastia Nausea (severe) Xanthopsia (distortion of yellow colour vision)

• Gentamicin (t1/2 2½ - >50 hours): o Increased risk of toxicity when:

Dehydrated (important as septic patients usually are) Hyponatraemic

o Toxic effects: Nephrotoxicity (renal tubular damage) Ototoxicity (can be irreversible)



[email protected]

13

Vitamin D and the kidney: • Vitamin D has to undergo 2 hydroxylation reactions within the body to

become active • Kidney forms the 1-hydroxy form of vitamin D and requires the

enzyme 1α-hydroxylase • In renal impairment, the above step may not happen • Bone disease caused by renal disease is termed renal

osteodystrophy: o Loss of vitamin D activity o Loss of phosphate (phosphaturic effect of PTH)

• Replacing vitamin D: o Alfacalcidol (the 1-hydroxylated form, thus negating need for

1α-hydroxylase) o Calcitriol (the active 1, 25-hydroxylated form) – rarely used

Nephrotoxic drugs:

• ACE inhibitors: o ⇓ GFR (if the arterial perfusion pressure is low):

Renal artery stenosis (especially bilaterally) Coarctation of the aorta

• Cyclosporin A: o Used in renal transplants o Is a substrate for P450 (levels may be increased by other drugs) o ⇓ GFR o Damages tubular function

• Gentamicin: o Renal tubular damage

• Lithium: o Nephrogenic diabetes insipidus o Renal tubular damage

• NSAIDs: o ⇓ GFR o Papillary necrosis:

Loss of PG-mediated vasodilatation o Na+ retention

• Others: o Urate stones:

Anticancer drugs (tumour lysis syndrome) o Myoglobinuria:

Alcohol Statins

Drugs to watch when patient has impaired hepatic synthetic function:

• Hypoalbuminaemia: o Drugs which bind to albumin and are cleared by the liver:

Diazepam Phenytoin Tolbutamide



[email protected]

14

• A1-acidic glycoprotein deficiency: o Binds basic drugs:

Chlorpromazine Imipramine Quinidine

• Reduced synthesis of clotting factors: o Warfarin:

If the liver is synthesising even less of factors II, VII, IX and X then warfarin’s effects will be potentiated

o Antibiotics: Interfere with vitamin K production in the gut by bacteria May compound the above problem

Drugs to watch in a patient with current / recent hepatic encephalopathy:

• Antidepressants: o Tricyclic antidepressants (TCAs) are safest (but use a ⇓ dose) o Avoid monoamine oxidase inhibitors (MAOIs):

Idiosyncratic hepatotoxicity • Anti-psychotics:

o Chlorpromazine • Anxiolytics / hypnotics:

o Oxazepam / temazepam are the safest o Avoid chlormethiazole (especially IV)

• Opiates: o Can precipitate coma o Even low levels are dangerous

Drugs with a high first-pass metabolism:

• These drugs will not be metabolised as much in liver impairment, thus the dose should be ⇓

• Chlorpromazine • Chlormethiazole • Imipramine • Morphine / pethidine

Hepatotoxic drugs:

• Cholestasis: o Chlorpromazine (reversible cholestasis) o Sulphonylureas (e.g. glibenclamide) o Carbimazole

• Hepatocellular necrosis: o Antibiotics:

Isoniazid Rifampicin Nitrofurantoin



[email protected]

15

o Anticonvulsants: Can cause liver damage at normal doses in some patients Carbamazepine Phenytoin Valproate

o Anti-hypertensives: Hydralazine:

• Also causes a SLE-like syndrome (ssDNA Abs) Methyldopa

o Halothane (repeated exposures) o Paracetamol (overdose)



[email protected]

16

Rheumatology

Drug treatment of osteoarthritis (OA): • Simple analgesics:

o Paracetamol (as good as Ibuprofen in early disease) • Topical therapy:

o NSAIDs (e.g. ibuleve) o Capsaicin:

Potent pain-producing agent After a few applications, the pain-producing effect

disappears and nociceptive responses to other stimuli disappear as well – hence it’s use here

• Glucosamine • Systemic NSAIDs

Drug treatment of rheumatoid arthritis (RA):

• NSAIDs • COX-II inhibitors:

o Indications: Age >65 years Previous history of DU / GU or GI bleed Large doses of NSAID required to control pain

o Absolute contraindications: Established IHD Cerebrovascular disease Heart failure (NYHA II – IV)

• Gastroprotection (if on NSAID / long-term steroids): o H2-receptor antagonists o Proton pump inhibitors (PPIs) o Misoprostol

• Disease modifying anti-rheumatic drug (DMARD): o Persisting synovitis >6 weeks o Several may have to be tried to find the right one:

Methotrexate Sulphasalazine Gold Penicillamine Hydroxychloroquine

• Anti-TNFα therapy: o Progressive RA after 2 DMARD failures

• Steroids are controversial but useful in acute flares

Drug treatment of osteoporosis: • Bisphosphonates:

o Are the mainstay of treatment • Calcium supplements



[email protected]

17

• Vitamin D • Calcitonin (may be considered) • HRT no longer has role

Glucosamine:

• Unclear mechanism of action • Probably similar efficacy to simple NSAIDs • Better tolerated than NSAIDs but not free of side-effects:

o Headache o Rash o Drowsiness

Non-steroidal anti-inflammatory drugs (NSAIDs):

• (Non- selectively) inhibit cyclo-oxygenase (COX) • COX converts arachidonic acid (derived from membrane phospholipids)

into endoperoxides • The endoperoxides are further converted into:

o Prostaglandins (PGs): Potentiate the activity of other pain mediators Vasodilatation

o Thromboxane A2: Platelet aggregation Vasoconstriction

o Prostacyclin: Inhibits platelet aggregation Vasodilatation

• There are 2 isoforms of COX-I and COX-II: o COX-I is a constitutional enzyme is important in the

maintenance of the protective GI mucus barrier in the stomach and of renal blood flow

o COX-II is expressed at sites of inflammation • NSAIDs are:

o Analgesic o Antipyretic (inhibits the rise in brain PGs that cause pyrexia) o Anti-inflammatory (at higher doses)

• Adverse effects: o GI:

Peptic ulceration o Renal:

Reduced renal blood flow Sodium retention - hypertension Interstitial nephritis Hyperkalaemia Papillary necrosis (chronic use)

o Other: Bronchospasm (especially in asthmatics) Allergies



[email protected]

18

Aspirin as a NSAID: • Aspirin is a NSAID but the large doses required to control the

inflammation in the arthritides led to an unacceptable number of adverse effects

• It irreversibly inactivates COX – activity returns only when new enzyme is synthesised:

o Hence it’s effectiveness in platelets (cannot synthesise new enzyme)

Paracetamol as a NSAID:

• Like aspirin, paracetamol is a NSAID • It’s mechanism of action is not fully understood and it has no anti-

inflammatory activity • It works, act least partly, by reducing COX tone:

o This activity is only seen in areas of low peroxide concentration o Hence, paracetamol works best when there is little or no

leucocyte infiltration (as leucocytes produce high levels of peroxide)

Relative risk of GI toxicity with NSAIDs:

• From least toxic to most toxic: o Ibuprofen o Diclofenac o Aspirin o Naproxen o Indomethacin o Ketoprofen

COX-II inhibitors:

• E.g. Celecoxib (Rofecoxib (Vioxx) has been withdrawn in the UK)) • No better at improving symptoms of pain / inflammation than NSAIDs • 50% reduction in GI:

o Ulceration o Perforation o Bleeds

• (Probable) increased risk of: o Myocardial infarction o Stroke

Methotrexate:

• Indications: o Malignancy o Psoriasis (when conventional therapy fails) o Rheumatoid arthritis



[email protected]

19

• Mechanism of action: o Inhibits dihydrofolate reductase o Leads to a reduction in the production of tetrahydrofolic acid

(which is essential for nucleic acid synthesis) o Prevents cells from dividing

• Administer concurrent folic acid to minimise symptoms • Adverse effects:

o Nausea o Fatigue o Pneumonitis (rare but can be life-threatening)

• Contraindications: o Renal / hepatic impairment o Pregnancy

• Interactions: o NSAIDs / probenicid:

Reduce the excretion of methotrexate Sulphasalazine:

• Mechanism of action in RA is unknown • Adverse effects:

o Nausea / abdominal discomfort o Reduced sperm count o Marrow suppression

• Contraindications: o Salicylate allergy o Renal impairment

Gold: • Adverse effects:

o Marrow suppression o Proteinuria o Hepatitis

Penicillamine:

• Adverse effects: o Marrow suppression o Proteinuria o Reduction in taste o SLE

• Contraindications: o Penicillin allergy o SLE

Hydroxychloroquine:

• Adverse effects: o Rash o Retinopathy (rare) o Tinnitus



[email protected]

20

• Cautions: o Hepatic impairment

• Very toxic in overdose Anti-TNFα therapy:

• TNFα is the major mediator of inflammation • Used in RA when patient has failed to respond to >=2 DMARDs

(including methotrexate) • Can be either:

o Soluble TNFα receptors (etanercept) o Anti-TNFα receptors (infliximab)

• Reduce inflammation, inhibit progression and improve radiological Sharp score (a measure of radiological RA severity)

• Adverse effects: o Local reactions o Increased risk of infections:

Especially tuberculosis (need to screen before therapy) o Demyelination syndromes o SLE-like syndrome:

Avoid in SLE-sufferers o Worsening of pre-existing heart failure

• Other disease indications: o Ankylosing spondylitis o Psoriatic arthritis

Bisphosphonates:

• E.g. alendronate, pamidronate • Are enzyme-resistant analogues of pyrophosphate • Bind to hydroxyapatite crystals and reduce bone resorption (via

inhibition of osteoclasts) • Indications:

o Osteoporosis (both primary and steroid-induced) o Paget’s disease o Malignant hypercalcaemia

• Adverse effects: o Alendronate can cause oesophagitis:

Swallow the tablet whole with a full glass of water on an empty stomach and remain upright for at least 30 mins

Vitamin D supplementation:

• Usually given as ergocalciferol (vitamin D2 – the usual dietary source of vitamin D)

• Is a fat-soluble vitamin so bile salts are necessary for absorption • Adverse effects:

o Hypercalcaemia • Interactions:

o Some anticonvulsants (carbamazepine, phenytoin) increase the requirement of vitamin D



[email protected]

21

Gastroenterology

Drug treatment of GORD / PUD: • Antacids • Acid suppression:

o H2-receptor antagonists o Proton pump inhibitors (PPIs)

• Helicobacter pylori eradication Drug treatment of constipation (laxatives):

• Bulk laxatives • Stimulant laxatives • Osmotic agents • Stool softeners • Suppositories / enemas • Novel:

o Motilin analogues (e.g. erythromycin) o 5-HT4 antagonists (e.g. tegaserod) o Probiotics

Drug treatment of diarrhoea:

• General: o Opioids

• Autonomic neuropathy (e.g. diabetes): o Clonidine o Octreotide (for secretory diarrhoea)

• Bacterial overgrowth: o Treat underlying cause o Cyclical antibiotics if above fails (e.g. neuropathy)

• Pancreatic insufficiency (e.g. diabetes, chronic pancreatitis): o Pancreatin + acid-suppressant (e.g. PPI)

Drug treatment of Crohn’s disease:

• Acute exacerbations: o Steroids (oral / rectal / IV) o Elemental diet o Anti-TNFα therapy (infliximab):

Severe (especially fistulating) disease • Maintenance:

o 5-Aminosalicylic acid (5-ASA) compounds o Azathioprine (if 5-ASA fails) o Methotrexate (if azathioprine intolerant)



[email protected]

22

Drug treatment of ulcerative colitis: • Acute exacerbations:

o Rectal 5-ASA (evidence shows benefit over steroids) o Steroids (oral / rectal / IV)

• Maintenance: o 5-ASA compounds

Antacids:

• Reduce gastric pH (this increases rate of emptying thus action is short) • All antacids can interfere with drug absorption – should be taken

separately • Sodium bicarbonate:

o Only useful water-soluble antacid o May cause metabolic alkalosis

• Magnesium hydroxide: o May cause diarrhoea

• Aluminium hydroxide: o May cause constipation

• Alginate-containing compounds (e.g. Gaviscon): o Form a “raft” on top of stomach contents and prevent reflux

H2-receptor antagonists:

• E.g. ranitidine, cimetidine • Block histamine receptors on the gastric parietal cell membrane and

reduce acid secretion • Indications:

o GORD o PUD

• Adverse effects (mainly cimetidine): o Liver enzyme inhibitor (increases levels of):

Anticonvulsants (carbamazepine, phenytoin, valproate) Theophylline Warfarin

o Hyperprolactinaemia o Anti-androgenic activity (gynaecomastia)

Proton pump inhibitors (PPIs):

• E.g. omeprazole, lansoprazole • Inactive at neutral pH but are activated in the stomach and irreversibly

inhibit the H+/K+-ATPase (proton pump) • Are more effective than H2-receptor antagonists and more cost-

effective • Indications:

o GORD o PUD o Zollinger-Ellison syndrome



[email protected]

23

• Adverse effects: o Liver enzyme inhibitor (increases levels of):

Phenytoin Warfarin

• Cautions: o Achlorhydria is associated with gastric cancer – unsure of long-

term effects of acid suppression H. pylori eradication therapy:

• One PPI and two antibiotics for two weeks • Usual combination (but there are many):

o Omeprazole o Clarithromycin o Amoxicillin (or metronidazole)

• Resistance to metronidazole is common Bulk laxatives:

• E.g. bran, ispaghula • Only good for mild constipation • Are usually indigestible polysaccharides • Increase the volume of the intestinal contents – thus stimulating

peristalsis by stretching mechanoreceptors • Gradual onset of action (~1 week) • Increase stool output as a function of initial stool weight:

o If stool volume is low initially then won’t see much of an increase

• Adverse effects: o Exacerbates bloating in slow-transit constipations

Stimulant laxatives:

• E.g. bisacodyl, picosulphate, senna • Are inactive glycosides that are activated in the colon by bacteria • Once in colon – have direct stimulant effect on the myenteric plexus:

o Smooth muscle contraction (peristalsis) • Also increase secretion of water and electrolytes • Rapid onset of action (~8 hours) – give in evening for morning stool • Adverse effects:

o Colic o Colonic atony o Hypokalaemia o Pseudomelanosis coli (colonic pigmentation with chronic use) o Unpredictable effect

Osmotic agents:

• E.g. Lactulose, magnesium salts • Poorly absorbed solutes that maintain a large stool volume by osmosis • Lactulose:

o Is a disaccharide (fructose-galactose)



[email protected]

24

o Cannot be cleaved by human disaccharidases – is cleaved by bacteria in the colon

o These sugars are poorly absorbed by the colon and act as osmotic laxatives

• Onset of action: o Salts – hours o Lactulose – 2 or 3 days

• Adverse effects: o Cramps o Flatulence o Hypermagnesaemia (especially in renal impairment)

Stool softeners:

• E.g. sodium docusate, arachis oil • Act like detergents in the colon and facilitate mixing of fat and water

in the stool • Adverse effects:

o Passive faecal leakage • Not effective enough to be used on their own

Suppositories / enemas:

• E.g. glycerine suppositories, phosphate enemas • Probably as effective as oral osmotic laxatives

Opioids and diarrhoea:

• E.g. loperamide, codeine, morphine • Stimulate µ-receptors on myenteric neurones and lead to

hyperpolarization: o Inhibits Ach release from myenteric plexus and reduces

peristalsis • Loperamide is most appropriate as it does not cross the blood-brain

barrier and is unlikely to cause dependence Pancreatin:

• Pancreatic enzyme supplement of porcine origin • Must be taken with an anti-acid drug (usually a H2-receptor

antagonist) to prevent it’s destruction in the stomach • Is inactivated by heat – caution if mixing pancreatin in with food • Indications:

o Cystic fibrosis o Chronic pancreatitis o Diabetes mellitus o Pancreatectomy

• Adverse effects: o Nausea / vomiting o Abdominal discomfort o Irritation of buccal / perianal mucosa



[email protected]

25

5-Aminosalicyclic acid (5-ASA) compounds: • E.g. mesalazine, olsalazine, sulphasalazine • Unknown mechanism of action • Indications:

o Induction of remission in UC (rectal preparation) o Maintenance of remission in UC and CD:

1 year relapse rate (73% placebo vs 21% sulphasalazine) • Probably reduce the cancer risk associated with UC • Drug structures:

o Olsalazine: Two 5-ASA molecules joined by an azo bond that is

cleaved by bacteria in the colon o Sulphasalazine:

5-ASA with sulphapyridine (a sulphonamide) The sulphapyridine carries the 5-ASA to the colon Most of the adverse effects are caused by sulphapyridine

• Adverse effects: o Few with the newer agents (lacking sulphapyridine)

Infliximab:

• An anti-TNFα monoclonal antibody • Indications:

o Crohn’s disease not controlled by steroids and a conventional immunosuppressant

o Refractory fistulating Crohn’s disease • 65% of patients initially respond to infliximab • 30% will go on to remission • Of those that respond to a single treatment – 50% maintain remission

when treated for 1 year • Infliximab closes 50% of refractory fistulas within 2 weeks and

improves healing in 65%: o However, only 30% of those who heal remain healed at 1 year

• Adverse effects: o Local reactions o Increased risk of infections:

Especially tuberculosis (need to screen before therapy) o Demyelination syndromes o SLE-like syndrome:

Avoid in SLE-sufferers o Worsening of pre-existing heart failure



[email protected]

26

Antivirals

Treatment of herpes simplex virus (HSV) and varicella zoster virus (VZV): • Aciclovir (topical / oral / IV) • Second-line:

o Famciclovir o Valaciclovir

Treatment of cytomegalovirus (CMV):

• Ganciclovir (IV) • Second-line:

o Valaciclovir o Foscarnet

Treatment of human immunodeficiency virus (HIV):

• Highly active anti-retroviral therapy (HAART): o Two NRTIs plus either an NNRTI or a PI

• NRTI = nucleoside reverse transcriptase inhibitor • NNRTI = non- nucleoside reverse transcriptase inhibitor • PI = protease inhibitor • Treatment of opportunistic infections

Drugs treatment of chronic hepatitis B (HBV) infection:

• 40% success rate • Interferon-α (IFN-α) • Lamivudine • Second-line:

o Famciclovir Drug treatment of chronic hepatitis C (HCV) infection:

• Combination therapy (most effective): o Peginterferon-α (⇑ bioavailability – once weekly) o Ribavirin

• Treatment depends on HCV genotype: o Genotypes 2, 3:

Better prognosis Treat for 6 months

o Genotypes 1, 4: Worse prognosis Treat for 12 months

• If HCV RNA has not decreased after 12 weeks treatment to <1% of initial level then consider discontinuing



[email protected]

