Standard Drug List 2

Parasympathetic Nervous System – Cholinomimetics (Cholinoceptor Agonists i.e. Nicotinic & Muscurinic) – DIRECTLY ACTING

Acetylcholine

Binds to nicotinic & muscurinic receptors (parasymp)

Eye: Contractn of ciliary body =

accommodation for near vision Contractn of Sphincter Pupillae (circular

muscle of the iris) = constricts pupil (miosis) & improves drainage of intra-ocular fliud (glaucoma)

Lacrimatn (tears)CVS: Bradycardia &↓ CO (↓ed contractn) Vasodilatn (NO producn on endothelium) Non-vascular Smooth Muscle: Lung – Bronchoconstrictn Gut – ↑ed peristalsis (& motility) Bladder – ↑ed emptyingExocrine Glands: Salivatn ↑ed bronchial & GI secretn SNS – sweating

Does not differentiate b/w muscurinic & nicotinic e.g. skeletal muscle contractn & symp activity

Bethanechol

Choline ester M3 AChR selective agonist Bladder emptying Enhance GI motility

Resistant to degradation Orally active (with limited access

to brain) Plasma t1/2 ≈ 3-4h

Sweating Impaired vision Nausea Bradycardia & Hypotension Respiratory difficulty

Pilocarpine

Alkaloids Selective agonist at muscarinic receptor

Partial agonist for many muscarinic responses – less effective on GI, smooth muscle & heart

Glaucoma (↑ed intraocular pressure) – by constritn of pupil

t1/2 ≈ 3-4h Sweating Blurred vision GI disturbance & pain Hypotension Respiratory distress

Parasympathetic Nervous System – Cholinomimetics (Cholinoceptor Agonists i.e. Nicotinic & Muscurinic) – INDIRECTLY ACTING (Anticholinesterase)

Neostigmine/Physostigmine

Donepezil

Alkaloids (tertiary amine)

Reversible Anticholinesterase: Donates carbamyl

group to the enzyme Blocks active site Carbamyl removed by

slow hydrolysis

Glaucoma Atropine Poisoning (iv – particularly in

children)

Tertiary amine Can readily cross bld-brain barrier Primarily acts at the post-

ganglionic parasympathetic synapse

t1/2 ≈ 30min

Effects on CNS (only non-polar organophosphates i.e. these ones) Low doses = excitation; convulsion High doses = unconsciousness,

resp depression & death Donepezil – Alzheimer’s disease& Autonomic side-effects (see next)

Ecothiapate Organo-phosphorus compunds

Irreversible Anticholinesterase – rapidly react with enzyme

Glaucoma (with prolonged action) Insecticides

Stable & resistant to hydrolysis Sweating; Blurred vision; GI pain; Bradycardia; Hypotension; Respiratory difficulty

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NAME OF DRUG TYPE MECHANISMS OF ACTION USES PHARMACOKINETICS SIDE-EFFECTS OF DRUG

active site leaving a blocking group

Autonomic Effects: Low Dose = ↑ muscurinic activity Moderate Dose – further

muscurinic activity & enhanced diffusion at all autonomic ganglia

High Dose – (toxic) depolarising block at ganglia

Pralidoxime

THIS IS NOT AN INDIRECTLY ACTING CHOLINOMIMETIC

Can split the phosphorus-enzyme bond initially & ‘regenerate’ the enzyme

Treatment of Organophosphate Poisoning: Signs/Symptoms – Salivation, Lacrimation, Urination, Diaphoresis, GI motility, Emesis, Bronchorrhea, Bronchconstriction, Bradycardia (SLUDGE BBB)

Cannot enter CNS – does NOT affect CNS symptoms of organophosphate poisoning

Highly lipid soluble – readily absorbed through the nasal mucosa, skin, lungs

Parasympathetic Nervous System – Cholinoceptor Antagonists – NICOTINIC RECEPTOR ANTAGONISTS