27

Drug treatment of influenza: • Influenza A only:

o Amantadine • Influenza A and B:

o Neuraminidase inhibitors: Olseltamivir Zanamivir

• Only used in at-risk adults who can start treatment within 48 hours of the onset of symptoms

• At-risk adults: o Chronic respiratory disease o Significant cardiovascular disease (excluding hypertension) o Chronic renal disease o Immunocompromised o Diabetes mellitus

Aciclovir:

• Aciclovir is converted to the monophosphate by thymidine kinase • Viral thymidine kinase has a much greater affinity for aciclovir than the

human enzyme • Aciclovir is therefore only activated in virally-infected cells, where it is

converted to the triphosphate: o Inhibits viral DNA polymerase and terminates the nucleotide

chain • Adverse effects:

o Rash (topical preparations) o Drip site inflammation o Renal damage

• Interactions: o Probenicid decreases excretion of aciclovir

Adverse effects of the NRTIs:

• All of these drugs have many side-effects, only important ones for each are listed here

• Abacavir: o Hypersensitivity (rash, Stevens-Johnson syndrome) o Hepatic impairment (lactic acidosis, hepatomegaly)

• Didanosine: o Pancreatitis

• Lamivudine: o Well tolerated o Caution in hepatic disease

• Stavudine: o Lipodystrophy o Peripheral neuropathy

• Zalcitabine: o Pancreatitis o Peripheral neuropathy



[email protected]

28

• Zidovudine (AZT): o Bone marrow suppression

Adverse effects of the NNRTIs:

• All of these drugs have many side-effects, only important ones for each are listed here

• Efavirenz: o Psychiatric manifestations

• Nevirapine: o Hypersensitivity (rash, Stevens-Johnson syndrome) o Many drug interactions:

E.g. methadone is metabolised much faster Adverse effects of the PIs:

o Many side effects although an important one is lipodystrophy • Amprenavir:

o Hypersensitivity (rash, Stevens-Johnson syndrome) • Indinavir:

o Renal calculi • Ritonavir:

o Peripheral and circumoral paraesthesia • Saquinavir:

o Liver impairment • Combination:

o Kaletra (lopinavir + ritonavir): The ritonavir ⇑ the concentration of the lopinavir Diarrhoea

Lipodystrophy:

• Also known as the fat redistribution syndrome • A common side effect of the PIs and stavudine • Features:

o Decreased subcutaneous fat o Buffalo hump o Breast enlargement o Hyperlipidaemia o Insulin resistance - hyperglycaemia

Amantadine:

• Indications: o Influenza A in at-risk adults within 48 hours of symptoms o Parkinson’s disease

• It’s anti-viral actions arise from it’s ability to inhibit a viral ion-channel • The putative mechanism in Parkinson’s disease is an increase in

dopamine release



[email protected]

29

Asthma / COPD

Severe asthma: • Unable to complete sentences • Respiratory rate >25/min • Pulse >110/min • PEFR <50% best or predicted

Life-threatening asthma:

• PEFR <33% best or predicted • Bradycardia • Hypotension • Silent chest • Feeble respiratory effort • Confusion • Blood gases:

o pCO2 > 5kPa o pO2 <8kPa o pH <7.35

BTS guidelines for the management of acute severe asthma in adults

• Initial management: o 100% High flow oxygen o Nebulised salbutamol (5mg) or terbutaline (10mg) o Add in nebulised ipratropium bromide (0.5mg) if poor

response o IV hydrocortisone (100mg)

• No improvement: o Consider ITU referral o Continue repeating nebulised salbutamol o IV magnesium sulphate (1.2-2g over 20 mins) o Aminophylline:

Omit loading dose if patient is taking theophylline o IV Salbutamol (but not with Aminophylline)

BTS 5 steps approach to the management of asthma:

• Step 1 (mild intermittent asthma): o Inhaled short-acting β2-agonist as required

• Step 2 (regular preventer therapy): o Step 1 + low dose inhaled steroid

• Step 3 (add-on therapy): o Step 2 + long-acting β2-agonist (LABA) o If partial response to LABA then:

Continue with LABA and increase dose of inhaled steroid o If no response to LABA then:

Stop LABA and increase dose of inhaled steroid



[email protected]

30

Consider adding in leukotriene antagonist or theophylline • Step 4 (persistent poor control):

o Step 3 + either: High-dose inhaled steroid Leukotriene antagonist (if not on one already) Oral theophylline

• Step 5 (continuous or frequent use of oral steroids): o Step 4 + daily oral steroids o Refer patient for specialist care

General principles of drug treatment of COPD:

• Discontinue drugs which may worsen COPD: o E.g. β2-blockers for hypertension

• Maintenance therapy: o Inhaled bronchodilators:

β2-agonists (short-/long-acting) Anti-muscarinics (short-/long-acting):

• These are more important than in asthma o Inhaled corticosteroids:

If FEV1 <50% predicted Repeated exacerbations

o Theophylline • Exacerbations:

o Oral steroids o Antibiotics (if infection suspected)

• Vaccination: o Influenza (definite benefit shown) o Pneumococcal (probable benefit)

Drug treatment of COPD by stage:

• Stage 0: o No COPD (but at risk)

• Stage 1 (mild COPD): o FEV1 <80% predicted o Short-acting β2-agonist

• Stage 2: o FEV1 50-80% predicted o Long-acting β2-agonist

• Stage 3: o FEV1 <50% predicted o Inhaled steroids (1000 - 2000µg daily)

• Stage 4: o FEV1 <30% predicted o Risk of cor pulmonale o May need oxygen therapy if hypoxic at rest



[email protected]

31

Inhaled β2-agonists: • Short-acting (last 4-6 hours):

o Salbutamol o Terbutaline

• Long-acting (last ~12 hours): o Salmeterol

• Indications: o Asthma o COPD with reversible component

• Mechanism of action: o Stimulates β2-receptors on airway smooth muscle o Leads to ⇑ cAMP which ⇓ intracellular Ca2+, leading to smooth

muscle relaxation • Adverse effects:

o Tachycardia o Tremor

• Interactions (Hypokalaemia with high doses of): o Corticosteroids o Diuretics (loop and thiazide) o Theophylline

Inhaled anti-muscarinics:

• Short-acting (last 3-6 hours): o Ipratropium bromide (Atrovent)

• Long-acting (once daily): o Tiotropium (Spiriva)

• Indications: o Asthma o COPD with reversible component (especially tiotropium)

• Mechanism of action: o Inhibits the parasympathetic nervous supply of the bronchioles

by binding to muscarinic receptors • Adverse effects (uncommon as poorly absorbed systemically):

o Dry mouth o Constipation

• Cautions: o Glaucoma o Prostatic hypertrophy

Inhaled corticosteroids:

• E.g. beclomethasone, budesonide, fluticasone • Indications:

o Asthma (from BTS step 2 onwards) • Mechanism of action:

o Decrease formation of numerous cytokines important in asthma o Inhibit generation of prostaglandins / leukotrienes o Inhibit the allergen-induced influx of eosinophils into the lung o Up-regulate β2-receptors



[email protected]

32

• Take up to 12 weeks to reach maximum efficacy • Reduce morbidity and mortality of asthma • Improve quality of life • Prevent long-term decrease in airway function • Inhaled steroids work best at a moderate dose combined with

bronchodilators • Adverse effects (fewer than systemic corticosteroids):

o High dose: Adrenal suppression (give patients steroid card) Cataracts Glaucoma Growth suppression (probably just initial growth

velocity) Osteoporosis

o Low dose: Candidiasis (reduced by using a spacer device) Hoarse voice

• Interactions: o Very few when inhaled

• Cautions: o Active or quiescent TB o Oral steroids may be required during times of high stress if on

long-term high dose inhaled steroids Methylxanthines:

• E.g. Aminophylline, theophylline • Aminophylline is a soluble form of theophylline:

o If given IV, must be by very slow IV injection • Indications:

o Asthma (BTS step 3 onwards) as theophylline o Severe acute asthma (as aminophylline)

• Mechanism of action: o Are phosphodiesterase inhibitors and lead to an ⇑ cAMP and

hence bronchial smooth muscle relaxation o May also effect increase cGMP levels and cause smooth muscle

relaxation • Adverse effects:

o Nausea / vomiting o Hypokalaemia o CNS stimulation

• Interactions (many – is metabolised by liver enzymes): o Adenosine:

Actions of adenosine are inhibited by the methylxanthines o Plasma concentration increased by:

COC pill Erythromycin Cimetidine Verapamil



[email protected]

33

o Plasma concentration decreased by: Carbamazepine Phenytoin Rifampicin

• Caution: o Half-life is increased by:

Cardiac failure Liver disease Viral infections

o Half-life is decreased by: Alcoholism Smoking

Leukotriene antagonists:

• E.g. montelukast • Taken orally • Indications:

o Asthma (BTS step 3 onwards) • Mechanism of action:

o Block the effects of cysteinyl leukotrienes (e.g. LTC4, LTD4 and LTE4) in the airways

• Advantages: o Improved compliance (oral and don’t have the steroid stigma) o Some patients respond well to them o Well tolerated

• Disadvantages: o Poor efficacy compared to inhaled steroids o Unpredictable response o Expensive

• Adverse effects: o GI disturbances o Drug-induced Churg-Strauss syndrome



[email protected]

34

Analgesics

Taxonomy of opioids: • Opioid:

o A compound acting at an opioid receptor • Opiate:

o An alkaloid derived from opium Adverse effects of opioids:

• CNS: o Respiratory depression:

Decreased respiratory rate Relief of dyspnoea

o Sedation o Euphoria o Meiosis o Anti-tussive o Nausea / vomiting

• Non-CNS: o Pruritis o Constipation o Urinary retention

• Opiates only: o Histamine release:

Not opioid receptor mediated Mechanism of action of opioids:

• Mimic endogenous opioids by acting on µ, δ and κ receptors in the: o Dorsal horn o Peri-aqueductal grey matter o Midline raphe nuclei

Contraindications to the use of strong opioids:

• Severe respiratory disease (e.g. COPD) • Head injury / raised intracranial pressure:

o Interfere with neurological assessment • Hepatic failure • Acute alcohol intoxication

WHO analgesic ladder:

• Step 1: o Non-opioid analgesics:

Aspirin Paracetamol NSAIDs



[email protected]

35

• Step 2: o Weak opioids /partial opioid agonists:

Codeine Tramadol

• Step 3: o Strong opioids:

Morphine Diamorphine

Paracetamol (acetaminophen):

• Indications: o Mild to moderate pain o Pyrexia

• Adverse effects: o Dangerous in overdose

• Overdose: o Signs / symptoms:

None (generally) Abdominal pain Hypoglycaemia Vomiting

o Investigations: ABG, FBC, glucose, LFTs (ALT), INR, U&Es

o Treatment: Remove the drug:

• If >12g and <1 hr since ingestion - gastric lavage • If <8 hrs since ingestion - activated charcoal

Find the time vs paracetamol concentration graph in A&E: • If above treatment line start N-acetylcysteine

o Rule of thumb: If PT (secs) > time since od (hrs) then bad prognosis

o Criteria for transfer to specialist liver unit: Encephalopathy / ⇑ ICP INR > 2.0 at < 48 hrs or INR >3.5 at 72 hours:

• If INR is normal at 48 hours, patient can go home Renal impairment (creatinine >200µmol/L) Blood pH <7.3 Systolic BP <80mmHg

• Cautions: o Hepatic / renal impairment o Alcohol dependence

Codeine phosphate:

• Indications: o Cough suppression o Diarrhoea o Mild to moderate pain

• Half-life of 3.5 hours



[email protected]

36

• Adverse effects: o Constipation (prominent) o See “adverse effects of opioids”

Tramadol:

• Synthetic analogue derived from codeine • Indications:

o Moderate to severe pain • Mechanism of action:

o µ-receptor agonist (like most opioids) o Inhibits uptake of noradrenaline and 5-HT

• Advantages over other opioids: o Does not depress respiration

• Disadvantage over other opioids: o Can cause seizures

Morphine:

• Indications: o Pain:

Acute (e.g. myocardial infarction) Chronic (e.g. chronic pancreatitis) Terminal (e.g. malignancy)

o Acute pulmonary oedema o Intractable cough in terminal care

• Half-life of 3 hours • Tolerance to morphine occurs after about 2 weeks of continuous use • Titration of morphine dose:

o Assess individual 24 hour requirement to relieve pain at rest and on movement

o Convert to modified release morphine (MST) bd with rapid release morphine prn for breakthrough pain

o Increase the dose of MST based on the basis of breakthrough requirements



[email protected]

37

The failing heart

Heart failure: • Acute:

o Myocardial infarction (MI): Acute Post-MI

o Pulmonary oedema without MI • Chronic:

o Chronic stable angina o Heart failure

Drug treatment of acute myocardial infarction:

• Oxygen • Aspirin 300mg (chewed) • Morphine 5-10mg IV + metoclopramide 10mg IV • GTN 2 puffs or 1 tablet prn • β-blocker (e.g. atenolol 5mg IV) unless contraindicated • Thrombolysis:

o Indications: Presentation within 12 hours of chest pain and ST elevation >2mm in 2 or more chest leads or ST elevation >1mm in 2 or more limb leads or New left bundle branch block or Posterior infarction

o Contraindications: Bleeding Prolonged / traumatic CPR Trauma / surgery (within 2 weeks) Recent haemorrhagic stroke Severe hypertension (>200/120mmHg) Pregnancy Suspected aortic dissection

o Thrombolytic agent: Streptokinase (SK):

• 1.5 million units in 100mls 0.9% saline over 1 hour • Usual first choice • Risk of allergy / anaphylaxis

Tissue plasminogen activator (tPA): • Give if patient already received SK • Alteplase infusion • Tenecteplase bolus injection



[email protected]

38

Drug treatment post-myocardial infarction: • Aspirin 75mg od • β-blocker (e.g. metoprolol 50mg qds) or verapamil if contraindicated • ACE inhibitor (especially if evidence of heart failure) • Statin (e.g. benefit shown even if “normal” cholesterol levels) • Treat other risk factors:

o Diabetes mellitus o Hypertension

Drug treatment of acute pulmonary oedema:

• Sit patient upright • Oxygen • Furosemide (40 – 80mg slow IV) • Diamorphine (2.5 – 5mg slow IV) • GTN 2 puffs or 2x0.3mg tablets • If systolic BP >100mmHg start nitrate infusion (keep >90mmHg) • If patient worsening:

o Repeat furosemide 40 – 80mg slow IV o Consider ventilation o Consider increasing nitrate infusion

Drug treatment of chronic stable angina:

• Aspirin • Nitrates:

o Relief: GTN

o Prevention: Long-acting nitrates

• β-blockers (e.g. atenolol 50-100mg/24 hours po) • Calcium-channel blockers:

Caution with concomitant use of β-blocker o Dihydropyridines:

Amlodipine o Non-dihydropyridines:

Diltiazem Verapamil (do not give with β-blockers)

• Potassium channel activator: o Nicorandil

Drug treatment of chronic heart failure:

• Diuretics: o Furosemide (symptomatic only) ± o Spironolactone:

Potassium-sparing Shown to reduce mortality

o Metolazone: Thiazide diuretic Synergistic with furosemide for refractory oedema



[email protected]

39

• ACE inhibitors: o Shown to reduce mortality

• β-blockers: o Shown to reduce mortality (probably via ⇓ arrhythmias) o Synergistic with ACEIs o “Start low, go slow” – needs careful titration

• Digoxin: o No reduction in mortality o ⇓ in hospital admissions

• Angiotensin II receptor antagonists: o Probably similar to ACEIs but little conclusive evidence

• Nitrates: o Probably reduce mortality (but less so than ACEIs) o Used in those in whom ACEIs are contraindicated

Nitrates:

• All function as nitric oxide (NO) donors • Cause mainly venous dilatation (hence ⇓ preload) • Mechanism of action of NO:

o NO stimulates guanylyl cyclase which leads to an ⇑ cGMP o ⇑ cGMP leads to smooth muscle relaxation

• Glyceryl trinitrate (GTN): o Onset is rapid and lasts for ~30 mins o Usually given sublingually

• Long-acting nitrates (isosorbide mono-/dinitrate): o More stable than GTN and last several hours o Isosorbide mononitrate is the active metabolite of isosorbide

dinitrate: The mononitrate avoids the unpredictable first-pass

metabolism of the dinitrate o Tolerance develops after as little as 24 hours – avoid by

omitting the evening dose (permits an 8 hour drug-free interval) • Adverse effects:

o Headaches (frequently dose-limiting) o Hypotension / fainting o Reflex tachycardia (prevented by administration of a β-blocker)

• Contraindications: o Constrictive pericarditis o Hypotension o Head trauma o Hypertrophic obstructive cardiomyopathy (HOCM) o Valvular stenosis (aortic / mitral)

• Interactions: o Sildenafil (Viagra):

Profound hypotension



[email protected]

40

β-blockers: • Non-selective:

o Propranolol • “Cardio-selective” (β1-antagonists):

o Atenolol o Metoprolol

• Indications: o Angina o Heart failure o Hypertension o Post-MI o Prevention of variceal bleeding in liver disease (propranolol) o Prophylaxis of migraine o “Stress”-induced arrhythmias

• Mechanism of action: o Most do not affect resting parameters (e.g. heart rate) but

prevent the exercise-induced cardiovascular changes caused by sympathetic stimulation

o Anti-hypertensive action probably arises from an alteration in the CNS “set-point”

• Adverse effects: o Lethargy / fatigue (usually improves with use) o Bradycardia o Cold hands / feet o Hypotension o Bronchospasm (including cardio-selective agents) o Nightmares o Worsened / precipitated heart failure

• Contraindications: o Asthma / COPD o Bradycardia / heart block

• Interactions: o Diltiazem / verapamil:

⇑ risk of bradycardia / AV block o Insulin / oral anti-diabetic agents:

β-blockers mask the signs of hypoglycaemia Calcium-channel blockers:

• Two classes: o Dihydropyridines:

Nifedipine (short-acting) Amlodipine (longer-acting)

o Non-dihydropyridines: Diltiazem Verapamil

• Indications: o All:

Angina (especially vasospastic angina)



[email protected]

41

Hypertension o Nifedipine:

Raynaud’s phenomenon o Verapamil:

Supraventricular arrhythmias: • Adenosine has largely replaced in acute situation • Can be used as prophylaxis against SVTs

• Mechanism of action: o Block L-type voltage-sensitive Ca2+ channels in:

Arterial smooth muscle (vasodilatation): • Both classes • Can cause a reflex tachycardia

Myocardial conduction system (negative inotropism): • Non-dihydropyridines (as they have a high

affinity for channels in the activated state • Amlodipine causes less tachycardia than nifedipine • Verapamil (and to a lesser extent diltiazem) depress the sinus node:

o Mild resting bradycardia • Verapamil slows conduction at the AVN • Diltiazem has actions in between verapamil and nifedipine:

o Popular in treatment of angina – does not cause tachycardia • Adverse effects:

o Dizziness o Hypotension o Flushing o Fluid retention (ankle oedema)