Trimetaphan2 blocking ways:a) Block receptor

(ligand cannot bind) – complete block

b) Block ion channel once activated (ligand can bind) – in-complete block

Ganglion Blocking Drugs: Block transmission at

all autonomic ganglia – does NOT block at skeletal muscle due to different nicotinic receptors

Affects more symp than parasymp

To cause hypotension during surgery – short-acting

CVS effects: Hypotension (dilation of blood vessels); ↓ed renin secretion; ↓ed postural reflex

Smooth Muscle: pupil dilation (impaired light reflex); bronchodilation; impaired bladder dysfunction; ↓ GI tone & motility

Exocrine: sweat, salivary, GI, bronchial & lacrimal glands all have ↓ed secretions

Hexametho-nium

1st hypertensive medication

Botulinum Toxin (BOTOX)

Toxin binds to SNARE complex – prevents exocytosis of ACh

Toxic – complete block of nicotinic receptors at autonomic ganglia

Parasympathetic Nervous System – Cholinoceptor Antagonists – MUSCURINIC RECEPTOR ANTAGONISTS

AtropineBlock ACh action at muscarinic receptors (i.e. all parasymp & sweat glands)

CNS Effects: Atropine mild restlessness to agitation Hyoscine sedation (both have similar structure, yet have opposite effects)Annaesthetic Premeditation (mimic effects of Hyoscine – sedation): Salivary glands copious, watery secretions Heart = ↑ rate & contractility Trachea & Bronchioles dilation (remember opposite to parasymp effects)Neurological: Motion sickness – Hyoscine patch Parkinson’s Disease – cholin/dopaminergic balance in basal gangliaResp – Asthma/COPD (bronchodilation)GI – Irritable Bowel Syndrome – ↓ motility & tone

↓ secretions ↓ sweating Cycloplegia (paralysis of the ciliary

muscle of the eye loss of accommodation)

CNS disturbances

(N.B. Atropine Poisoning hyperactivity then CNS depression, ↑ed body temp., dry mouth, blurred vision, urinary retention)

Hyoscine

Tropicamide Examination of the retina – binds to circular muscle on the eye & ↑es pupil sizeIpratropium Treatment of chronic obstructive lung diseases (e.g. asthma)

Sympathetic Nervous System – Adrenoceptor Agonists – DIRECTLY ACTINGAdrenaline Non-selective α/β Allergic reactions & anaphylactic shock

( sev hypotension & bronchoconstrictn) RoA (Route of Admin) – iv DoA (Duration of Action) – few

CVS effects: Tachycardia; Arrhythmias; Cold extremities; sev

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COPD & asthma emergencies Acute management of heart block Maintains bp during spinal anaesthesia Prolongs duration of local anaesthesia by

local vasoconstrictn Glaucoma (↓ aq humour production)

mins Hypertension (overdose) Cerebral haemorhage & Pul oedema

↓ed & thickened Mucous secretions (dry mouth)

Tremor (skeletal muscle)

Phenylephrine

α1 selective (α1>>α2>>>β1/β2)

Related to adrenaline Vasoconstrictor – stop superficial bleeding from skin & mucous membranes hypertension & reflex ↓ in heart rate

Mydriatic (eye drops) Nasal decongestant (nose drops; oral

administration) via vasoconstrictn

RoA – iv, oral or nasal drops More resistant to COMT but not

MAO

Clonidine

α2 selective(α2>>α1>>>β1/2)

↓es symp tone via:o α2 adrenoceptor mediated pre-synaptic inhibition of NA releaseo (in brainstem) baroreceptor pathway to ↓ sympathetic outflow

Treats hypertension & migraine

RoA – iv or oral

Isoprenaline

Non-selective β (i.e.β2/β1)(β1=β2>>>>α1/2)

Heart block (cardiogenic shock or MI) Bronchodilator – asthma but discontinued

due to unwanted actions (reflex tachycardia, dysrhthmias)

RoA – oral; iv; inhalation DoA – t1/2 ≈ 30min Less susceptible to Uptake 1 &

MAO than adrenaline

Dobutamineβ1 selective(β1>>β2>>>α1/2)