• Contraindications: o All:

Cardiogenic shock o Dihydropyridines:

Severe aortic stenosis Unstable angina

o Non-dihydropyridines: Myocardial conduction defects (e.g. bradycardia) Heart failure:

• Further depression of cardiac function

o Nifedipine: Angina (short-acting preparation may ⇑ mortality)

o Verapamil: Ventricular tachycardia (potentially lethal)

• Interactions: o Diltiazem:

Digoxin: • Diltiazem ⇑ plasma concentration of digoxin

Carbamazepine: • Diltiazem ⇑ plasma concentration of carbamazepine



[email protected]

42

Phenytoin: • Diltiazem ⇑ plasma concentration of phenytoin

o Nifedipine: Diltiazem:

• ⇑ plasma levels of nifedipine Phenytoin:

• Nifedipine ⇑ plasma levels of phenytoin Grapefruit juice:

• ⇑ plasma levels of nifedipine (and other dihydropyridines but not Amlodipine)

o Verapamil: β-blockers (asystole, severe hypotension, heart failure) Digoxin:

• Verapamil ⇑ plasma concentration of digoxin Cyclosporin:

• Verapamil ⇑ plasma concentration of cyclosporin Angiotensin converting enzyme inhibitors (ACEIs):

• E.g. captopril, enalapril, lisinopril • Indications:

o Diabetic nephropathy o Hypertension o Heart failure o Post-MI

• Inhibit ACE, thus reduce circulating angiotensin II • Actions of angiotensin II (mediated via the AT1 receptor):

o Potent vasoconstrictor o Aldosterone secretion:

Na+ retention K+ excretion

• Advantages: o Do not affect blood lipids o May improve cardiac remodelling

• Adverse effects: o Postural hypotension o Dry cough (Chinese are more susceptible) o Hyperkalaemia o Angioedema (in 1 – 2% of patients)

• Contraindications: o Poor renal arterial perfusion pressure:

Renal artery stenosis / coarctation of the aorta: • Loss of renal efferent arteriole tone (caused by the

ACEI) and ⇓ afferent arteriole pressure leads to renal ischaemia

o Aortic stenosis o Pregnancy



[email protected]

43

• Interactions: o NSAIDs:

⇑ risk of renal impairment o Potassium-sparing diuretics:

⇑ risk of hyperkalaemia o Lithium:

ACEIs ⇓ excretion of lithium o Diuretics:

⇑ risk of hypotension Angiotensin II (AII) receptor antagonists:

• E.g. losartan, irbesartan, candesartan • Indications:

o Diabetic nephropathy o Hypertension o Heart failure (unlicensed indication)

• Mechanism of action: o Block the AT1 receptor, inhibiting the actions of angiotensin II o As they do not block ACE, they do not affect the metabolism of

bradykinin – possibly why they do not cause a cough • Adverse effects/contraindications/interactions – as for ACE inhibitors

Digoxin:

• Indications: o Supraventricular dysrhythmias (esp. AF) o Heart failure (improves symptoms not mortality)

• Mechanism of action: o Is a cardiac glycoside extracted from foxglove leaves o Inhibits cardiac membrane Na+/K+-ATPase:

⇑ intracellular Na+ Secondary ⇑ in intracellular Ca2+

• Clinical effects: o ⇑ force of cardiac contraction o ⇑ cardiac vagal activity:

⇓ heart rate ⇓ AV conductance ⇑ AVN refractory period

• Common adverse effects: o Anorexia o Nausea o Vomiting

• Toxic levels: o Digoxin requires therapeutic drug monitoring o Risk of toxicity increased with:

Hypokalaemia (reduced competition for pump binding) Hypercalcaemia Hypothyroidism



[email protected]

44

o May require digoxin specific antibody fragments (Fab) o Features:

Nausea (severe) Dysrhythmias:

• VT • Heart block

Xanthopsia (distortion of yellow colour vision) • Contraindications:

o Complete heart block o HOCM o Wolff-Parkinson-White syndrome

• Caution in renal impairment: Digoxin is excreted by the kidneys

• Drugs increasing risk of digoxin toxicity: o Anti-arrhythmics:

Amiodarone Quinidine

o Calcium channel blockers (non-dihydropyridines)): Diltiazem Verapamil

o Diuretics (loop and thiazide): Cause hypokalaemia, thus ⇑ risk of digoxin toxicity

Nicorandil:

• Indications: o Angina

• Mechanism of action: o Potassium channel activator with a nitrate component o Causes both arterial and venous vasodilatation

• Adverse effects: o Headache o Flushing o Oral ulceration (rarely)

• Interactions: o Sildenafil:

Profound hypotension – avoid concomitant use



[email protected]

45

Endocrinology

Drug treatment of hyperthyroidism: • Immediate symptom control:

o Propranolol • Long-term treatment:

o Thionamides: Carbimazole or Propylthiouracil

o Radioiodine (131I) • Prior to surgery to decrease thyroid vascularity:

o Lugol’s iodine solution Immediate management of thyrotoxic storm:

• IV fluids • Take blood for T3, T4 (and cultures if infection suspected) • Sedate if necessary:

o E.g. chlorpromazine • Propranolol (oral or IV if no contraindications) • Digoxin:

o May be needed to slow the heart • Anti-thyroid drugs:

o Carbimazole o Lugol’s solution

• Corticosteroids (IV hydrocortisone or oral dexamethasone) Drug treatment of hypothyroidism:

• Hypothyroidism: o Levothyroxine (T4)

• Myxoedema coma: o Liothyronine (T3)

Drug treatment of Addison’s:

• Disease: o Oral hydrocortisone:

20mg in the morning 10mg in the evening Double during febrile illness, stress or injury

o Fludrocortisone: Only needed if:

• Postural hypotension • ⇓ Na+, ⇑K+ or ⇑ renin

Give every second day • Crisis:

o Hydrocortisone 100mg IV stat o IV fluids (colloid to resuscitate then crystalloids)



[email protected]

46

o Glucose IV if hypoglycaemic o Antibiotics if infection present

Drug treatment of Cushing’s syndrome:

• Treat the underlying cause – rarely need drug therapy long-term • Suppression of plasma cortisol level:

o Aminoglutethemide o Ketoconazole o Metyrapone

Drug treatment of Conn’s syndrome:

• Definitive treatment is with surgery • Spironolactone

Drug treatment of diabetes insipidus (DI):

• Cranial DI: o Treat the underlying cause o Intranasal desmopressin (DDAVP)

• Nephrogenic DI: o Treat the underlying cause o Bendrofluazide (paradoxically, as this is a diuretic)

Drug treatment of acromegaly:

• Best treated with trans-sphenoidal surgery of irradiation • Somatostatin analogues (first line):

o Octreotide (short-acting) o Lanreotide (long-acting)

• Dopamine agonists: o Bromocriptine o Cabergoline

Drug treatment of hypopituitarism:

• Need to replace what is missing • ACTH:

o Hydrocortisone • GH:

o Recombinant GH is available • FSH, LH:

o Testosterone - males o Oestrogen (via COC pill) - females

• TSH: o Thyroxine (if hypothyroid, but can’t use to TSH to monitor)

• No need to replace prolactin



[email protected]

47

Drug treatment of hypogonadism: • Males:

o Testosterone • Females:

o COC pill Drug treatment of hyperprolactinaemia:

• Definitive treatment is surgical • Dopamine agonists:

o Bromocriptine o Cabergoline

Drug treatment of hypercalcaemia:

• Treat underlying cause if possible • IV fluids • Bisphosphonates • Salmon calcitonin:

o Rarely used o Faster onset than bisphosphonates

• Steroids: o E.g. for sarcoidosis

• Furosemide (once rehydrated) Drug treatment of hypocalcaemia:

• Mild: o Oral calcium supplements (e.g. sandocal)

• Severe: o 10mls 10% calcium gluconate IVI over 30 mins o Repeat as necessary

• Must correct magnesium levels – will never correct Ca2+ otherwise Drug treatment of phaeochromocytoma crisis:

• Control BP with IV phentolamine (short-acting α-antagonist) • When BP controlled, give phenoxybenzamine (irreversible α-

antagonist) • Give β1-blocker • Arrange for surgery within next few weeks

Thionamides:

• E.g. carbimazole, propylthiouracil • Indications:

o Carbimazole: Hyperthyroidism

o Propylthiouracil: Usually reserved for patients intolerant to carbimazole



[email protected]

48

• Mechanism of action: o All:

Inhibition of thyroid peroxidase Immunosuppressive properties (controversial)

o Carbimazole: Is a prodrug (converted to methimazole)

o Propylthiouracil: Inhibits peripheral conversion of T4 T3

• How to use: o Aim is to render the patient euthyroid and then give a ⇓ dose for

maintenance o It is often possible to stop treatment after 1 or 2 years (50%

relapse rate) • Adverse effects:

o GI disturbances o Carbimazole:

Pruritis Rash

o Agranulocytosis: Carbimazole (0.1%) Propylthiouracil (0.4%) Patients should be told to seek medical attention if they

develop symptoms of infection (e.g. sore throat): • If neutropenia confirmed stop treatment

• Cautions: o Pregnancy:

Low doses should be used as carbimazole crosses the placenta and can cause neonatal hypothyroidism / goitre

Radioiodine (131I):

• Treatment of choice in pts >40 years (can be used in younger pts) • Indications:

o Hyperthyroidism o Disseminated thyroid malignancy

• Mechanism of action: o The radioactive iodine is localised to the thyroid where it

destroys thyroid tissue via β-radiation • Treatment renders the pt euthyroid within 4-6 weeks, when thyroxine

replacement therapy can be undertaken (lifelong) • Adverse effects:

o Causes hypothyroidism o May precipitate thyroid storm

• Contraindications: o Children o Pregnancy (also, pregnancy must not be allowed to occur

within 3 months) o Mothers who are unable to leave their children in others care for

at least 10 days (to avoid exposure)



[email protected]

49

Thyroxine: • May be either T4 (Levothyroxine) or T3 (liothyronine) • T3 is faster acting than T4 but with a shorter half-life • Adverse effects (mainly in overdose):

o Angina o Dysrhythmias o MI o Tachycardia

• Cautions: o Thyroxine should be introduced slowly in those with IHD

• Interactions: o Warfarin:

Thyroxine ⇑ the effect of warfarin Corticosteroids:

• E.g. hydrocortisone, prednisolone, dexamethasone • Indications (many):

o Anti-inflammatory: Topical:

• Asthma • Skin disorders (e.g. eczema)

Systemic: • Anaphylaxis • IBD • Rheumatoid arthritis

o Immunosuppression: Connective tissue diseases (e.g. temporal arteritis) Leukaemia Sarcoidosis Transplant rejection

o Replacement: Addison’s disease Congenital adrenal hyperplasia

• Mechanism of action: o Bind to cytoplasmic receptor that diffuses into nucleus and binds

to steroid-response elements on DNA: Either increases or decreases transcription

o Inhibits phospholipase A2 (thus ⇓ production of arachidonic acid) o ⇓ B and T cell responses to antigens

• Adverse effects (many): o CNS:

Depression Psychosis

o Endocrine: Adrenal suppression Hirsuitism Impotence Oligo-/amenorrhoea



[email protected]

50

Weight gain o Eyes:

Cataracts Glaucoma

o Gastrointestinal: Candidiasis Peptic ulceration Pancreatitis

o Immune system: ⇑ susceptibility to and ⇑ severity of infections

o Metabolic: Hyperglycaemia Hypertension

o Musculoskeletal: Growth suppression Myopathy Osteoporosis

o Skin: Abdominal striae Buffalo hump Easy bruising Poor wound healing Thinning

• Differences between the different steroids: o Hydrocortisone:

Replacement therapy IV in shock / status asthmaticus

o Prednisolone: Orally for anti-inflammatory effects

o Dexamethasone: No salt-retaining properties Very potent Useful when high doses required (e.g. cerebral oedema)

o Budesonide / beclomethasone: Pass membranes very poorly Much more active topically (e.g. aerosol, gut)

• Interactions: o Enhances activity of warfarin o Live vaccines (impairs response) o Reduces activity of anticonvulsants (carbamazepine,

phenytoin) • Withdrawal of glucocorticoids – withdrawal gradually in the following:

o Course duration >3 weeks o Received >40mg prednisolone (or equivalent) daily o Been given repeated doses in the evening o Taken a short course within 1 year of taking long-term therapy



[email protected]

51

• Notes: o “Physiological” dose of steroid is ~7.5mg prednisolone o Patients should be given a steroid card

Metyrapone:

• Indications: o Cushing’s syndrome:

Especially that not amenable to surgery (e.g. lung ca) o Resistant oedema due to aldosterone secretion in:

Cirrhosis Congestive cardiac failure

• Mechanism of action: o Competitive inhibitor of 11β-hydroxylase o Inhibits endogenous production of cortisol (and to a lesser

extent aldosterone) by the adrenals • Contraindications:

o Adrenocortical insufficiency o Pregnancy / breast feeding

• Adverse effects: o Hypoadrenalism

Desmopressin (DDAVP):

• Synthetic vasopressin (ADH) analogue • Indications:

o Cranial diabetes insipidus (diagnosis and treatment) o Haemophilia o Persistent enuresis

• Mechanism of action: o Selectively agonises V2 receptors on renal tubular cells:

Leads to increased reabsorption of water Thus devoid of vasoconstrictor activity (V1)

o Also increases the plasma concentration of factor VIII • Adverse effects:

o Dilutional hyponatraemia o Fluid retention

• Contraindications: o Heart failure

Somatostatin analogues:

• E.g. octreotide (given tds), lanreotide (given once monthly) • Indications:

o Acromegaly o Carcinoid syndrome o Variceal bleeding (octreotide, unlicensed indication)

• Mechanism of action in acromegaly: o Inhibit GH release from the pituitary gland o 90% of patients respond and 60% have GH level normalisation

• Adverse effects:



[email protected]

52

o Gallstones o GI disturbances

• Interactions: o Anti-diabetic agents (oral and insulin):

Octreotide may ⇓ requirements for these drugs Dopamine agonists:

• E.g. bromocriptine (short-acting), cabergoline (long-acting) • Indications:

o Acromegaly o Hyperprolactinaemia o Idiopathic Parkinson’s disease o Suppression of lactation o Cyclical benign breast disease

• Mechanism of action: o Directly stimulate dopamine receptors in the CNS (anti-

Parkinson’s effect) o Inhibits release of prolactin from anterior pituitary o Inhibits the release of GH in acromegalics:

Increases GH levels in non-acromegalics • Lead to a maximum ⇓ of GH of 7-60%:

o Only 10-15% of patients achieve GH normalisation • Adverse effects:

o Nausea / vomiting o Postural hypotension o Drowsiness / confusion o Dyskinesia o Fibrotic reactions (rare):

Pericardial / pulmonary and retroperitoneal fibrosis • Domperidone (D2 antagonist):

o Can be used to relieve the peripheral adverse effects of bromocriptine (does not cross the BBB so has no effect on CNS effects)

• Contraindications: o Hypersensitivity

• Interactions: o Erythromycin and sympathomimetics (e.g. dobutamine):

Increase the plasma concentration of bromocriptine Growth hormone:

• E.g. somatrophin • Indications:

o Adults: GH deficiency

o Children: GH deficiency Chronic renal impairment Turner’s syndrome



[email protected]

53

Testosterone: • E.g. restandol (oral), sustanon (IM), andropatch (transdermal patch) • Indications:

o Male androgen deficiency • Adverse effects:

o Androgenic effects: Fusion of epiphyses in prepubertal boys (stunted

growth) Hirsuitism Male pattern baldness Acne

o Prostate abnormalities (enlargement ± malignancy) o Cholestatic jaundice

• Contraindications: o Cancers:

Male breast Primary liver tumour Prostate


Potentiates actions of warfarin Combined oral contraceptive (COC) pill:

• E.g. cilest, microgynon • Are preparations containing both an oestrogen and a progestogen • Indications:

o Contraception o Menstrual cycle control / menorrhagia o Mild endometriosis o Premenstrual symptoms

• Mechanism of action: o Exerts a negative feedback on the pituitary and inhibits

gonadotrophin release, and thus inhibits ovulation • Adverse effects:

o Major: ⇑ risk of venous thromboembolism (VTE) ⇑ risk of hypertension ⇑ risk of breast carcinoma (small)

o Minor: Breast tenderness Headaches Nausea Weight gain

• Contraindications: o Absolute:

History of CVA / IHD / VTE Migraine (severe / focal) Blood clotting disorders



[email protected]

54

Active breast / endometrial cancer o Relative:

Age > 40 years Obesity Smokers

• Interactions: o Drugs reducing the efficacy of the COC pill:

Broad-spectrum antibiotics P450 inducers:

• Carbamazepine • Phenytoin • Rifampicin

o Warfarin: Oestrogens (including the COC pill) reduce the effect of

warfarin • The COC pill should be stopped several weeks prior to an elective

surgical procedure to ⇓ risk of VTE Calcitonin:

• E.g. calcitonin (porcine natural), salcatonin (synthetic salmon calcitonin)

• Indications: o Hypercalcaemia (rarely) o Malignant bone pain o Osteoporosis o Paget’s disease of bone (especially pain relief)

• Mechanism of action: o Lowers serum calcium:

Inhibits osteoclast activity Increases renal Ca2+ excretion

• Adverse effects: o Facial flushing o Nausea / vomiting o Tingling sensation in the hands o Unpleasant taste in the mouth

α1-antagonists:

• Non-selective (α1 and α2): o Phentolamine (short-acting) o Phenoxybenzamine (irreversible, long-acting)

• α1: o Prazosin o Doxazosin o Tamsulosin (Flomax)

• Indications: o Non-selective α-blockers:

Phaeochromocytoma o α1-blockers:



[email protected]

55

Hypertension Benign Prostatic hypertrophy (doxazosin, tamsulosin)

• Mechanism of action: o Antagonism of post-synaptic α1-adrenoceptors leads to

vasodilatation o α1 blockade also leads to relaxation of the internal urethral

sphincter, resulting in ⇑ urinary flow • Adverse effects:

o First-dose hypotension • Interactions:

o Other hypotensive agents - ⇑ risk of hypotension



[email protected]

56

Lipids

Which patients require lipid-lowering therapy? • Primary prevention:

o Guidelines are frequently changing Total [chol] >5mmol/L and CHD risk >30% over 10yrs or 10yr CHD risk >=15%

• Secondary prevention: o History of CVS event (angina, MI, PVD, CVA) ± o [chol] >=5mmol/L

• Choice of drug: o First choice therapy:

Statin o Second choice therapy:

Fibrates Anion exchange resins

Drugs used to treat obesity:

• Orlistat • Sibutramine

Statins:

• E.g. simvastatin, atorvastatin, pravastatin • Reduce incidence of all cardiovascular events and total mortality • Mechanism of action:

o Are HMG-CoA reductase inhibitors – block the rate-limiting step in hepatic cholesterol synthesis

o Due to the ⇓ concentration of cholesterol in the hepatocytes, there is an ⇑ in the number of hepatic LDL receptors

o This leads to a ⇓ in plasma LDL o Those with homozygous familial hypercholesterolaemia do not

respond to statins (as they have no LDL receptors) • Adverse effects (all uncommon):

o Myositis: If CK >5x upper limit of normal discontinue Can lead to rhabdomyolysis and renal failure

o Altered LFTs • Contraindications:

o Liver disease o Pregnancy

• Interactions: o Drugs increasing the risk of myositis:

Cyclosporin Fibrates

o Warfarin: Statins potentiate the actions of warfarin



[email protected]

57

• Patients should have their LFTs monitored regularly whilst on a statin Fibrates:

• E.g. bezafibrate, gemfibrozil • Actions:

o Unclear mechanism – possibly stimulate lipoprotein lipase o ⇓ TGs (~30%) o ⇓ LDL (~10%) o ⇑ HDL (10%)

• Are first line drugs in patients with hypertriglyceridaemia (who are at risk of pancreatitis)

• Adverse effects: o GI disturbance o Myositis

• Contraindications: o Hepatic / renal impairment o Pregnancy

• Interactions: o Statins:

⇑ risk of myositis o Warfarin:

Potentiate the actions of warfarin Anion exchange resins:

• E.g. cholestyramine, cholestipol • Mechanism of action:

o Bind bile acids in the bowel o Forces the liver to synthesise more bile acids – causes an

increase in the expression of LDL receptors and lowering of LDL • Adverse effects:

o GI disturbance: Bloating Constipation Nausea / vomiting

o May aggravate hypertriglyceridaemia o May impair the absorption of fat soluble vitamins:

May require supplements of vitamins A, D and K Orlistat:

• Indications: o Adjunct in obesity management:

BMI >30 if no diabetes BMI >27 if diabetic

• Mechanism of action: o Pancreatic lipase inhibitor o Impairs absorption of dietary fat

• Adverse effects: o GI disturbance:



[email protected]

58

Probably why the drug works as patients reduce their fat intake to reduce the side-effects

o May impair the absorption of fat soluble vitamins: May require supplements of vitamins A, D and K

• Contraindications: o Cholestasis o Pregnancy


Difficulty in controlling the INR Sibutramine:

• Indications: o As for orlistat

• Mechanism of action: o Centrally acting anorectic o Inhibits reuptake of noradrenaline and 5-HT

• Adverse effects: o Hypertension o Many others

• Contraindications: o Many, mainly cardiovascular



[email protected]

59

Clotting

Antiplatelet drugs: • Aspirin • Dypyridamole • Clopidogrel • GP IIb/IIIa receptor antagonists:

o Abciximab Anticoagulants:

• Oral: o Warfarin

• Parenteral: o Unfractionated heparin o Low molecular weight heparin (LMWH)

Thrombolytic agents:

• Streptokinase • Tissue plasminogen activator (tPA)

Indications for antiplatelet drugs:

• Acute coronary syndromes • Primary prevention of cardiovascular events:

o If 10yr CVD risk >=20% (with a controlled blood pressure) • Secondary prevention of cardiovascular events:

o CVA / TIA o IHD o PVD

• Heart valve replacements • AF (in those who cannot be anti-coagulated)

Indications for oral anti-coagulants:

• AF • Prophylaxis / treatment of VTE:

o DVT o PE

• Mechanical heart valve replacements • Dilated cardiomyopathy / left ventricular aneurysm • ? TIAs

Indications for parenteral anti-coagulants:

• Acute coronary syndromes • Acute arterial obstruction • Treatment of VTE:

o DVT o PE



[email protected]

60

Indications for thrombolytic agents: • Acute myocardial infarction • Arterial thrombus • Life-threatening PE • Occluded lines / shunts

Aspirin:

• Indications: o Mild to moderate pain o Pyrexia o Anti-platelet:

Acute myocardial infarction History of:

• Angina • Intermittent claudication • Myocardial infarction • Stroke • TIA

AF (in patients where warfarin is contraindicated) Kawasaki syndrome (only childhood indication)

• Mechanism of action: o Irreversibly inactivates platelet COX o Platelets cannot synthesise new COX:

Takes 4 – 7 days for new platelets to be synthesised following a single dose (300mg)

Reduction in production of the platelet aggregating compound thromboxane A2

• Adverse effects: o Bleeding o Bronchospasm o GI irritation / bleeding o Dangerous in overdose

• Overdose: o Signs / symptoms:

Coma Dehydration Hyperventilation Tinnitus Seizures Sweating Vertigo Vomiting

o Investigations: Levels (salicylate and paracetamol, may have taken

both): • Levels >700mg/L are potentially fatal

ABG, FBC, Glucose, LFTs, INR, U&Es



[email protected]

61

o Treatment: Remove drug:

• Gastric lavage if od <1 hour ago Correct acidosis with 1.26% HCO3

- >500mg/L:

• Consider alkalinization of the urine Consider dialysis when:

• Levels >700mg/L • Cardiac / renal failure • Seizures

• Cautions: o Asthma o Uncontrolled hypertension

• Contraindications: o Children <16 years (unless Kawasaki’s syndrome):

Risk of Reye’s syndrome o Active peptic ulceration o Bleeding disorders (e.g. haemophilia)


Increased risk of bleeding o Methotrexate:

Aspirin ⇑ risk of toxic effects of methotrexate Dipyridamole:

• Indications: o Secondary prevention of CVA / TIA:

Some synergistic benefit with aspirin Used in those patients who have had a CVA on aspirin

o Prevention of thromboembolism from prosthetic heart valves: Adjunct to oral anti-coagulation

• Mechanism of action: o Phosphodiesterase inhibitor o Leads to an ⇑ in cAMP and potentiation of prostacyclin

• No increased risk of bleeding (cf aspirin) • Adverse effects:

o Headache • Contraindications:

o Myasthenia gravis (risk of exacerbation) • Interactions:

o Adenosine: Dipyridamole prolong / enhances the effects of adenosine

Clopidogrel:

• Indications: o Secondary prevention of CVD:

Within 35 days of MI Within 6 months of CVA



[email protected]

62

o Acute coronary syndrome (without ST elevation): Given with aspirin Not for >12 months

o Coronary artery stents • Mechanisms of action:

o Irreversibly blocks the action of ADP on platelets – leading to a reduction of platelet aggregation

• Adverse effects: o Bleeding o Bone marrow suppression (rare)

• Cautions: o First few days following MI / CVA


Increased risk of bleeding Abciximab:

• Indications: o Patients awaiting PTCA:

Short-term prevention of MI in those with ACS o Patients undergoing PTCA:

Adjunct to aspirin and heparin • Mechanism of action:

o Monoclonal antibody to GP IIb/IIIa o Inhibit platelet aggregation

• Adverse effects: o Bleeding o Thrombocytopenia

Warfarin:

• Indications: o Prevention / treatment of VTE:

DVT PE

o Prevention of thromboembolism: AF Prosthetic heart valves

• Mechanism of action: o Vitamin K antagonist o Inhibits the vitamin K-dependent synthesis of clotting factors II,

VII, IX and X o Also inhibits formation of protein C and S:

Has an initial procoagulant effect o Takes at least 2–3 days to work (due to the half-life of pre-

existing clotting factors in the circulation) o Prolongs the prothrombin time (PT)

• Pharmacokinetics: o Long half-life (40 hours)



[email protected]

63

o Takes ~5 days after stopping treatment for INR to normalise o Highly protein-bound (albumin)

• Dosage: o Loading:

Warfarin therapy begins with a loading dose, usually: • Day 1 - 10mg • Day 2 – 10mg measure INR and adjust dose • Day 3 – 5mg (if still not target INR)

o Daily dose: Daily maintenance is usually 3-9mg daily (taken at same

time each day) • INR (International Normalised Ratio):

o Prothrombin results can vary depending on the thromboplastin reagent used

o The INR is a conversion unit that takes into account the different sensitivities of thromboplastins

o Target INRs: 2 – 2.5:

• Prophylaxis of DVT 2.5:

• AF • Treatment of DVT / PE • Rheumatic mitral valve disease

3.5: • Recurrent DVT / PE • Mechanical prosthetic heart valves

o Monitoring the INR: The INR should be determined daily (or alternate days) in

the early days of therapy, then at longer intervals (depending on response) then up to every 12 weeks

• Adverse effects: o Bleeding / bruising o Skin necrosis o Alopecia o Liver damage o Pancreatitis

• Management of warfarin-induced haemorrhage: o Major bleeding:

Stop warfarin Give vitamin K (phytomenadione) by slow IV injection FFP

o INR >8 (no bleeding or minor bleeding): Stop warfarin and restart when INR <5 Vitamin K (either IV or oral)

o INR 6-8: (no bleeding or minor bleeding): Stop warfarin and restart when INR <5

o INR <6 but >0.5 units above target value: Reduce or stop warfarin and restart when INR <5



[email protected]

64

• Contraindications: o Pregnancy:

Teratogenic (1st trimester) Foetal haemorrhage (3rd trimester)

o Peptic ulcer o Severe hypertension

• Interactions (many!): o Drugs ⇑plasma levels of warfarin:

Alcohol Cimetidine Omeprazole Simvastatin

o Drugs ⇓ plasma levels of warfarin: Carbamazepine COC pill Rifampicin

o Drugs increasing risk of haemorrhage: Aspirin

Heparin:

• Low molecular weight heparins (LMWHs) include: o Enoxaparin o Tinzaparin

• Indications: o Treatment of VTE o Unstable angina o Acute peripheral arterial occlusion o Prophylaxis in surgery o Extracorporeal circuits (e.g. cardiac bypass surgery)

• Mechanism of action: o Heparin potentiates the actions of antithrombin III o Antithrombin III inactivates factor IIa (thrombin) o Prolongs the APTT

• Structure: o Both types of heparin are extracted from bovine lung or hog

intestine o Unfractionated heparin:

Mixture of sulphated glycosaminoglycans with a range of molecular weights up to 40,000

o LMWH: Fragments of heparin with weights 4000 – 15,000

• Unfractionated or LMWH? o Unfractionated heparins are best used when there is a high risk

of bleeding their effect can be terminated rapidly by stopping the infusion

o LMWHs do not require monitoring of the APTT and only need to be given once-daily

o LMWHs have a more predictable subcutaneous absorption



[email protected]

65

• Adverse effects: o Thrombocytopenia:

Immune-mediated Develops ~6 days after start of treatment

o Hyperkalaemia: Heparin inhibits aldosterone activity

o Haemorrhage o Osteoporosis o Skin necrosis o Hypersensitivity o Alopecia

• Contraindications:

o Bleeding disorders (e.g. haemophilia) o Thrombocytopenia o Peptic ulcer o Recent cerebral haemorrhage o Severe hypertension o Severe liver disease (especially variceal disease) o Hypersensitivity

• The effects of heparin can be reversed by IV protamine sulphate: o A strongly basic protein that forms an inactive complex with

heparin Streptokinase (SK):

• Indications: o Acute MI o Thromboembolic events:

PE Thrombosed arteriovenous shunts

• Mechanism of action: o Binds circulating plasminogen and converts it to plasmin o Plasmin then lyses fibrin with the thrombus and dissolves it

• Adverse effects: o Allergic reactions:

Rash (common) Anaphylaxis

o Hypotension o Guillain-Barre syndrome

• Contraindications: o Bleeding o Prolonged / traumatic CPR o Trauma / surgery (within 2 weeks) o Recent haemorrhagic stroke o Severe hypertension (>200/120mmHg) o Pregnancy o Suspected aortic dissection



[email protected]

66

• Interactions: o Warfarin (increased risk of haemorrhage)

• Patients develop antibodies to streptokinase: o If a patient requires thrombolysis and has received SK in the

past – they should be given recombinant tPA Tissue plasminogen activator (tPA):

• E.g. alteplase (requires infusion), tenecteplase (bolus) • Indications:

o As for SK but in those patients who cannot receive SK • In contrast to SK, co-administration of tPA and heparin produces

added benefit (but increases the risk of stroke)



[email protected]

67

Mood disorders

Which antidepressant? • No hard and fast rules, although TCAs and SSRIs are generally first

choice • All antidepressants take 2-6 weeks to work • Antidepressants should be continued for 4-6 months after resolution

of symptoms • When to use a TCA:

o Severe depression o When insomnia is prominent symptom

• When to use a SSRI: o Suicidal patient (safer in overdose) o Intolerance to TCAs:

Prostatism Dementia Cardiac illness

• When to use a MAOI: o “Atypical” depression o Depression refractory to first-line drugs

• When to use venlafaxine: o Severe depression with hypersomnia

Drugs used as mood stabilisers:

• Lithium carbonate • Anticonvulsants:

o Carbamazepine o Valproate

Tri-Cyclic Antidepressants (TCAs):

• More sedating: o Amitriptylline o Clompiramine o Dothiepin

• Less sedating: o Imipramine

• Indications: o Moderate to severe depression o Neuropathic pain (amitriptylline – unlicensed indication) o Nocturnal enuresis (children)

• Mechanism of action: o Inhibit noradrenaline (NA) and serotonin (5-HT) uptake in

central nerve terminals o Most TCAs act on several other neurotransmitter receptors and

this is the reason for their large side-effect profile: Anti-muscarinic most TCAs



[email protected]

68

Histamine receptor blockade • Adverse effects:

o Sedation (some more than others) o Confusion o Blurred vision (loss of accommodation) o Dry mouth o Heart block o Postural hypotension o Constipation o Impotence

• Contraindications: o Dysrhythmias (especially heart block) o Epilepsy o Severe coronary heart disease o Suicidal patient (danger in overdose)

• TCA overdose: o Clinical features:

Tachycardia Mydriasis Convulsions Arrhythmias Hypotension

o Management: Treat convulsions with diazepam Treat SVT / VT with sodium bicarbonate (even in absence

of acidosis) • Interactions:

o MAOIs: Danger of potentially fatal hyperthermia syndrome

o Anti-arrhythmics: Increased risk of ventricular dysrhythmias

o Anticonvulsants: TCAs lower the seizure threshold and thus antagonise the

effect of anticonvulsants o Antipsychotics:

Increased risk of ventricular dysrhythmias Selective Serotonin Reuptake Inhibitors (SSRIs):

• E.g. fluoxetine (prozac), paroxetine (seroxat), citalopram • Indications:

o Depression: High suicide risk Those intolerant to TCAs (e.g. Prostatism)

o Obsessive compulsive disorder (OCD) o Eating disorders

• Mechanism of action: o “Selectively” block the uptake of 5-HT by central nerve terminal,

thus increasing it’s concentration



[email protected]

69

o Fewer side-effects than the TCAs: Less anti-muscarinic effects Safer in overdose

• Adverse effects: o Nausea / anorexia o Insomnia o Sexual dysfunction:

Loss of libido Failure of orgasm

• Contraindications:

o Children <18 years of age: ⇑ risk of self-harm / suicidal behaviour

o Mania • Interactions:

o MAOIs: Do not start an SSRI until at least 2 weeks after stopping

a MAOI Risk of hyperthermia syndrome:

• Hyperthermia • Tremor • Collapse

o Anticonvulsants (e.g. carbamazepine, phenytoin): SSRIs ⇑ plasma levels of these drugs

o Haloperidol: SSRIs ⇑ plasma levels of haloperidol

Monoamine Oxidase Inhibitors (MAOIs):

• Non-selective (inhibit MAO-A and MAO-B): o Phenelzine

• MAO-AIs: o Moclobemide

• MAO-BIs: o Selegiline

• Indications: o “Atypical” depression:

Weight gain Hypersomnia

o Second-line use in depression (after TCA / SSRI) • Mechanism of action:

o MAO is found throughout body tissues (including the gut) o There are 2 isoforms of MAO - A and B o MAO-A has a preference for 5-HT (this is seen to be beneficial in

depression) o MAO-B has a preference for dopamine (hence an anti-Parkinson

effect with selegiline) o MAO regulates intra-neuronal concentration of it’s substrates (it

is not involved in the inactivation of released transmitter)



[email protected]

70

• Adverse effects: o Hypotension o Weight gain o Sedation o Anti-muscarinic effects

• Contraindications: o Hepatic impairment o Phaeochromocytoma o Non-compliant patients (unable to monitor diet)

• Interactions: o Main hazard is with foods – the “cheese reaction”:

Caused by foods containing high levels of tyramine: • Hard cheeses • Yeast extracts (e.g. marmite) • Red wine / beer

MAO in the gut wall usually metabolises tyramine, thus preventing it reaching the systemic circulation

In the presence of a MAOI, tyramine reaches the circulation and acts as a sympathomimetic and can lead to severe hypertension

Treat with: • α1-antagonist (e.g. phentolamine) or • Nifedipine

o Antidepressants (TCAs, SSRIs): Avoid concomitant use (allow washout period in between) Potentiation of all side-effects and risk of hyperthermia

syndrome o Pethidine:

Hyperthermia CNS depression or excitement

o Carbamazepine: MAOIs can ⇓ the plasma levels of carbamazepine

• The selective MAO-AIs have a much smaller risk of the “cheese reaction”

Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs):

• E.g. venlafaxine • Indications:

o Severe / refractory depression o Anxiety disorders

• Adverse effects: o Nausea o Insomnia o Hypertension (at high doses) o Withdrawal problems common

• Interactions: o MAOIs:

Risk of hyperthermia syndrome



[email protected]

71

• Fewer side-effects than the TCAs but no more efficacious Noradrenaline and Specific Serotenergic Antidepressants (NaSSAs):

• E.g. mirtazapine • Indications:

o Depression (especially with insomnia) • Adverse effects:

o Drowsiness (even at low doses) o ⇑ appetite / weight gain o Blood dyscrasias (rarely)

• Interactions: o Other sedatives (including alcohol) o MAOIs

• Safe in overdose • Minimal effects on sexual function

Lithium carbonate:

• Indications: o Acute mania o Prophylaxis of bipolar disorder o Recurrent depression o Aggressive / self-mutilating behaviour

• Toxicity: o Lithium requires therapeutic drug monitoring:

Normal range is 0.4 – 1.0mmol/L • Adverse effects:

o 0.4 – 1.0mmol/L: Nausea Diarrhoea Polyuria / polydipsia Weight gain

o 1.0 – 2.0mmol/L: Blurred vision Anorexia / vomiting Ataxia / dysarthria / tremor Drowsiness

o >2.0mmol/L: Convulsions Hyperreflexia Oliguria Circulatory failure - death

• Long-term effects: o Can cause renal tubular damage and hypothyroidism

• Contraindications: o Pregnancy (although consider relative risks of drug cessation) o Renal impairment o Thyroid disease o Sick sinus syndrome