Use to treat cardiogenic shock, acute heart failure, MI & heart block

Lacks isoprenaline’s reflex tachycardia

RoA –iv DoA – t1/2 ≈ 2min (rapid

metabolism by COMT)

Salbutamol

Β2 selective(β2>>β1>>>α1/2)

Synthetic catecholamine derivative with relative resistance to MAO & COMT

Asthma – relaxatn of bronchial smooth muscle & inhibitn of release of broncho-constrictor substance from mast cells

Treatment of threatened uncomplicated premature labour

RoA – Asthma (oral; inhalation); Premature Labour (i.v.)

Reflex tachycardia TremorCaution with cardiac patients, hyperthyroidism & diabetes – ↑ed sensitivity to adrenoceptors

Sympathetic Nervous System – Adrenoceptor Agonists – INDIRECTLY ACTING (act at adrenergic nerve terminal NOT receptor)

Cocaine

Local anaesthetic in ophthalmology Readily crosses bld brain barrier (unlike AD & NA)

Degraded by plasma esterases Plasma t1/2 ≈ 30mins Excreted in urine

Euphoria, ↑ed motor activity (CNS effect); may depression

Tachycar, vasoconstrictn, ↑ed bp Tremors & convulsions ( vomit) Resp Failure

Tyramine Competes with catecholamines for Uptake 1, Displaces NA from intracellular storage vesicles into cytosol; NA & tyramine compete for sites

on MAO; cytoplasmic NA leaks through neuronal memb to act at postsynaptic adrenoceptors

Dietary a.a. – cheese, red wine & soya sauce

Hypertensive crisis (when MAO is inhibited)

Sympathetic Nervous System – Adrenoceptor Antagonists

PhentolamineNon-selective α (i.e. α2/α1)

↑ NA release from nerve terminals (α2 actions)

Hypotension (vasodilatn) Reflex tachycardia [due to fall in arterial

pressure (β-receptors)]

No longer clinically used ↑ed GIT motility Diarrhoea

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Doxazosin/ Prazosin α1 selective Does NOT ↑ NA release

from nerve terminals Hypotension (vasodilatn), so ↓ CO ↓ tachycardia (as above) – ↓ NA release ↓in LDL & an ↑in HDL cholesterol

Propranolol

Non-selective β (i.e.β2/β1)

Class II antiarrhythmics Glaucoma ↓ in peripheral resistance ↓ in bp Bradycardia ↓ CO

Very little change in cardiac bp & HR but very effective as antiarrhythmics

Bronchoconstriction (asthmatics) Cardiac Failure – pts with heart

disease rely on a degree of symp drive to the heart to maintain CO

Hypoglycaemia – symp response to hypoglycaemia useful symptoms in warning diabetic pts (sweating, palpitations, tremor)

Fatigue – ↓ed CO & muscle perfusion

Cold Extremities – loss of β-receptor mediated vasodilatation in cutaneous vessels

Atenolol

β1 selective Angina – stabe, unsablte or variable Hypotension & bradycardia (like

propranolol

LabetololNon-selective α1/β1

(ratio 4:1 for β1: α1) Hypotension by ↓ peripheral resistance No change in heart rate

Sympathetic Nervous System – False Transmitters

Methyldopa

1. Taken up by NA neurones2. Decarboxylated & hydroxylated to form

false transmitter, α-methyl-NA3. Not deaminated by MAO, so accumulates: Less active than NA on α1-receptors More active on presynaptic (a2) receptors

(auto-inhibitory feedback) CNS effects, stimulates vasopressor centre in

the brain stem to inhibit sympathetic outflow

In hypertensive patients with renal insufficiency or cerebrovascular disease

Hypertensive pregnant women

Rarely used due to side-effects Dry mouth Orthostatic hypotension Sedation Male sexual dysfunction

Neuromuscular Block Drugs – NON-DEPOLARISING (Competitive Nicotinic Antagonists)