[email protected]

72

o Poor compliance • Interactions:

o Lithium levels increased by: Diuretics (thiazides > loop) ACEIs NSAIDs Alcohol

o Lithium levels decreased by:

Xanthines (e.g. theophylline) Antacids Acetazolamide



[email protected]

73

Anti-arrhythmic drugs

Vaughan-Williams classification: • Class I:

o Are all Na+ channel blockers (local anaesthetics) o Ib only works in the ventricles o Ia (A, SAN, AVN, V):

E.g. quinidine, disopyramide, procainamide ⇑ AP duration Hardly ever used in the UK (but used in the USA)

o Ib (V only): E.g. lidocaine (lignocaine) AP duration unaffected or slightly ⇓

o Ic (A, SAN, AVN, V): E.g. flecainide AP duration slightly ⇑ Primarily act by slowing conduction

• Class II (A, SAN, AVN, V): o β-blockers (e.g. propranolol) o ⇓ automaticity o ⇓ AP duration acutely (may prolong it with prolonged use) o ⇓ refractory period

• Class III (A, SAN, AVN, V): o E.g. amiodarone, sotalol (a β-blocker) o All have effects on various K+ channels o ⇑ AP duration o ⇑ refractory period

• Class IV (SAN, AVN): o Ca2+ channel blockers (e.g. verapamil) o Dihydropyridines (e.g. amlodipine) have no role in arrhythmias

• Unclassified: o Digoxin (AVN) o Adenosine (AVN)

Supraventricular arrhythmias:

• Supraventricular tachycardias (SVTs) are often due to re-entry: o SNRT (sinus node re-entry tachycardia) o AVNRT (atrioventricular node re-entry tachycardia) o AVRT (atrioventricular re-entry tachycardia):

Caused by an accessory pathway • Atrial arrhythmias:

o Atrial tachycardia o Atrial flutter



[email protected]

74

o Atrial fibrillation (AF): Paroxysmal Persistent Permanent

Treatment of SVTs:

• Vagal manoeuvres • Adenosine:

o 6mg 12mg 12mg • If adenosine fails:

o Cardiovascular instability: Synchronised cardioversion

o No cardiovascular instability: Verapamil or Digoxin or Amiodarone

• Prophylaxis: o β-blockers o Flecainide (AVRT) o Verapamil (AVNRT)

• Wolff-Parkinson-White (WPW) syndrome: o If pt has AF and fast ventricular rate:

Adenosine, digoxin and verapamil are absolutely contraindicated

Use Flecainide Treatment of atrial tachycardia:

• Treat underlying coronary / structural heart disease if present • Exclude digoxin toxicity • β-blockers • Verapamil • Often refractory to drug treatment - RFA

Treatment of atrial flutter:

• Drugs are generally ineffective, but can try: o Amiodarone:

Drug most likely to work o Digoxin:

Rate control only o β-blockers:

Rate control Chance of return to sinus rhythm (SR)

o Verapamil: Rate control Chance of return to SR

• DC cardioversion ± anticoagulation can work • RFA is the treatment of choice



[email protected]

75

Treatment of atrial fibrillation (AF): • Acute:

o Treat underlying cause (e.g. pneumonia) o DC cardioversion (first-line choice):

Anticoagulation is not essential if AF is of recent onset (<48 hours) with a structurally normal heart (but most people do)

If required, give warfarin for at least 3 weeks before and least 4 weeks after

o Control ventricular rate: Digoxin If ventricular rate still too fast:

• β-blocker o Chemical cardioversion:

Amiodarone or Flecainide (if haemodynamically stable) or β-blocker

• Chronic: o Control ventricular rate:

Digoxin If rate still too fast consider:

• (Cautiously) ⇑ digoxin dose • β-blocker • Amiodarone

o Anticoagulation: > 65 years:

• Warfarin (INR 2.5 – 3.5) <65 years with no risk factors or > 65 years and unable

to be warfarinised: • Aspirin

Treatment of ventricular tachycardia (VT):

• Acute: o Haemodynamically stable:

Amiodarone or Lidocaine

o Not haemodynamically stable: Synchronised DC cardioversion Amiodarone

• Recurrent / paroxysmal: o Drugs:

Amiodarone β-blocker (works synergistically with amiodarone) Sotalol

o Implantable defibrillator: ⇓ mortality



[email protected]

76

Drug treatment of Torsade de Pointes: • Often associated with prolongation of the QT interval • Causes of QT prolongation:

o Electrolyte disturbances: Hypokalaemia Hypocalcaemia

o Congenital long QT syndromes o Drugs:

Class Ic and III anti-arrhythmics TCAs

o Ischaemia • Treatment:

o IV MgSO4 Treatment of bradyarrhythmias:

• Haemodynamically compromised: o Drugs:

Atropine ± Isoprenaline / adrenaline

o Pacing: External Temporary transvenous

• Stable: o Withdraw any negatively chronotropic drugs (e.g. β-blockers) o Exclude secondary causes:

ACS Hypothyroidism

o Assess need for permanent pacemaker Adenosine:

• Indications: o Paroxysmal SVT o To aid diagnosis of broad or narrow complex SVTs

• Mechanism of action: o Binds to adenosine (A1) receptors in the cardiac conduction

system: Opens ACh-sensitive K+ channels

o Slows conduction in the heart by prolonging the refractory period in the AVN / bundle of His

• Adverse effects: o All are short-lived (half-life of 8 – 10secs) o Bronchospasm o Chest pain o Flushing o Severe bradycardia (rare)

• Contraindications: o Asthma o 2nd or 3rd degree heart block (unless pacemaker in-situ)



[email protected]

77

• Interactions: o Dipyridamole:

Prolongs / enhances action of adenosine o Theophylline:

Inhibits adenosine Amiodarone:

• Indications: o Paroxysmal:

SVT Nodal tachycardia VT

o Atrial flutter o AF o VF

• Amiodarone is generally used when other drugs have been ineffective or are contraindicated

• Mechanism of action: o Not fully understood o Blocks several channels:

α-adrenoceptors, β-adrenoceptors, Na+ and Ca2+ o Generally slows conduction through the heart

• Pharmacokinetics: o Very long half-life:

10 – 100 days (average 36 days) o Requires a loading dose in life-threatening arrhythmias:

Central vein (causes phlebitis in peripheral veins) o This means that drug interactions can occur long after

amiodarone has been stopped • Adverse effects:

o Common: Corneal microdeposits (reversible):

• Can cause driver headlight dazzling at night Photosensitive rash

o Less common: Thyroid dysfunction (hyper- or hypo-) Pulmonary fibrosis Grey skin colour Peripheral neuropathy Ataxia

• Special notes: o Thyroid function must be checked before treatment and every 6

months: If hyperthyroidism develops, this can be very refractory

and may require cessation of amiodarone o Shortness of breath suggests development of pulmonary fibrosis



[email protected]

78

• Contraindications: o Thyroid disease o Pregnancy o Iodine allergy (as amiodarone contains iodine)

• Interactions: o β-blockers / non-dihydropyridines (e.g. diltiazem, verapamil):

⇑ risk bradycardia, AV block and myocardial depression o Digoxin:

Amiodarone ⇑ plasma levels of digoxin o Class Ia drugs:

⇑ QT interval o Phenytoin:

Amiodarone ⇑ plasma levels of phenytoin o Warfarin:

Amiodarone ⇑ plasma levels of warfarin Lidocaine (lignocaine):

• Indications: o Ventricular arrhythmias (especially after MI):

Stops VT and ⇓ risk of VF Does not ⇓ mortality when used prophylactically

o Local anaesthesia • Mechanism of action:

o Class Ib anti-arrhythmic agent o Not active orally (massive 1st-pass metabolism) o Blocks fast Na+ channels:

Slows conduction in the heart (only ventricles) Inhibits AP propagation in never axons

• Adverse effects: o Uncommon:

Convulsions Drowsiness Bradycardia Cardiac arrest

• Contraindications: o AV node block (all degrees) o Severe heart failure o Hypovolaemia

• Interactions: o Cimetidine:

⇑ plasma levels of lidocaine



[email protected]

79

Flecainide: • Indications:

o AVRT o WPW syndrome associated arrhythmias o Paroxysmal AF (chemical cardioversion)

• Mechanism of action: o Class Ic anti-arrhythmic agent o Na+ channel blocker

• Contraindications: o Previous MI o Haemodynamically significant Valvular disease



[email protected]

80

Hypertension

British hypertension society (BHS) classification of BP levels: • Optimal:

o <120 / <90 mmHg • Normal:

o <130 / <85 mmHg • High normal:

o 130-139 / 85-89 mmHg • Hypertension:

o Grade 1 (mild): 140-159 / 90-99 mmHg

o Grade 2 (moderate): >160 – 179 / 100-109 mmHg

o Grade 3 (severe): >=180 / >=100 mmHg

o Isolated systolic: Systolic BP is more important than diastolic Grade 1:

• 140-159 / <90 mmHg Grade 2:

• >=160 / <90 mmHg Complications of hypertension:

• Cerebral: o Encephalopathy o Haemorrhage o Thromboembolism o TIA

• Other: o MI (hypertension accounts for 25% of MIs) o Heart failure o Dissecting aneurysm o Renovascular disease o Peripheral vascular disease

When to treat patients with anti-hypertensive agents:

• Definitely treat: o >=160 / >=100 mmHg

• Treat if o >=140 / >=90 mmHg and o Target organ damage or o CVS complications or o Diabetes or o CV event risk >=2%/year (>=20% at 10 years)



[email protected]

81

Target blood pressure for patients on anti-hypertensive medication:

• There is evidence for these systolic values but the diastolic is arbitrary • Patients with diabetes, renal impairment or CVS disease:

o <=130 / <=80 mmHg • Other patients:

o <=140 / <=85 mmHg The BHS ABCD approach to the treatment of hypertension:

• Key: o ACE inhibitor o Beta blocker o Calcium channel blocker o Diuretic (thiazide)

• Step 1: o Young (<55 yrs) and non-black:

A (or B*) o Older (>55 yrs) or black:

C or D • Step 2:

o A (or B*) + C or D • Step 3:

o A (or B*) + C + D • Step 4 (resistant hypertension):

o Add either: α-blocker Spironolactone

• *β-blockers will probably be removed from this algorithm as they may induce new onset diabetes mellitus



[email protected]

82

Antibiotic therapy

Below are empirical treatments only – the correct antibiotic will depend upon sensitivities determined by bacteriological culture Treating pneumonia:

• Community acquired: o Mild (streptococcus, haemophilus, mycoplasma):

Amoxicillin po Erythromycin po (if penicillin sensitive)

o Severe (same bugs as for mild): Co-amoxiclav IV or Cefuroxime IV and Erythromycin IV

o Atypical: Legionella:

• Clarithromycin ± rifampicin Chlamydia:

• Tetracycline Pneumocystis carinii:

• Co-trimoxazole • Hospital acquired (Gram (–ve), pseudomonas, anaerobes):

o Aminoglycoside IV and o 3rd generation cephalosporin IV ± o Anti-pseudomonal penicillin IV

• Aspiration: o Cefuroxime IV and o Metronidazole IV

Treating meningitis:

• Immediate treatment: o Outside hospital:

Benzylpenicillin 1.2g IV/IM o Inside hospital:

Cefotaxime 2g IV • Subsequent treatment:

o Depends on sensitivities o Generally cefotaxime o Benzylpenicillin and rifampicin for meningococcal meningitis

• Contacts – eradicate carriage: o Rifampicin (2 days) o Ciprofloxacin (single dose)



[email protected]

83

Treating tuberculosis: • Initial phase (8 weeks on 3–4 drugs):

o Rifampicin o Isoniazid o Pyrazinamide o Ethambutol (if isoniazid resistance is possible)

• Continuation phase (4–10 months on 2–3 drugs, depends on site): o Rifampicin o Isoniazid ± o Ethambutol

• Give pyridoxine throughout treatment (prevents isoniazid neuropathy) Treating septicaemia – source unknown:

• Take blood cultures first! • Anti-pseudomonal penicillin (e.g. ticarcillin) and • Cefuroxime IV or • Gentamicin IV

Treating Neutropenic sepsis:

• Take blood cultures first! • First-line:

o Piperacillin + Gentamicin • Second-line:

o Ceftazidime + vancomycin • Third-line:

o Add amphotericin B Treating a UTI:

• Depends on sensitivities • Cystitis:

o Mild: Trimethoprim

o More severe: Co-amoxiclav Ciprofloxacin

• Acute pyelonephritis: o Cefuroxime

Treating MRSA infection:

• Vancomycin or • Teicoplanin

Treating clostridium difficile:

• Metronidazole po or • Vancomycin po



[email protected]

84

Treating cellulitis: • Depends on the organism, but a good start would be:

o Benzylpenicillin and o Flucloxacillin

Prophylactic antibiotics and surgery:

• Single bolus as good as prolonged therapy: o Metronidazole IV and o Cefuroxime IV

Helicobacter pylori eradication therapy:

• One PPI and two antibiotics for two weeks • Usual combination (but there are many):

o Omeprazole o Clarithromycin o Amoxicillin (or metronidazole)

• Resistance to metronidazole is common



[email protected]

85

Antibiotics

Antibiotics that inhibit cell wall synthesis: • β-lactams:

o Penicillins o Cephalosporins

• Glycopeptides: o Vancomycin o Teicoplanin

• Carbapenems: o Imipenem

• Monobactams: o Aztreonam

Antibiotics that inhibit protein synthesis:

• 30S ribosome: o Aminoglycosides:

Gentamicin Amikacin

o Tetracyclines: Tetracycline Doxycycline

• 50S ribosome: o Macrolides:

Erythromycin Clarithromycin

o Chloramphenicol o Fusidic acid

Antibiotics that inhibit nucleic acid synthesis:

• Quinolones: o Ciprofloxacin

• Metronidazole • Trimethoprim • Rifampicin • Sulphonamides

Antibiotics that do not accumulate in renal impairment:

• Chloramphenicol • Co-trimoxazole • Doxycycline • Isoniazid • Macrolides • Quinolones • Rifampicin



[email protected]

86

Penicillins: • Are all active against Gram +ve bugs • A common mechanism of resistance is the production of an enzyme (β-

lactamase) that degrades the drug • Penicillin:

o Benzylpenicillin (penicillin G) – parenteral o Phenoxymethylpenicillin (penicillin V) – oral o Indications:

Pneumococcus Streptococcus Meningococcus Leptosprial infections

• Broad-spectrum (activity against some Gram –ve bugs as well): o Amoxicillin o Indications:

(As for penicillin) Escherichia coli Haemophilus influenzae Salmonella

• β-lactamase resistant: o Flucloxacillin:

Indications: • β-lactamase-producing staphylococci

o Co-amoxiclav: Amoxicillin + Clavulanic acid (β-lactamase inhibitor) Indications:

• Amoxicillin resistant URTIs and UTIs • Anti-pseudomonal:

o Ticarcillin (IV only) • Adverse effects:

o Rash: Common to all penicillins Maculopapular rash in glandular fever if given amoxicillin

o Nausea / vomiting o Uncommon:

Anaphylactic shock Convulsions

• Contraindications: o Penicillin hypersensitivity

• Interactions: o COC pill:

Penicillins reduce the efficacy of the pill o Probenicid:

Probenicid ⇓ excretion of the penicillins Allows for a ⇓ dose of penicillin to be used



[email protected]

87

Cephalosporins: • Have a similar range of activity to amoxicillin but are more β-

lactamase stable • Are 3 “generations” of parenteral cephalosporins:

o As the generations progress, the cephalosporins become more effective against Gram –ve bugs

o First generation have pretty much been replaced o Second:

Cefuroxime o Third:

Cefotaxime: • Important drug in the treatment of meningitis

Ceftazidime: • Pseudomonas and others

Ceftriaxone: • Long-half life (once daily administration) • Effective in serious infections:

o Pneumonia o Septicaemia

• Are 2 “generations” of orally active cephalosporins: o Both have similar spectrums of action:

URTIs Refractory UTIs Otitis media

o First (e.g. cefalexin) o Second (e.g. cefaclor)

• Adverse effects: o Bleeding o Diarrhoea o Nausea / vomiting o Thrombophlebitis (parental cephalosporins)

• Contraindications: o Hypersensitivity:

There is also a 10% cross-reactivity with penicillins • Interactions:

o Probenicid: Probenicid ⇓ excretion of the penicillins Allows for a ⇓ dose of penicillin to be used

Glycopeptides:

• E.g. vancomycin, teicoplanin • Active against aerobic and anaerobic Gram +ve bacteria • Vancomycin (oral or IV):

o Indications: IV:

• Infective endocarditis • MRSA



[email protected]

88

Oral: • Clostridium difficile (pseudomembranous colitis)

• Teicoplanin: o Indications (IV or IM):

Used for serious Gram +ve infections • IV Vancomycin requires therapeutic drug monitoring • Adverse effects:

o Ototoxicity (tinnitus and deafness) o Nephrotoxicity (less so with teicoplanin) o Neutropenia

• Interactions: o Increased risk of ototoxicity with:

Loop diuretics o Increased risk of nephrotoxicity with:

Aminoglycosides Cyclosporin

Carbapenems:

• E.g. imipenem, meropenem • Incredibly broad spectrum:

o Active against both Gram +ve and –ve bacteria o β-lactamase stable o Is effective against MRSA and anaerobes o Best single agent choice for nosocomial infection

• Imipenem: o Rapidly degraded by renal dipeptidase o Must be given in conjunction with cilastatin (a dipeptidase

inhibitor) • Meropenem:

o Similar to imipenem but is stable to renal dipeptidase, does not need to be given with cilastatin

• Adverse effects: o Nausea / vomiting / diarrhoea (3–4% of patients) o Cross-reactivity with β-lactam antibiotics o Seizures (imipenem >> meropenem)

Aminoglycosides:

• E.g. Gentamicin, amikacin, streptomycin • Active against many Gram –ve and some Gram +ve bacteria • Indications:

o Second line treatment for severe Gram –ve infection: Infective endocarditis Septicaemia Acute pyelonephritis

o Topical: Eye Eye

o Streptomycin is reserved for resistant tuberculosis



[email protected]

89

• Mechanism of action: o Bactericidal o Inhibit bacterial protein synthesis by binding to the 30S

ribosome • Pharmacokinetics:

o Inactive orally (must be given IV / topically) o Excreted unchanged by the kidneys:

Use with caution in renal impairment (adjust dose) o Therapeutic drug monitoring is required

• Adverse effects: o Nephrotoxicity (renal tubular damage) o Ototoxicity (damage to CN VIII)

• Contraindications: o Myasthenia gravis:

Aminoglycosides can impair neuromuscular transmission by inhibiting Ca2+-influx into nerve terminal and preventing release of ACh

o Pregnancy • Interactions:

o Drugs potentiating the nephrotoxicity of aminoglycosides: Cyclosporin Loop diuretics:

• Also potentiate ototoxicity o Anticholinesterases (e.g. neostigmine):

Aminoglycosides antagonise the effects of these drugs Tetracyclines:

• E.g. tetracycline, doxycycline • Indications:

o Good for some intracellular organisms (as they penetrate macrophages):

Chlamydia (STD) doxycycline Rickettsia (Q-fever) Borrelia burgdorferi (Lyme disease)

o Acne o Anthrax (doxycycline)

• Pharmacokinetics: o Were the first orally-active broad-spectrum antibiotics (can be

given IV) o Bacteriostatic o Absorption from gut is variable - ⇓ by:

Ca2+ (milk) Mg2+ (antacids) Iron preparations

o Excreted unchanged in the urine (except doxycycline) • Adverse effects:

o Deposited in growing bones / teeth:



[email protected]

90

Causes staining and (occasionally) dental hypoplasia Do not use in children <12 years or in pregnancy

o Renal impairment (except doxycycline) • Contraindications:

o Renal impairment (except doxycycline) Fusidic acid:

• Potent narrow-spectrum anti-staphylococcal antibiotic • Always used in combination to prevent resistance • Indications:

o Infections caused by penicillin-resistant staphylococci o Especially:

Osteomyelitis (well concentrated in bone) Staphylococcal endocarditis

o Can be used topically • Adverse effects:

o Reversible jaundice o Acute renal failure (monitor renal function) o Liver impairment (monitor LFTs)

Macrolides:

• E.g. erythromycin, clarithromycin • Indications:

o Erythromycin: Active against Gram +ve bacteria (staphylococci,

streptococci, mycoplasma, chlamydia, legionella) A good “respiratory” antibiotic A substitute for penicillin in those with hypersensitivity

o Clarithromycin: More potent than erythromycin (except H. influenzae) Part of helicobacter pylori eradication therapy

• Do not cross the blood-brain-barrier (no good for meningitis) • Adverse effects:

o Erythromycin causes nausea / vomiting / diarrhoea: Is an agonist at the motilin receptor in the gut

o Phlebitis • Interactions:

o Inhibit cytochrome P450: ⇑ levels of warfarin, theophylline (and many others)

o Digoxin: ⇑ plasma levels of digoxin

o Cyclosporin: ⇑ plasma levels of cyclosporin

o Terfenadine (non-sedating antihistamine): ⇑ risk of arrhythmias



[email protected]

91

Quinolones: • E.g. ciprofloxacin, ofloxacin • Active against many Gram –ve and some Gram +ve bacteria:

o Campylobacter o Escherichia coli o Pseudomonas o Salmonella

• Indications: o UTI o Salmonella infection o Cystic fibrosis lung infections o Gonorrhoea o Tuberculosis (3rd-line drug) o Anthrax

• Pharmacokinetics: o Ciprofloxacin has a near 100% bioavailability when taken

orally • Adverse effects:

o GI disturbance o Tendon damage (including rupture) o Seizures (lowers seizure threshold)

• Cautions: o Epilepsy o Myasthenia gravis o History of tendon damage

• Interactions: o Inhibits cytochrome P450 (many interactions):

⇑ levels of warfarin, theophylline Metronidazole:

• Indications: o Anaerobes o Protozoal infections:

Entamoeba histolytica Giardia lamblia Trichomonas vaginalis

o Part of helicobacter eradication therapy o Pseudomembranous colitis (C. difficile)

• Pharmacokinetics: o Oral, IV or rectal o Clinical / laboratory monitoring if treatment > 10 days

• Adverse effects: o GI disturbances (uncommon and well tolerated)

• Cautions: o Hepatic impairment



[email protected]

92

• Interactions: o Disulfiram (Antabuse)-like reaction with alcohol:

Flushing Hypotension Abdominal pain

o Phenytoin: ⇑ plasma levels of phenytoin

o Warfarin: ⇑ plasma levels of warfarin

Rifampicin:

• Indications: o Tuberculosis o Leprosy o Meningitis contact prophylaxis o MRSA

• Adverse effects: o Deranged LFTs (usually mild but can be serious) o Stains secretions pink / orange:

Saliva Tears Urine

• Contraindications: o Jaundice

• Interactions: o Potent cytochrome P450 inducer (many reactions):

⇓ efficacy of: • Carbamazepine • COC pill • Corticosteroids • Phenytoin • Warfarin

Isoniazid:

• Indications: o Tuberculosis

• Adverse effects: o Peripheral neuropathy (more likely in):

Alcoholism Chronic renal failure Diabetics HIV Malnutrition Can be prevented by pyridoxine (vitamin B6)

o Hepatitis o Psychosis

• Contraindications: o Hepatic impairment



[email protected]

93

• Interactions: o Anticonvulsants (carbamazepine, phenytoin):

Isoniazid ⇑ plasma levels of these drugs Pyrazinamide:

• Indications: o Tuberculosis

• Pharmacokinetics: o Good CSF penetration (good in TB meningitis)

• Adverse effects: o Hepatocellular toxicity

• Contraindications: o Gout (avoid in acute attack) o Hepatic impairment o Porphyria

Ethambutol:

• Indications: o Tuberculosis (if isoniazid resistance is suspected)

• Adverse effects: o Visual disturbances (reversible if drug stopped early)

• Contraindications: o Renal impairment (⇑ risk of visual damage)



[email protected]

94

Diabetes

Treatment of diabetes: • Both types:

o Diet o Address associated risk factors:

Hyperlipidaemia Hypertension (<=130 / <=80 mmHg) Smoking

• Type I: o All require insulin

• Type II: o BMI < 25:

Sulphonyurea o BMI > 25:

Meformin (a biguanide) o If not controlled on a sulphonylurea, add metformin o If not controlled on metformin, add a sulphonylurea o If not controlled on 2 drugs or intolerant consider adding:

A glitazone Acarbose

o Insulin if poor glycaemic control with oral agents: 50% of pts will require insulin with 6 years of diagnosis

What to check at a diabetic’s annual review:

• Blood glucose record • BP • HbA1c • Lipids • Renal function • Urine (protein / glucose)

Treatment of diabetic ketoacidosis (DKA):

• Only occurs in type I diabetes • IV fluids • Monitor (initially hourly):

o Creatinine o Glucose o HCO3

- o K+ (Initially plasma levels ⇑ - masks body wide K+ depletion)

• Insulin: o Aim for a glucose fall of 5mmol/h o Initial bolus then sliding scale

• Potassium replacement (monitor plasma levels) • If acidosis severe (pH <7.0) consider bicarbonate • Identify the cause of the DKA(e.g. infection)



[email protected]

95

• LMWH (to prevent thrombosis) until mobile Treatment of hyperglycaemic hyper-osmotic non-ketotic (HHONK) coma

• Only occurs in type II diabetes • No acidosis (as ketosis is suppressed by endogenous insulin) • IV fluids • Insulin (small doses):

o Wait until 1 hour after fluids (may not be needed) • Full heparin anticoagulation

Treatment of hypoglycaemia:

• If able to take oral treatment: o Lucozade (or other high sugar drink / sweet)

• Else: o 20–30mg dextrose IV (e.g. 200–300mls 10% dextrose) o Glucagon 1mg IV/IM:

Almost as fast as IV dextrose but won’t work in drunks • Once conscious:

o Give the patient a meal Sulphonylureas:

• E.g. tolbutamide (very short-acting), glicazide (short-acting), glibenclamide (once daily)

• Mechanism of action: o Are insulin secretagogues (thus require some functional β-

cells) o Reduce the K+ permeability of β-cells by blocking ATP-sensitive

K+ channels: Causes depolarisation and Ca2+ entry Thus causing insulin secretion

• Pharmacokinetics: o All bind strongly to albumin (several drug interactions)

• Adverse effects: o Weight gain (largely due to ⇑ appetite) o Hypoglycaemia (can be severe / fatal):

Admit (as the hypoglycaemia can persist for up to 24 hrs) o GI disturbances (~3% of patients) o Bone marrow suppression (rare)

• Cautions: o Elderly ± renal impairment:

⇑⇑ risk of hypoglycaemia (mainly glibenclamide) o Breast-feeding

• Interactions: o Drugs potentiating the hypoglycaemic effect:

Sulphonamides (including co-trimoxazole) Chloramphenicol



[email protected]

96

Metformin: • A biguanide (the only available one!) • Mechanism of action:

o Is an insulin-sensitizer o ⇓ gluconeogenesis o ⇑ peripheral utilization of insulin o ⇓ LDL / VLDL

• Does not cause hypoglycaemia • Adverse effects:

o GI disturbances (nausea / anorexia / vomiting / diarrhoea) o Lactic acidosis (uncommon) o ⇓ absorption of vitamin B12

• Contraindications: o Conditions predisposing to metformin-induced lactic acidosis:

Mild renal impairment Severe hepatic impairment Severe heart failure

o Pregnancy / breast-feeding • Interactions:

o Alcohol: ⇑ risk of lactic acidosis

Glitazones (thiazolidinediones):

• E.g. pioglitazone, rosiglitazone • Indications:

o Type II diabetes: Patients who cannot tolerate (or there are

contraindications to) combination therapy with metformin and a sulphonylurea

In such cases, the glitazone should replace whichever drug in the combination is poorly tolerated / contraindicated

• Mechanism of action: o Interact with a nuclear receptor (peroxisome proliferator-

activator receptor gamma PPAR-γ) o PPAR-γ regulates genes involved in lipid metabolism and insulin

action o Reduce insulin resistance o ⇓ circulating insulin relative to plasma glucose but do not ⇓

glucose levels to normal • Adverse effects:

o Hepatotoxicity: Monitor LFTs before and during treatment

o Weight gain o Anaemia (uncommon)



[email protected]

97

• Contraindications: o Hepatic impairment o Combination with insulin (risk of heart failure)

Acarbose:

• Mechanism of action: o Intestinal α-glucosidase inhibitor o Delays the digestion of starch and sucrose o Is taken with meals and lowers the post-prandial increase in

blood glucose (~1-2mmol/L) • Adverse effects:

o Abdominal pain / bloating o Flatulence

• Contraindications: o IBD o History of abdominal surgery o Pregnancy

Insulin:

• Indications: o All T1DM o T2DM where control / symptoms / complications poor o Hyperkalaemia (with glucose)

• Pharmacokinetics: o Physical state:

Short-acting (rapid onset): • E.g. Actrapid, NovoRapid, Humalog • Inject 15–30 mins before meals • Onset in 30–60 mins • Maximum effect 2–4 hours • Duration up to 8 hours

Intermediate- and long-acting: • E.g. insulatard (intermediate), glargine,

ultratard (long-acting) • Onset in 1–2 hours • Maximum effect 4–12 hours • Duration 16–35 hours

o Human insulin absorbed faster than porcine / bovine insulin o Factors affecting absorption:

Temperature Exercise



[email protected]

98

• Insulin effects: o Adipose tissue:

⇑ lipoprotein lipase activity: • ⇓ TGs

⇑ GLUT-4 activity: • ⇑ glucose storage as fat

⇓ lipolysis: o Liver:

⇓ glycogenolysis ⇓ gluconeogenesis Inhibition of ketogenesis

o Muscle: ⇓ proteolysis ⇑ GLUT-4 activity:

• ⇓ plasma glucose levels • Insulin regimes:

o Twice daily mixed insulins: Possibly better for children or older T2DM

o Basal bolus (qds) regime: More “physiological” Involves more injections Best regimen for ⇓ diabetic complications

• Problems with Actrapid (short-acting human insulin): o Needs to be given 15 minutes before meals o Can cause a late post-prandial hypoglycaemia:

Leads to post-prandial hyperglycaemia (as patients don’t give enough as they fear the hypoglycaemia)

• Problems with insulin glargine (long-acting human insulin analogue): o Nocturnal hypoglycaemia o Uniform action (not physiological)

• Adverse effects: o Hypoglycaemia:

30% of T1DM ever (10%/year, 3% frequent episodes) Sweating Tachycardia Tremor Aggression Confusion Coma

o Fat hypertrophy at injection site (rotate site to avoid this) o Weight gain



[email protected]

99

Epilepsy

Classification of epilepsy: • Generalised:

o Implies bilateral abnormal electrical activity in the brain with bilateral motor manifestations

o Consciousness is impaired o Types:

Tonic-clonic (grand-mal) Absence (petit-mal) Myoclonic

• Partial: o A localised seizure that may be either:

Simple (without loss of consciousness): • Jacksonian seizure

Complex (with loss of awareness) o May progress to a generalised seizure

Management of status epilepticus:

• Remember 25% of status turns out to be pseudostatus • ABC (need to maintain airway) • Oxygen • If alcoholism / malnutrition five thiamine • If hypoglycaemic give glucose • Stop the seizure:

o Lorazapam (slow IV bolus) if fails o Phenytoin (IV infusion) if fails o Phenobarbital IV if fails o Anaesthetise with thiopentone / propofol

Drug treatment of epilepsy (NICE recommendations):

• Generalised seizures: o First-line (all):

Valproate o Second-line (tonic-clonic):

Carbamazepine Phenytoin

o Second-line (absence): Ethosuximide

o Second-line (myoclonic): Lamotrigine Ethosuximide

• Partial seizures: o First-line:

Carbamazepine Valproate



[email protected]

100

o Second-line: Lamotrigine Gabapentin Vigabatrin

o Third-line: Phenytoin

Carbamazepine:

• Indications: o Partial seizures (first-line) o Tonic-clonic seizures (second-line) o Trigeminal neuralgia o Bipolar disorder

• Mechanism of action: o Related to the tri-cyclic antidepressants o Induces a use-dependent block of neuronal Na+ channels

• Pharmacokinetics: o Has an active metabolite (produced in the liver) o t½ of 10–20 hours o Is an enzyme inducer (even of it’s own metabolism) o Requires therapeutic drug monitoring

• Adverse effects: o Ataxia o Nausea o Neutropenia o Sedation o SIADH o Teratogenic:

Foetal neural tube defects • Contraindications:

o AV conduction abnormalities (unless paced) o History of bone marrow depression o Porphyria

• Interactions (many as is an enzyme inducer): o Carbamazepine ⇓ the efficacy of:

COC pill Corticosteroids Cyclosporin Phenytoin Warfarin

o Drugs that ⇑ the level of carbamazepine: Cimetidine Erythromycin



[email protected]

101

Phenytoin: • Indications:

o All types of epilepsy (except absence seizures) but not first-line

o Trigeminal neuralgia • Mechanism of action:

o Related to the barbiturates o Induces a use-dependent block of neuronal Na+ channels

• Pharmacokinetics: o t½ of 20–60 hours o Has a saturable metabolism (zero-order kinetics):

This means that over the therapeutic plasma concentration range, the rate of inactivation does not ⇑ in proportion to the plasma concentration

This means that the t½ ⇑ as the dose is ⇑ o ~90% protein bound:

Some drugs (e.g. valproate, salicyclates) inhibit this binding competitively

This ⇑ the free [phenytoin] but also ⇑ the hepatic clearance of phenytoin

The net result is unpredictable o Is a potent enzyme inducer o Once daily dosage (should be nocte) o Requires therapeutic drug monitoring

• Adverse effects: o Acne o Ataxia o Folate deficiency o Gum hypertrophy o Hirsuitism o Lymphadenopathy o Sedation

• Cautions: o Hepatic impairment (⇓ dose) o Pregnancy:

Cleft palate • Interactions (many):

o Phenytoin ⇓ the efficacy of: COC pill Rifampicin Warfarin

o Drugs that ⇑ the level of phenytoin: Alcohol (acutely, ⇓ the level chronically) Aspirin Cimetidine



[email protected]

102

Sodium valproate: • Indications:

o All types of epilepsy (first-line) • Mechanism of action:

o Not fully understood o Causes a significant ⇑ in brain [GABA]

• Pharmacokinetics: o t½ of 8–15 hours o Metabolised by the liver but not an enzyme inducer (may be an

enzyme inhibitor) • Adverse effects (fewer severe effects than most anticonvulsants):

o Hepatotoxicity: Need to monitor LFTs

o Teratogenicity: Neural tube defects

o Thinning / curling of the hair o Thrombocytopenia o Tremor o Sedation o Weight gain

• Contraindications: o Severe liver disease

• Interactions: o Drugs that ⇓ the efficacy of valproate:

Neuroleptics Tri-cyclic antidepressants

Phenobarbital:

• Indications: o All types of epilepsy (except absence seizures) but not first-line o Status epilepticus

• Mechanism of action: o Is a barbiturate o Bind to the GABA receptor and enhance it’s actions

• Pharmacokinetics: o Well absorbed o 50% protein bound o t½ 36–120 hours o Enzyme inducer

• Adverse effects: o Sedation with impairment of intellectual and motor

performance o Ataxia o Osteomalacia o Folate deficiency



[email protected]

103

• Cautions: o Elderly o Respiratory depression o Impaired hepatic / renal function

• Interactions (many more than shown below): o Phenobarbital ⇓ the efficacy of:

COC pill Warfarin

Vigabatrin:

• Indications: o Epilepsy (usually second- or third-line)

• Mechanism of action: o Was the first “designer” drug in the field of epilepsy o Is a irreversible GABA-transaminase inhibitor:

⇑ [GABA] in the CSF • Pharmacokinetics:

o t½ 5 hours (although duration of action is long) o Is not an enzyme inducer

• Adverse effects: o Depression o Psychotic disturbances o Visual field defects (~30% of patients)

• Contraindications: o Those with visual field defects

Lamotrigine:

• Indications: o Can be used as monotherapy of:

Generalised seizures (especially absence seizures) Partial seizures

• Pharmacokinetics: o t½ 15–70 hours

• Adverse effects: o Rashes (very common):

Can be as severe as Stevens-Johnson syndrome o Drowsiness o Tremor

• Interactions: o Valproate:

Valproate ⇑ the plasma levels of lamotrigine Primidone:

• Is a pro-drug of Phenobarbital • ? an anticonvulsant in it’s own right • Adverse effects:

o As for Phenobarbitone



[email protected]

104

Ethosuximide: • Indications:

o Absence seizures (second-line) • Pharmacokinetics:

o t½ of 30–70 hours o Is not an enzyme inducer

• Adverse effects: o Nausea / anorexia o Sedation o Ataxia o Hypersensitivity (rare)

Gabapentin:

• Indications: o Adjunctive treatment of partial seizures o Neuropathic pain o It’s role is likely to increase in the future

• Pharmacokinetics: o t½ of 5–7 hours o Not metabolised o Few (if any) interactions

• Adverse effects: o Ataxia o Drowsiness



[email protected]

105

Migraine

Prophylaxis against migraine: • Avoid precipitating factors (if possible):

o Foods o Irregular meals / sleeping patterns o Alcohol

• 5-HT antagonists: o e.g. pizotifen, (methysergide – historical)