Tubocurarine/ Atracurium

4° ammonium compound (alkaloid & is

Competitive nAChR antagonist

70 - 80% block

Flaccid paralysis:o Extrinsic eye muscles (double vision)

RoA – i.v. (highly charged) Does not cross bbb or placenta (so

can be used in caesarean section)

Due to ganglion block & histamine release: Hypotension:

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powerful positive charge)

necessary (all or nothing action)

Graded block = different proportions of fibres blocked

o Small muscles of face, limbs, pharynx

o Respiratory muscles Relaxation of skeletal muscles during

surgical operations esp abdominal muscles (therefore require less anaesthetic so safer)

Permit artificial ventilation

Onset of action: 2-3min (relatively long)

Duration of paralysis: 40-60 min (long)

Not metabolised Excretion: 70% urine; 30% bile

(care if renal or hepatic function impaired)

o Ganglion Blockade (¯ TPR)o Histamine release from mast

cells via H1 receptors Bronchospasm – due to histamine

release Tachycardia: (may arrhythmias) Excessive secretions (bronchial &

salivary) –histamine release Apnoea (always assist respiration)

Neuromuscular Block Drugs – DEPOLARISING (Nicotinic Agonists)

Suxamethonium

Structure similar to ACh (2 ACh bonded together via a acetyl group)

Normally, ACh binds to nicotine receptor opens Na V-gated channels degradation of ACh by acetylcholinesterase

Sux cannot be hydrolysed by acetylcholinesterase but by pseudocholinesterase not degraded prevents muscle cell to ‘reset’ & keeps the new restign potential below threshold muscle fasiculations

Anaesthesia – allow intubation of the trachea or to maintain relaxation for short surgical procedures

RoA – i.v. Onset of action: immediate Duration of paralysis: 5-10 min

(short) Not metabolised Excretion: 10% urine; 80% bile

Hyperkalaemia Bradycardia Raised intracranial & intraocular

pressure Muscle pain due to fasiculations

Drugs & the HeartAtenolol Beta-blocker for

1. NEGATIVE CHRONOTOPE & IONOTROPE

Competitive antagonists for mainly 1 adrenoceptors

reductn in CO, renin

Angina & improves survival post MI Cardiac dysrhythmias Heart failure Thyrotoxicosis

No longer 1st line for hypertension in UK

Do NOT ↓peripheral resistance (PVR) (except partial agonists or

Due to actions on beta1 (& sometimes beta2 receptors):

Bronchoconstriction Cardiac failure & Heart block

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2. CONTROL or CORRECT DYSRHYTHMIA

release & NA release by symp nerves

Glaucoma Anxiety states Migraine

vasodilatory beta blockers) Bradycardia Fatigue Cold extremities Exacerbation of arterial disease Hypoglycaemia in diabetics taking

insulin

Nicorandil

Organic nitrate for REDUCING PRELOAD

Drug release NO from endothemium

Stimulating guanylate cyclase

Formation of cyclic GMP

relaxing smooth muscle in veins

↓ing venous return

Venodilators (if dilatn of coronary arteries have reached max) of veins ↓ preload

Coronary artery vasodilators – potassium channel openers used in angina (e.g. nicorandil) open KATP channels & also act as nitric oxide (NO) donors

Angina Antiplatelet agents Acute & chronic heart failure BP control during anaesthesia

Nitrates undergo extensive ‘first pass’ metabolism by the liver

Long acting forms of nitrate (e.g. isosorbide mononitrate, or glyceryl trinitrate via a transdermal patch) are available for sustained actions

Glyceryl trinitrate is often given sublingually for rapid relief of angina – has a short t1/2 ≈ 30mins

Hypotension Headaches Flushing (due to vasodilation)Excessive/prolonged use of nitrates is associated with tolerance – avoided by eccentric (asymmetric) dosing

Glyceryl Trinitrate

Organic nitrate for CORONARY VASODILATORS

Isosorbide mononitrate Organic nitrate

VerapamilRate-limiting Calcium channel blockers for CORONARY VASODILATORS (acting on afterload)

cardiac & smooth muscle actions

↓ Ca2+ entry in cardiac & smooth muscle cells

Negative inotropic effect (verapamil > diltiazem, not dihydropyridines)

Inhibit AV node conduction (verapamil)

Angina Hypertension (mainly dihydropyridines) Verapamil is used to treat paroxysmal SVT

& atrial fibrillation

PHENYLALKYLAMINES Bradycardia AV block Worsening of heart failure ConstipationDiltiazem BENZOTHIAZEPINES

Amlodopine

only smooth muscle actions

Only inhibit Ca2+ entry in smooth muscle cells

DIHYDROPYRIDINES Ankle oedema Headache/Flushing Palpitations

Adenosine

Antidysrhythmic Produced by the metabolism of ATP

Acts on adenosine (A1) receptors to hyperpolarize cardiac tissue & slow conductn through AV node

Terminate superventricular tachyarrhythmias (SVT)

Iv actions are short-lived (20-30s) &

it is consequently safer than verapamil

Chest pain Shortness of breath Dizziness Nausea

Amiodarone

Antidysrhythmic Momplex action –multiple ion channel block

Useful for a number of superventricular and ventricular tachyarrhythmias

Accumulates in the body (t½ = 10 - 100days)

Photosensitive skin rashes Hypo- or hyper-thyroidism Pulmonary fibrosis Corneal deposits Neurological & GI disturbances

Digoxin (Cardiac Glycosides)

Antidysrhythmic Inhibits Na-K-ATPase (Na/K pump) ↑ed accumulation of intracellular Na+ ↑es intracellular Ca2+ via Na+/Ca2+ exchange

Slows ventricular rate in atrial fibrillation & relieves symptoms in chronic heart failure

Cardiac Effects:o Cardiac slowing & ↓ed rate of

conductn through the AV node (due

Dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)

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Central vagal stimulation ↓ed rate of conduction through the AV node

to central vagal stimulation)o ↑ed force of contractiono Disturbances of rhythm especially:

block of AV conduction & ↑ed ectopic pacemaker activity

IvabradineAntidysrhythmic Blocks If channel – a Na/K

channel imp in the sinoatrial node so slows heart rate

Angina in patients in normal sinus rhythm Contraindications: Severe bradycardia/sick sinus syndrome/2-3rd degree heart block; Cardiogenic shock; Recent MI

Bradycardia First-degree heart block Ventricular & SVA

Dobutamineβ1 selective for POSITIVE CHRONOTROPHES

↑es the force of cardiac contraction

Acute heart failure in some situations (e.g. after cardiac surgery or in cardiogenic or septic shock)

Drugs & the Vasculature

EnalaprilACE Inhibitors for REDUCING PRELOAD & AFTERLOAD

Prevent the conversion of angiotensin I to angiotensin II by ACE

Hypertension Heart failure Post-myocardial infarction Diabetic nephropathy Progressive renal insufficiency

Hypotension Angioedema Hyperkalaemia Foetal injury Renal failure in pts with renal

artery stenosisCaptopril

Losartan

Angiotensin Receptor Blockers for REDUCING PRELOAD & AFTERLOAD

At AT1 receptors – preventing the renal & vascular actions of Ang II (agents act as insurmountable)

Hypertension Alternative for ACEI for heart failure

patients who cannot tolerate ACEI

Hypotension Foetal injury Renal failure in patients with renal

artery stenosis

Spirono-lactone

Aldosterone Antagonist for REDUCING PRELOAD & AFTERLOAD

Antagonist of aldosterone – inhibits the sodium retaining effects

Heart failure Resistant cases of hypotension

Hyperkalemia – aldosterone antagonism

Steroid-like effects such as gynaecomastia, menstrual disorders & testicular atrophy