• β-blockers: o E.g. propranolol, atenolol, metoprolol o High doses often needed

• Amitriptylline: o Unrelated to it’s antidepressant effect

• Sodium valproate: o Refractory migraines

Treatment of migraine:

• Simple analgesics: o E.g. paracetamol / aspirin / NSAIDs o Give with metoclopramide:

Anti-emetic and ⇑ gastric emptying (thus ⇑ absorption of the analgesic)

o Must be given early in an attack • 5-HT1D agonists:

o E.g. sumatriptan o Is a (relatively) selective vasoconstrictor o ~70% efficacy o Adverse effects:

Dizziness Flushing

o Avoid: In patients with IHD or uncontrolled hypertension With SSRIs and MAOIs

• Ergotamine: o Rarely used now o Primarily a vasoconstrictor o Adverse effects:

Nausea / vomiting Peripheral /coronary vasoconstriction



[email protected]

106

Multiple sclerosis

Drug treatment of an acute relapse of MS: • IV methylprednisolone:

o High dose o Short course (3–5 days) o Does not alter the long-term prognosis

• No other approaches have shown any benefit Prevention of relapse in MS:

• Interferon-β1 (IFN-β1a and IFN-β1b): o Given SC / IM o Trials have shown a 30%⇓ in relapses (only in relapsing /

remitting disease) o Probably does not alter the natural history o Expensive:

~£10,000/person/year o Adverse effects:

‘Flu-like symptoms Depression

• Glatiramer: o May prevent relapsing as for IFN-β but does not alter the long-

term prognosis Symptomatic treatment of MS:

• Spasticity / painful spasms: o Baclofen:

Inhibits nerve transmission at the spinal level Adverse effects:

• Sedation • Hypotonia • Urinary disturbance

Serious side effects can occur on abrupt withdrawal: • Convulsions • Hyperthermia • Psychiatric reactions

o Dantrolene: Inhibits muscle contraction:

• Prevents Ca2+ release from sarcoplasmic reticulum Adverse effects:

• Aggravates weakness • Hepatotoxic

• Detrusor instability: o Anticholinergics (e.g. oxybutynin, TCAs)

• Paroxysmal pain: o Anticonvulsants / TCAs



[email protected]

107

Parkinson’s disease

Features of Parkinson’s disease: • Bradykinesia • Rigidity (“lead-pipe”) • Tremor (4–7 Hz, “pill-rolling”) • Festinant gait • Loss of arm swinging • Monotonous speech • Loss of facial expression • Micrographia

Drug treatment of Parkinson’s disease (PD):

• Treatment should not be started before it is necessary because of delayed unwanted effects

• Levodopa (L-dopa): o First-line therapy

• Direct dopamine agonists: o E.g. apomorphine, bromocriptine, lisuride, pergolide o Used as an alternative or adjunct to L-dopa

• Amantadine: o Useful in mild / moderate PD o May have a use in late disease with marked dyskinesia

• Anticholinergics: o E.g. benzhexol o Most useful in mild PD with tremor in younger patients

• Monoamine oxidase B inhibitors (MAO-BIs): o E.g. selegiline o Used as an adjunct to L-dopa to allow a ⇓ in dose:

Can also ⇓ dose-related response fluctuations • Catechol – O – methyl transferase (COMT) inhibitors:

o E.g. entacapone o May be useful in ⇓ end-of-dose fluctuations with L-dopa

Levodopa:

• Must be combined with a peripheral dopa-decarboxylase inhibitor: o E.g. carbidopa, benserazide o Prevents L-dopa metabolism in the periphery o Do not cross the blood-brain barrier (BBB) o Thus ⇓ dose (by about 10 fold) o ⇓ adverse effects

• Pharmacokinetics: o t½ of 2 hours o There is a large individual variation in kinetics, thus slow

titration is essential



[email protected]

108

• Mechanism of action: o Is a pro-drug of dopamine o (Dopamine is not used as it cannot cross the BBB) o L-dopa crosses the BBB and is rapidly converted to dopamine

by dopa-decarboxylase in the brain o This dopamine replaces the deficiency in the basal ganglia

• With L-dopa, ~80% show improvement in rigidity and hypokinesia and ~20% are restored to near-normal function (for a period)

• Adverse effects: o Short-term:

Nausea / vomiting: • Treat with domperidone (dopamine antagonist)

GI disturbances Postural hypotension Cardiac dysrhythmias Haemolytic anaemia (rarely)

o Long-term: Neuropsychiatric syndromes:

• Delirium • Hallucinations • Psychosis • Treatment:

o Dose ⇓ o Atypical neuroleptics (e.g. clozapine)

Response fluctuations: • Akinesia:

o End-of-dose • Dyskinesia:

o Peak dose o Onset / end-of-dose

• Unpredictable on-off responses (“yo-yo”-ing) • Treatment:

o Careful regulation of plasma L-dopa levels o Use modified-release preparations o Try:

COMT inhibitor MAO-BI Dopamine agonist

Loss of response: • Usually within 2–5 years • ~50% are back to pre-treatment status after 5 yrs • Treatment:

o Try dopamine agonist • Contraindications:

o Closed angle glaucoma



[email protected]

109

• Interactions: o Non-selective MAOIs:

Risk of hyperthermia syndrome with concomitant use Withdraw MAOIs 2 weeks before starting L-dopa

o Anti-hypertensives: Enhanced hypotensive effect

o Neuroleptics: Neuroleptics antagonise the action of L-dopa (and vice-

versa) Apomorphine:

• PD indications: o Advanced disease with “on-off” periods with L-dopa

• Pharmacokinetics: o Must be parenterally (SC)

• Mechanism of action: o Very potent dopamine D1 and D2 agonist

• Adverse effects: o Profound nausea / vomiting o As for L-dopa

• Contraindications: o Respiratory / CNS depression o Neuropsychiatric problems / dementia

Dopamine agonists:

• Older compounds (ergot derivatives): o Bromocriptine, cabergoline, lisuride, pergolide

• Recent compounds (synthetic): o Pramipexole, ropinirole o Side-effects are less than the older agents

• Indications: o Can be used as an alternative to L-dopa but are usually used as

adjuncts • Pharmacology:

o Duration of action: Pergolide = cabergoline > bromocriptine > lisuride

o Potency: Pergolide = lisuride > cabergoline > bromocriptine

• Are less effective than L-dopa but are associated with fewer late unwanted dyskinetic effects

• Adverse effects: o Nausea / vomiting o Hypotension



[email protected]

110

Amantadine: • Mechanism of action:

o Unknown o May cause release of dopamine o May be a weak anticholinergic

• Is less effective than L-dopa or even bromocriptine but it’s use may be revived for late onset dyskinesia

• Adverse effects: o Dizziness o Insomnia o Livedo reticularis o Peripheral oedema

Anticholinergics:

• E.g. benzhexol, procyclidine • Until L-dopa was discovered, anti-muscarinic agents were the only

available treatment for PD • Mechanism of action:

o As the nigrostriatal neurones progressively degenerate in PD, the release of (inhibitory) dopamine ⇓ and the excitatory cholinergic interneurones in the striatum become relatively overactive

o Blocking these mACh receptors “resets” this balance o Only really reduce the tremor of PD (little effect on rigidity

and Bradykinesia) • Use is declining rapidly (especially in the elderly) largely due to

their unwanted effects on memory • Adverse effects:

o CNS: Confusion Hallucinations Memory impairment

o Other: Blurred vision Dry mouth Postural hypotension Constipation

Monoamine oxidase B inhibitors (MAO-BIs):

• E.g. selegiline • Indications:

o May allow L-dopa dose ⇓ o ⇓ end-of-dose deteriorations in advanced PD o Can be used alone to delay need for L-dopa for a few months

• Adverse effects (reasonably well tolerated): o No “cheese reaction” (does not affect MAO-A) o Potentiates L-dopa related symptoms o Insomnia



[email protected]

111

Catechol-O-methyl transferase (COMT) inhibitors: • E.g. entacapone • Mechanism of action:

o Prolongs the action of a single dose of L-dopa o Has no anti-PD activity when used alone but ⇓ the “off” time

in late disease when used with L-dopa • Adverse effects:

o GI disturbances o Dyskinesias o Urine may be coloured reddish-brown



[email protected]

112

Drug-induced movement disorders

The most commonly implicated drugs in this section are the antipsychotics (but also more common drugs such as metoclopramide) To be covered:

• Acute dystonias • Akathisia • Parkinsonism • Tardive dyskinesia • Neuroleptic malignant syndrome

Acute dystonias:

• Dystonia is a syndrome of sustained muscle contractions that produce twisting and repetitive movements or abnormal postures

• Presentation: o Most common in young males o Occurs within hours / days of starting the implicated drug o Usually oculogyric:

Spasm of the extra-ocular muscles, forcing the eyes into upward or lateral gaze

• Treatment: o IV anticholinergics (e.g. procyclidine) o ? continue oral anticholinergics for ~48 hours

Akathisia:

• This is a restless, repetitive and irresistible need to move • Can culminate in suicide • Occurs within days or months of starting the implicated drug • Equal sex incidence • May persist even after drug is stopped • Treatment:

o Often ineffective o May respond to:

Amantadine Anticholinergics β-blockers



[email protected]

113

Parkinsonism: • Bradykinesia and rigidity but little tremor • Affects up to 20% of patients on antipsychotics • Presentation:

o Usually in first few months of starting the drug o More common in the elderly

• Treatment: o Withdraw / ⇓ dose of drug if possible o Anticholinergics / Amantadine may be effective:

Do not use L-dopa o May persist even after drug is stopped

Tardive dyskinesia (TD):

• Are involuntary movements of the tongue, lips, face, trunk and extremities

• Presentation: o Occurs after many months / years of using the drug o Affects up to ~20% of patients o More common in women and the elderly

• Treatment: o Some neuroleptics are less likely to cause TD:

Clozapine, risperidone, sulpiride o A change of neuroleptic may help

Malignant hyperthermia syndrome:

• Is a rare idiosyncratic drug reaction that is unpredictable • Commonly implicated drugs:

o Antipsychotics o Suxamethonium

• Presentation: o Often a young male o Extreme rigidity o Hyperthermia o Fluctuating conscious level

• There is a very high mortality if the syndrome goes unrecognised • Treatment:

o Stop the causative drug o Dantrolene:

Stops Ca2+ release in muscle Thus stopping the excessive muscle contractions



[email protected]

114

Myasthenia gravis

The Tensilon (edrophonium) test: • Give edrophonium IV as a bolus dose • Positive test:

o Improvement of weakness occurs within seconds and the response lasts for 2–3 minutes

• To be certain, the test should be preceded by a bolus of saline to act as a control

Drug treatment of myasthenia gravis (MG):

• Oral anticholinesterases: o Provide symptomatic improvement (complete relief is rare)

• Corticosteroids: o Lead to a rapid improvement in most patients o Can produce total remission o High doses are usually needed (60mg on alternate days)

• Immunosuppressants: o E.g. azathioprine, cyclophosphamide, cyclosporin o Lead to an improvement in most patients o Are steroid-sparing agents o More effective in older patients

• Thymectomy: o Improves prognosis (especially in women <40 years with

positive AChR antibodies and a history of <10 years) o Must always remove a thymoma if present o Complete remission is rare

• Plasmapheresis: o Useful during exacerbations o Effects may last up to 3 months

Anticholinesterases:

• E.g. neostigmine, pyridostigmine • Indications:

o Myasthenia gravis (oral) o Reversal of non-depolarising muscle relaxants (IV)

• Mechanism of action: o Inhibit acetylcholinesterase, thus ⇑ the concentration of ACh

in the synaptic cleft o Myasthenia gravis:

The ⇑ concentration of ACh has an ⇑ probability of bind to a receptor at the neuromuscular junction

o Reversal of muscle relaxants: The ⇑ concentration of ACh overcomes the non-

competitive blockade of the muscle relaxant



[email protected]

115

• Adverse effects:

o Abdominal cramps o Bradycardia o Hypersalivation o Nausea / vomiting o Sweating

• Interactions: o Aminoglycosides:

⇓ the action of anticholinesterases



[email protected]

116

Diuretics

Loop diuretics: • E.g. furosemide • Indications:

o Acute pulmonary oedema o Chronic heart failure o Oliguria secondary to acute renal failure

• Mechanism of action: o Inhibit NaCl reabsorption in the thick segment of the

ascending loop of Henle: Inhibit the Na+/K+/2Cl- pump

o This section has a high capacity for absorbing NaCl and so loop diuretics produce the most profound diuresis

o The ⇑ Na+ that reaches the distal tubule also leads to an osmotic effect, drawing yet more water into the lumen

o Also possess venodilator properties that are independent of their diuretic effect

• Adverse effects: o Hypokalaemia o Hypocalcaemia o Hypomagnesaemia o Hyperuricaemia (can cause gout) o Deafness (high doses – effects on the endolymph) o Postural hypotension

• Contraindications: o Renal failure with anuria

• Interactions: o Aminoglycosides:

⇑ risk of ototoxicity and nephrotoxicity o Digoxin:

Hypokalaemia caused by furosemide ⇑ risk of digoxin toxicity

o Lithium: ⇓ excretion of lithium - ⇑ plasma levels

Thiazide diuretics:

• E.g. bendrofluazide, metolazone • Indications:

o Hypertension o Heart failure

• Mechanism of action: o Moderately powerful diuretics (metolazone > bendrofluazide) o ⇓ reabsorption of Na+ in the distal tubule



[email protected]

117

o The ⇑ Na+ load in the distal tubule stimulates Na+ exchange with K+ and H+ ions thus ⇑ their excretion and tending towards hypokalaemia and a metabolic alkalosis

• Adverse effects: o Hypokalaemia o Hyponatraemia o Hyperglycaemia o Hyperlipidaemia o Hyperuricaemia o Postural hypotension o Impotence

• Contraindications: o Severe hepatic / renal impairment o Gout

• Interactions: o Digoxin:

Hypokalaemia caused by thiazides ⇑ risk of digoxin toxicity


Spironolactone (a potassium-sparing diuretic):

• Indications: o Chronic heart failure (shown to ⇓ mortality) o Refractory hypertension (BHS step 4) o Ascites / oedema caused by cirrhosis o Conn’s syndrome (primary hyperaldosteronism) o Potassium conservation with thiazide and loop diuretics

• Mechanism of action: o Is a competitive aldosterone antagonist o Aldosterone causes Na+ reabsorption and K+ excretion in the

distal tubule o Inhibition of this action leads to a mild diuresis and retention of

K+ o It is a weak diuretic because only 2% of the total Na+

reabsorption is under aldosterone control • Adverse effects:

o Hyperkalaemia o Gynaecomastia o Impotence

• Contraindications: o Hyperkalaemia o Addison’s disease

• Interactions: o ⇑ risk of hyperkalaemia:

ACE inhibitors / AII receptor antagonists NSAIDs



[email protected]

118


o Potassium salts (⇑ risk of hyperkalaemia) Other potassium-sparing diuretics:

• E.g. amiloride, triamterene • Indications:

o Potassium conservation with thiazide and loop diuretics • Mechanism of action:

o Block Na+ channels in the distal tubule o ⇑ Na+ excretion (thus causing a diuresis) and ⇓ K+ excretion

• Adverse effects: o Hyperkalaemia

• Contraindications: o Renal impairment

• Interactions: o ⇑ risk of hyperkalaemia:

ACE inhibitors / AII receptor antagonists NSAIDs


o Potassium salts (⇑ risk of hyperkalaemia) Osmotic diuretics:

• E.g. mannitol • Indications:

o Cerebral oedema • Mechanism of action:

o Mannitol is a compound that is filtered by the kidneys but is not reabsorbed

o Is given in amount such that it significantly contributes to plasma osmolarity

o The ⇑ plasma osmolarity (by compounds which cannot cross the blood-brain barrier) leads to extraction of water from the brain

• Adverse effects: o Chills o Fever

• Contraindications: o Congestive cardiac failure o Pulmonary oedema



[email protected]

119

Muscle relaxants

Types of muscle relaxants: • Depolarizing:

o Suxamethonium • Non-depolarizing (competitive):

o Can be reversed with an anticholinesterase (unlike suxamethonium)

o Pancuronium: Long-duration of action Atropine-like effects

o Vecuronium: No cardiovascular effects Short duration of action

o Atracurium: Decomposes spontaneously in plasma: Does not depend on liver / kidneys for excretion

o Rocuronium: Rapid onset (almost as fast as Suxamethonium)

Suxamethonium:

• Pharmacokinetics: o Is 2 ACh molecules linked by their acetyl groups o Rapid onset (1–1.5 minutes) o Very short duration of action (3–7 minutes):

Metabolised by plasma pseudocholinesterase • Mechanism of action:

o Suxamethonium diffuses slowly to the motor endplate and persist for long enough to cause loss of electrical excitability

o Before paralysis occurs, the muscle fibres are activated causing twitching (fasciculation)

• Adverse effects: o Muscle aches (caused by the fasciculation) o Prolonged block:

~1 in 2000 people have a deficiency of plasma pseudocholinesterase and paralysis may last several hours

o Bradycardia o K+ release (from muscle) o Malignant hyperthermia:

Very high mortality (~65%) Treated with dantrolene

• Contraindications: o Family history of malignant hyperthermia o Hyperkalaemia



[email protected]

120

• Interactions: o Drugs ⇑ action of Suxamethonium (many):

Aminoglycosides Metoclopramide Verapamil

Non-depolarizing muscle relaxants:

• E.g. pancuronium, vecuronium, atracurium, rocuronium • Mechanism of action:

o Do not cross the BBB or the placenta o Block the nicotinic ACh receptor at the motor endplate,

thus inhibiting muscle contraction • Adverse effects:

o These vary between the various drugs (see above) o Hypotension o Anaphylactoid reactions



[email protected]

121

Anti-emetics

Causes of nausea and vomiting: • Drugs:

o Antibiotics (e.g. erythromycin) o Cytotoxic agents o Digoxin o Opioids

• Vestibular disease (e.g. labyrinthitis) • Provocative movement (e.g. seasickness) • Migraine • Abdominal disease • Pregnancy

Physiology of nausea:

• Emesis is coordinated by the vomiting centre (medulla oblongata) • An important input to the vomiting centre is the chemoreceptor

trigger zone (CTZ) in the area postrema: o The CTZ is not protected by the BBB, therefore circulating

toxins/drugs can stimulate it o Possesses the following receptors:

Dopamine (D2) Serotonin (5HT3)

• The vomiting centre also receives cholinergic (muscarinic) and histamine input

• Thus the following drug classes are helpful anti-emetics: o D2 receptor antagonists o 5-HT3 receptor antagonists o Anti-muscarinic agents o Antihistamines (H1)

• Dexamethasone is a useful anti-emetic following cancer chemotherapy

• Vomiting is easier to prevent than it is to stop D2 receptor antagonist anti-emetics:

• E.g. metoclopramide, domperidone • Indications:

o Nausea and vomiting due to: Abdominal disease Drugs (especially opioids) Migraine Post-operative nausea / vomiting

• Mechanism of action: o Blocks D2 receptors in the CTZ o Prokinetic actions on the gut (⇑ absorption of many drugs):



[email protected]

122

Can be an advantage (e.g. analgesics in migraine with vomiting)

• Adverse effects: o Acute dystonia (especially if age <20 years and female) o Hyperprolactinaemia

• Domperidone does not readily cross the BBB and is much less likely to cause central reactions (e.g. dystonic reactions)

• Contraindications: o GI obstruction / perforation / haemorrhage o Recent (3–4 days) GI surgery

• Interactions: o NSAIDs:

⇑ absorption of NSAIDs ⇑ their beneficial (and toxic) effects

5-HT3 antagonist anti-emetics:

• E.g. ondansetron, granisetron • Indications:

o Nausea and vomiting due to: Cytotoxic agents Radiotherapy Post-operative nausea / vomiting

• Adverse effects: o Headache o Constipation

Anti-muscarinic anti-emetics:

• E.g. hyoscine • Indications:

o Prophylaxis against motion sickness • Adverse effects:

o Blurred vision o Dry mouth o Drowsiness

• Contraindications: o Prostatic enlargement o Glaucoma o Myasthenia gravis o Paralytic ileus

• Interactions: o Alcohol:

Sedative effects of hyoscine are enhanced by alcohol



[email protected]

123

Antihistamine anti-emetics: • E.g. cinnarizine, cyclizine • Indications:

o Nausea and vomiting due to: Vestibular disease Drugs

• Adverse effects: o Drowsiness o Anti-muscarinic effects, e.g.:

Blurred vision Dry mouth

• Contraindications: o Prostatic enlargement o Glaucoma o Urinary retention



[email protected]

124

The eye Maintenance of intraocular pressure (IOP):

• The IOP is determined by aqueous humour volume • Production:

o Aqueous humour is produced by the highly vascularised processes of the ciliary body

The ciliary epithelial cells (which contain ATPase and carbonic anhydrase) absorb Na+ from the stroma and transport it to the intercellular clefts (which open on the aqueous humour side)

o The hyperosmolality in the clefts leads to water flow from the stroma, producing a continuous flow of aqueous

o The ciliary epithelium is also leaky and ~30% of aqueous is formed by ultrafiltration

• Drainage: o Pupil trabecular meshwork canal of Schlemm episcleral

veins Treatment of acute narrow-angle glaucoma:

• This must be treated quickly to prevent permanent retinal damage • ⇓ aqueous production:

o Acetazolamide IV stat • ⇑ aqueous outflow:

o Pilocarpine eye drops stats o Mannitol IV stat:

To draw water out of the eye • Prevent recurrence:

o Surgery (Peripheral iridotomy) Drug treatment of chronic open-angle glaucoma:

• All of the following treatments are given topically (eye drops) • ⇓ aqueous production:

o β-blockers o α-agonists o Carbonic anhydrase inhibitors

• ⇑ aqueous outflow: o Muscarinic agonists

Age-related macular degeneration (AMD):

• Most common cause of blindness in the UK • New blood vessels form under the retina and leakage of fluid and blood

from the vascular complexes causes severe loss of vision within a few years



[email protected]

125

• Treatment (relatively new): o Verteporfin (photodynamic therapy):

Is a light-sensitive dye that is given IV and is taken up by vascular endothelium

A laser is then applied to the eye and this activates the dye, which releases free radicals that destroy the new vessels

Mydriatic drugs:

• Muscarinic antagonists: o Also cause cycloplegia (paralysis of the ciliary muscle) o Tropicamide o Cyclopentolate

• α-agonists: o Do not affect the pupillary light reflex or accommodation o Phenylephrine

β-blockers and glaucoma:

• E.g. timolol • Drugs of choice in chronic open-angle glaucoma • Mechanism of action:

o Block β2 receptors on the ciliary processes and ⇓ aqueous secretion

o May also block β-receptors on afferent blood vessels to the ciliary processes (this vasoconstriction ⇓ ultrafiltration)

• Adverse effects (may be absorbed systemically): o Bradycardia o Bronchospasm

• Contraindications: o Asthma o Heart block o Heart failure

α-agonists in glaucoma:

• E.g. adrenaline • ⇓ IOP by vasoconstriction of the ciliary body afferent blood vessels • Interestingly, α-antagonists and β-agonists also ⇓ IOP:

o ⇑ aqueous outflow rather than ⇓production o Dilatation of the aqueous / episcleral veins

Carbonic anhydrase inhibitors:

• E.g. Acetazolamide (IV / IM / oral), dorzolamide (topical) • Inhibition of carbonic anhydrase prevents HCO3

- formation • Since HCO3

- and Na+ transport are linked, this leads to a ⇓ in aqueous formation

• Dorzolamide can be used alone in those in whom β-blockers are contraindicated



[email protected]

126

• Dorzolamide is a sulphonamide and systemic side effects can occur: o Rashes o Bronchospasm

Muscarinic agonists:

• E.g. pilocarpine • ⇓ IOP by contracting the ciliary muscle • This pulls the scleral spur and results in the trabecular meshwork

being stretched and separated • The fluid pathways are opened up and aqueous outflow is increased • Adverse effects:

o Miosis: Causes near-sightedness (blurred distance vision) Brow ache Headache Poor night vision



[email protected]

127

Antipsychotics (neuroleptics) The dopamine hypothesis of psychosis:

• Psychotic symptoms result from ⇑ dopamine neurotransmission • Dopamine receptors:

o D1-like: D1 and D5 Are post-synaptic Stimulate adenylate cyclase and ⇑ cAMP

o D2-like: D2, D3 and D4 Are both pre- and post-synaptic Inhibit adenylate cyclase and ⇓ cAMP

• Dopaminergic pathways: o Mesolimbic / mesocortical:

Concerned with mood and emotional stability Ventral tegmental area:

• Ventral striatum and the frontal cortex o Nigrostriatal:

Concerned with movement Substantia nigra and the dorsal striatum

• Neuroleptics block D2 receptors: o Explains why they cause movement disorders as a side effect

Clinical classification of neuroleptics:

• Typical: o Produce extrapyramidal symptoms (EPS)

• Atypical: o So-called because they have a low incidence of EPS o However, all apart from clozapine can cause EPS at high doses

Chemical classification of neuroleptics:

• Typical: o Phenothiazines:

Propylamines (chlorpromazine): • Sedation ++ • Anticholinergic ++ • EPS ++

Piperidines (thioridazine): • Sedation ++ • Anticholinergic ++ • EPS +

Piperazines (fluphenazine): • Sedation + • Anticholinergic + • EPS +++



[email protected]

128

o Thioxanthines (flupenthixole): Sedation + Anticholinergic + EPS ++

o Butyrophenones (haloperidol): Sedation - Anticholinergic + EPS +++

• Atypical: o “True”:

Clozapine: • Sedation ++ • Anticholinergic + • EPS -

o “Apparent”: Sulpiride:

• Sedation + • Anticholinergic – • EPS +

Risperidone: • Sedation ++ • Anticholinergic + • EPS +

General effects of the neuroleptics:

• Early (hours): o Desired:

Sedation (histamine / α-receptor blockade) Tranquilisation (dopamine blockade)

o Unwanted: Acute dystonic reactions

• Medium (days–weeks): o Desired:

Suppression of: • Delusions • Disordered thinking • Hallucinations

o Unwanted: Akathisia Parkinsonism

• Late (months–years): o Desired:

Prevention of relapse o Unwanted:

Tardive dyskinesia • Any time:

o Neuroleptic malignant syndrome



[email protected]

129

Chlorpromazine: • Indications:

o Psychotic disorders (e.g. schizophrenia / mania) o Labyrinthine disorders / vertigo o Nausea / vomiting o Chronic hiccups

• Adverse effects: o Common:

Sedation Anticholinergic effects:

• Blurred vision • Dry mouth • Postural hypotension • Constipation • Urinary retention

Extrapyramidal effects: • Acute dystonia • Akathisia • Parkinsonism • Tardive dyskinesia

Hyperprolactinaemia: • Amenorrhoea • Galactorrhoea • Impotence

o Uncommon: Neuroleptic malignant syndrome Agranulocytosis Cholestatic jaundice

• Interactions: o ACE inhibitors:

Can cause severe hypotension Haloperidol:

• Indications: o Psychosis o Motor tics

• Adverse effects: o Common:

Extrapyramidal effects: • Acute dystonia • Akathisia • Parkinsonism

Postural hypotension o Uncommon:

Convulsions Neuroleptic malignant syndrome Tardive dyskinesia Weight loss



[email protected]

130

• Interactions: o Amiodarone:

⇑ risk of ventricular arrhythmias o Carbamazepine:

⇓ plasma levels of haloperidol (metabolism accelerated) o Fluoxetine:

⇑ plasma levels of haloperidol Clozapine:

• Regarded by many as the only “true” atypical neuroleptic: o EPS is not evident even at high doses o Effective in patients refractory to other neuroleptics o Can treat the negative symptoms of schizophrenia

• Mechanism of action: o Blocks D4 and 5-HT2 receptors o Weak blockade of striatal D2 receptors

• Adverse effects: o Agranulocytosis (requires regular blood monitoring) o Myocarditis / cardiomyopathy o Ileus

• Contraindications: o Severe cardiac disorders o History of neutropenia / agranulocytosis

• Interactions: o Avoid concomitant use with drugs that have a high risk of

causing agranulocytosis (e.g. carbimazole)



[email protected]

131

Drugs in the elderly, young or pregnant Pharmacokinetics in the elderly:

• Distribution: o ⇓ body water:

Thus water soluble drugs have a ⇓ volume of distribution (Vd)

Thus ⇑ [water soluble drugs] o ⇑ body fat:

Lipid soluble drugs have an ⇑ Vd Thus ⇓ [fat soluble drugs]

o ⇓ plasma albumin: ⇓ drug protein binding Thus ⇑ levels of drugs that usually bind to protein

o ⇓ weight (no longer a 70kg man!): Thus standard dose will lead to ⇑ [drug]

• Metabolism: o ⇓ oxidation o ⇓ first-pass metabolism o ⇓ induction of liver enzymes o Warfarin is more effective

• Excretion: o ⇓ GFR o ⇓ tubular secretion

Altered end-organ sensitivity in the elderly:

• Autonomic nervous system: o Defective compensatory mechanisms:

E.g. antihypertensives postural hypotension o β-receptors (⇓ density)

• Brain: o ⇑ sensitivity to anxiolytics and hypnotics (may lead to confusion)

• Heart (failing): o ⇓ perfusion of liver / kidneys ⇓ function of these organs

Two groups of drugs in the elderly cause 2/3 of all adverse drug reactions:

• Drugs acting on the: • Brain:

o Antidepressants o Anti-Parkinson’s drugs o Hypnotics

• Circulation: o Antihypertensives o Digoxin o Diuretics



[email protected]

132

Compliance issues in the elderly: • Living alone / unsupervised • Confusion because of change in tablet shape / colour • Impaired vision • Arthritic hands

Pharmacokinetics in neonates:

• Absorption: o ⇓ gastric motility o Variable peripheral perfusion (care with IM injections)

• Distribution: o Blood brain barrier is immature o ⇑ body water:

Thus ⇓ [water soluble drugs] o ⇓ body fat:

Thus ⇑ [fat soluble drugs] o Protein binding low (adult levels at 1 year of age)

• Metabolism: o ⇓ P450 activity o ⇓ conjugation:

E.g. chloramphenicol grey baby syndrome • Excretion:

o ⇓ GFR: The neonate has 30% of adult GFR and 20% of adult

tubular secretion This ⇑ to 50% at 1 week of age ⇑ to 100% at 6 months of age

Drugs with adverse effects on foetal development:

• ACE inhibitors • Alcohol • Androgens • Anticonvulsants • Folate antagonists (e.g. methotrexate) • Tetracyclines • Thalidomide • Warfarin

Drugs to avoid in later pregnancy:

• Aspirin: o Haemorrhage o Kernicterus

• Aminoglycosides: o CN VIII damage

• Anti-thyroid drugs (e.g. carbimazole): o Goitre o Hypothyroidism



[email protected]

133

• Benzodiazepines: o “Floppy baby” syndrome

• Chloramphenicol: o Grey baby syndrome

• Warfarin: o Haemorrhage

• Sulphonylureas: o Kernicterus



[email protected]

134

Cytotoxic chemotherapy Classification of anti-cancer drugs:

• Alkylating agents: o Cyclophosphamide o Cisplatin o Dacarbazine o Ifosfamide o Mitomycin C

• Anti-metabolites: o Folate antagonists:

Methotrexate o Pyrimidine analogues:

5-Fluorouracil (5-FU) Cytarabine (cytosine arabinoside) Gemcitabine

o Purine analogues: Azathioprine

• Cytotoxic antibiotics: o Anthracyclines:

Doxorubicin (adriamycin) o Bleomycin

• Plant derivatives: o Taxanes:

Paclitaxel o Vinca alkaloids:

Vincristine Vinblastine

• Epipodophyllotoxins: o Etoposide

• Hormonal: o Antagonists:

Anti-androgens: • Cyproterone

Anti-oestrogens: • Tamoxifen

o Corticosteroids o GnRH analogues:

Goserelin o Somatostatin analogues:

Octreotide • Miscellaneous compounds:

o Hydroxyurea



[email protected]

135

Some example chemotherapy regimens: • BEP:

o Bleomycin o Etoposide o Cisplatinum o Testicular teratoma

• CHOP: o Cyclophosphamide o Hydroxydaunomycin (doxorubicin) o Oncovin (vincristine) o Prednisolone o Radical treatment of non-Hodgkin’s lymphoma (NHL)

• ABVD: o Adriamycin (doxorubicin) o Bleomycin o Vinblastine o Dacarbazine o Hodgkin’s lymphoma

• FEC: o 5-Fluorouracil o Etoposide o Cyclophosphamide o Breast cancer

General adverse effects of cytotoxic agents:

• Nausea / vomiting • Alopecia • Oral / intestinal ulceration • Diarrhoea • Bone marrow suppression:

o Anaemia o Leucopenia o Thrombocytopenia

• Teratogenicity • Carcinogenesis

Emesis-risk:

• High risk: o Treat with granisetron + dexamethasone + domperidone) o Cisplatinum (high dose) o Etoposide (high dose) o Dacarbazine o Ifosfamide

• Moderate risk: o Cisplatinum (low dose) o Cyclophosphamide o Doxorubicin o Methotrexate (high dose)

patient’s biggest concern

physician’s biggest concern



[email protected]

136

• Low risk: o Treat with domperidone ± dexamethasone o Bleomycin o Methotrexate (low dose) o Mitomycin o Vincristine

Prevention of nausea / vomiting:

• Acute: o 5-HT3 antagonist (e.g. granisetron) + o Dexamethasone

• Delayed: o Domperidone / metoclopramide o Dexamethasone

Alkylating agents:

• E.g. cyclophosphamide, cisplatin, dacarbazine, ifosfamide, mitomycin • Mechanism of action:

o Readily form covalent bonds with the bases in DNA o Prevent cell division by cross-linking the two strands of the

double helix o Their main action occurs during replication (i.e. during S phase

with a block at G2) o Results in apoptotic cell death

• Cyclophosphamide: o Indications:

Malignancy Autoimmune disease (e.g. SLE, rheumatoid arthritis) Nephritic syndrome Vasculitis

o Adverse effects (in addition to the general ones above): Haemorrhagic cystitis:

• Due to the metabolite acrolein • Can be ameliorated by:

o ⇑ fluid intake o Mesna (a sulphydryl donor)

Infertility in men: • Long-term use • May be irreversible

• Cisplatin: o A platinum containing alkylating agent o Revolutionised the treatment of tumours of the testes / ovary o Adverse effects:

Nephrotoxicity Very severe nausea / vomiting Peripheral neuropathy Ototoxicity Anaphylactoid reactions



[email protected]

137

Pyrimidine analogues: • E.g. 5-FU, cytarabine, gemcitabine • 5-FU:

o Mechanism of action: Interferes with thymidylate synthetase (essential for

the production of thymidylic acid) Impairs DNA synthesis (but not RNA or protein

synthesis) • Cytarabine:

o Mechanism of action: Incorporated into DNA and RNA Inhibits DNA replication and (to a lesser extent) DNA

repair • Gemcitabine:

o An analogue of cytarabine o Has fewer unwanted effects:

‘Flu-like symptoms Mild myelotoxicity

Purine analogues:

• E.g. 6-mercaptopurine (6-MP), azathioprine (a pro-drug of 6-MP) • Indications:

o Autoimmune diseases (e.g. rheumatoid arthritis, SLE) o Prevention of transplant rejection o Steroid-sparing agent

• Mechanism of action: o 6-MP is converted to a “fraudulent” nucleotide o Is incorporated into and interferes with replicating DNA o Also impairs the de novo pathway of purine synthesis

• Adverse effects: o Nausea / vomiting o Bone marrow suppression o Alopecia o Jaundice

• Interactions: o Allopurinol:

Allopurinol inhibits the metabolism of azathioprine, thus ⇑ it’s toxicity

Cytotoxic antibiotics:

• E.g. doxorubicin • Mechanism of action:

o Inserts itself between base pairs (intercalation): Alters the topography of DNA Causes unwinding of DNA

o Causes topoisomerase II-associated DNA strand breaks



[email protected]

138

o Causes free-radical formation: Responsible for cardiac toxicity (as the heart cannot

inactivate them due to a lack of catalase activity) • Adverse effects:

o Cardiac toxicity: Acute Myocarditis / pericarditis Late onset cardiac failure:

• 5% of patients after high dose therapy Taxanes:

• E.g. paclitaxel (taxol) • Derived from Yew tree bark • Mechanism of action:

o Stabilise cell microtubules (in effect “freezing” them) o Prevents spindle formation in mitotic cells and causing cell cycle

arrest in metaphase • Adverse effects:

o Bone marrow suppression o Hypersensitivity:

Must pre-treat the patient with: • Antihistamines • Corticosteroids

o Neurotoxicity Vinca alkaloids:

• E.g. vincristine, vinblastine • Extracts of the periwinkle plant • Mechanism of action:

o Bind to tubulin and inhibit it’s polymerisation into microtubules

o This prevents spindle formation o Leads to cell cycle arrest in metaphase

• Adverse effects: o Relatively non-toxic o Neurotoxicity:

Paraesthesia Neuromuscular abnormalities

o Fatal if given intrathecally Hydroxyurea:

• Indications: o Malignancy o Sickle cell anaemia (⇑ production of fetal Hb)

• Mechanism of action: o A urea analogue o Inhibits ribonucleotide reductase o Interferes with the conversion of ribonucleotides to

deoxyribonucleotides

Pharmacology Book

Documents

Transcript of Pharmacology Book