Bendrofluazide

Thiazide Diuretic for REDUCING PRELOAD & AFTERLOAD

Causes a fall in smooth muscle Na+ 2° reduction in Ca2+

Hypertension Heart Failure

Hypokalaemia Diabetes Gout

Doxazosinα-adrenoceptor antagonist for CORONARY VASODILATOR

Specific for alpha1 Postural Hypotension

PhenoxybenzamineNon-selective alpha antagonist Pheochromocytoma Tachycardia

Clonidine/ -methydopa

2-adrenoceptor agonists for VASODILATION

Specific for alpha2 by reducing sympathetic activity

Hypertension

Hydralazine

K+ Channel Openers for CORONARY VASODILATION

Opening ATP-sensitive K+ channels hyperpolarisation closing voltage-sensitive

Severe Hypertension Used in combination with a beta-blocker & diuretic

Reflex tachycardia angina, headaches & fluid retention

Lupus syndrome fever, malaise & hepatitis

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Ca2+ channelsMinoxidil Severe fluid retention oedema

Sumitriptan

5HT1D receptor Agonist for Vasoconstriction

Vasoconstriction of large arteries & inhibits trigeminal nerve transmission

Migraine attacks Contraindicated in pts with coronary disease as it also causes coronary vasoconstriction

Anti-coagulants, Fibrinolytics & Anti-platelet drugs

Warfarin

Anticoagulant Prevents the activation of vitamin K (an important co-factor in the synthesis of a number of clotting factors (II, VII, IX & X)

Oral, absorbed quickly from GI tract

Binds strongly to plasma proteins (slow turnover of clotting factors)

Metabolised by hepatic mixed function cyt P450

Haemorrhage (especially into the brain or bowel

Teratogenicity (not given to pregnant mothers)

Reversal of effects: vitamin K or prothrombin

Interactions with drugs e.g. drugs which inhibit cyt P450: (will increase plasma conc of warfarin)

Heparin/LMWH

Anticoagulant Activates anti-thrombin III which inhibits factor Xa & thrombin by binding to the active serine sites

Poorly absorbed after oral administration, therefore given either subcut. or intravenously

Short half-life so immediate effect

Bleeding Thrombocytopenia Osteoporosis Hypersensitivity Chills, fever, urticaria, anaphylaxis Reversal of effects: stop heparin

Aspirin

Anti-platelets Irreversibly inhibits COX-1

Inhibits the production Of TXA2 in platelets

Oral Highly plasma protein bound

GI sensitivity

Clopidogrel

Anti-platelets Pro-drug which inhibits fibrinogen binding to glycoprotein IIb/IIIa receptors

Oral Peak plasma conc 4hrs after a

dose but inhibitory effect on platelets not seen until after 4 days of regular dosing

Bleeding (GI haemorrhage) Diarrhoea Rash

Abciximab

Anti-platelets Antagonist of the glycoprotein IIb/IIIa receptor

In acute coronary syndromes – used in combination with heparin & aspirin to prevent ischemia in patients with unstable angina

IV Binds rapidly to platelets Cleared with platelets Effect persists for 24-48hrs

Bleeding (may potentially be immunogenic)

Streptokinase

Thrombolytics (fibrinolytics)

Binds to plasminogen conformational change exposing the active site plasmin activity degrades fibrin

Acute myocardial infarction Acute thrombotic stroke – within 3hrs Deep vein thrombosis; pulmonary

embolus; acute arterial thromboembolism; local thromboembolism in the anterior chamber of the eye

IV 30-60 min infusion Rapidly cleared; t1/212-18 mins

Bleeding (may potentially be antigenic)

Alteplase Thrombolytics (fibrinolytics)

Recombinant tPA Activates plasmin

IV 30min infusion

Bleeding

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degrades fibrin & dissolving the clot

Rapidly cleared; t1/212-18 mins

Statins (& Other LDL Lowering Drugs)

Simvastatin

HMG CoA Reductase Inhibitors

Inhibition of the enzyme leads to ↓ed hepatic cholesterol synthesis

More enzyme tending to restore cholesterol synthesis to normal

Fall in production of cholesterol also induces a compensatory ↑in hepatic LDL receptors which ↑ clearance of cholesterol from the plasma

Non-cholesterol effects of statins include: Increased NO synthesis Inhibition of free radical release Reduced number and activity of

inflammatory cells Inhibition of platelet adhesion and

aggregation together with reduced blood viscosity

Main Uses: Reduce LDL levels & ↓in CHD

(congestive/coronary heart disease) mortality/morbidity

Support treatment in women, elderly & diabetics

Do not work in patients with familial hyperchloesterolamia (who have no LDL receptors)

Doubling the dose of statins only leads to a 6% reduction in LDL

Reduce plasma LDL by 25-35%

Myopathy can occur Contraindication for pregnancy as

cholesterol is essential for normal foetal development

Benzafibrate

Fibrate Act as ligands for the nuclear transcription receptor PPAR-α (peroxisome proliferators-activated receptor alpha) stimulates lipoprotein lipase activity (↑ed hydrolysis)

Produce a moderate decrease in LDL (10%) and moderate increase in HDL (10%) and a marked fall in plasma triglycerides (30%)

First line treatment for people with very high triglyceride levels

Ezetimibe Inhibitors of Intestinal Cholesterol Absorption

Decreases cholesterol by 18% with little change in HDL Needs combination therapy with statins or fibrates

Nicotinic Acid Reduces release of VLDL and so lowers plasma

triglycerides by 30-50% Lowers cholesterol by 10-20% and increases HDL

Number of adverse effects

Colestipol

Anion Exchange Resins Increase the excretion of bile acids more lipids to be converted into bile acids & so ↑ed lipid excretion

Fall in hepatocyte cholesterol concentration ↑ in HMG CoA Reductase & LDL receptors

Adverse effects are confined to the gut as the resins are not absorbed: Bloating Diarrhoea, constipation

NSAIDs (Non-Steroidal Anti-inflammatory Drugs)

Aspirin

Binds irreversibly to cyclo-oxygenase enzymes

Only be reversed by de novo synthesis of new enzyme

Binds 200-fold more avidly to COX-1 than to COX-2

Analgesic, antipyretic & anti-inflammatory actions

Gastric irritation, ulceration, bleeding &, in extreme cases, perforation

Reduced creatinine clearance & possible nephritis

Prolonged bleeding times, due to

UC


reduced platelet aggregation Bronchoconstrction in susceptible

individuals

Ibuprofen

Inhibits COX-1/2 REVERSIBLY

Lowers the pain threshold Pyrogenic – stimulates hypothalamic

neurones initiating a rise in body temperature (therefore, NSAIDS reduce raised temperature)

Enhances production of a number of pro-inflammatory cytokines including Th2 cytokines such as IL4 & IL5

Inhibits the production of others including Th1 cytokines such as IFNγ & IL2

Gastric cytoprotection – downregulates HCl secretion – PGE2 stimulates mucus & bicarbonate secretion (which would otherwise gastric ulceration)

PGE2 enhances renal blood flow and therefore GFR

Celecoxib

Selectively inhibits COX-2 Loss of COX-2 physiological function: Regulation of ovulation Regulation of parturition Renal blood flow Regulation of blood pressure Therefore, increases risk of MI

Paracetamol

It is not a NSAIDs Inhibits peroxidation (conversion of PGG2 PGH2

Good analgesic for mild-to-moderate pain Anti-pyretic action

Paracetamol poisoning – andidote is add a compound with –SH groups (i.v. Acetylcysteine or oral methionine)

Irreversible liver failure (overdose): A reactive metabolite of

paracetamol, (N-acetyl-p-benzoquinoneimine) is normally safely conjugated with glutathione

If glutathione is depleted the metabolite oxidises thiol groups of key hepatic enzymes & causes cell death hepatotoxicity

Inflammatory Bowel Disease

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Prednisolone

GLUCOCORTICOIDS Activate intracellular Glucocorticoid Receptors which can then act as positive or negative transcription

Anti-inflammatory actions of GCs: Reduce influx and activation of pro-

inflammatory cells o Reduce adhesion molecules on

endothelial cells and leukocytes o Reduce synthesis of some chemokines

Reduce production of mediators causing the signs of inflammation by reducing synthesis of:o Some cytokines and their receptors

(such as IL-1 & TNFα)o Proteolytic enzymes (such as elastase)o Enzymes catalysing mediator

synthesis (e.g. cyclo-oxygenase) o Eicosanoids (such as prostaglandins

and leukotrienes) o Nitric oxide

Immunosuppressive actions of GCs: Reduced antigen presentation Reduced production of mediators (e.g. IL-

2, IL-4, IFNg ) resulting in Reduced cell proliferation & clonal

expansion

Osteoporosis Increased risk of Gastric ulceration Suppression of HPA axis Type II diabetes Hypertension Susceptibility to infection Skin thinning, bruising and slow

wound healing Muscle wasting & buffalo hump

Minimising unwanted effects of GCs Start with high dose & taper down Use drug with high therapeutic

index (e.g. fluticasone) Administer topically – fluid or

foam enemas or suppositories Use an oral or topically

administered drug which is degraded locally e.g. budesonide

Fluticasone

Budesonide

Sulfasalazine

AMINO-SALICYLATES ↓ synthesis of

eicosanoids ↓ free radical ↓ cytokines ↓ leukocyte

infiltration No immune-

suppressive effects

Metabolised by colonic flora/liver

Site of Absorption: colon

Mainly used to maintain remission & prevent relapse

Anti-inflammatory

Pharmacokinetics of 5-ASA: Topical delivery (suppositories,

enemas) pH-dependent release capsules

( small intestine) Slow release microspheres (small

and large bowel):o Leads to gradual release of

mesalazine as it travels through the bowel

o 33% released in upper small intestine, remainder in distal ileum and colon

Mesalazine

5-aminosalicylic acid (5-ASA) Metabolised by…? Site of Absorption:

small bowel & colon

Olsalazine

(2 x 5-ASA molecules linked by an azo bond) Metabolised by colonic

flora Site of Absorption:

colonAzathioprine IMMUNO-

SUPPRESSIVE AGENTS

Azathioprine is a pro-drug which is activated in vivo by gut flora to 6-mercaptopurine –

More effective in Crohn’s disease May enable reduction of glucocorticoid

dose or postponement of colostomy May induce remission in some cases of

Bone marrow suppression If administered with drugs which

inhibit xanthine oxidase e.g. allopurinol, a drug used for the

UC


interferes with purine biosynthesis

Interferes with DNA synthesis & cell replication

It impairs: Cell-& antibody-

mediated immune responses

Lymphocyte proliferation

Mononuclear cell infiltration

Synthesis of antibodies It enhances – T-cell apoptosis

active disease treatment of gout, 6 –Mercaptopurine levels rise & blood dyscrasias may result

Infliximab

CURATIVE THERAPY – Anti-TNFα

Crohn’s is a Th1-mediated autoimmune response TNFα plays an important role in disease pathogenesis

Anti-TNFa ↓es activation of TNFα receptors in the gut

Production of other cytokines, infiltration & activation of leukocytes is reduced

Also binds to membrane associated TNFα

Mediates complement activation & induces cytolysis of cells expressing TNFα

Promotes apoptosis of activated T cells

Given intravenously Very long half-life (9.5 days) Benefits can last for 30 weeks after a single

infusion Most patients relapse after 8 – 12 weeks Therefore repeat infusion every 8 weeks

4x - 5x increase in incidence of tuberculosis & other infections

Increased risk of septicaemia, therefore can’t be used if abcess

Worsening of heart failure Increased risk of demyelinating disease Increased risk of malignancy Can be immunogenic – therefore given

with azathioprine

Diuretics – drugs that act on the renal tubule to promote the excretion of Na+, Cl- & H2O

Mannitol

Osmotic Diuretic ¯ H2O reabsorption / H2O excretion (Small ↑ in Na+/Cl- loss)

Prevent acute renal failure – H2O excretion

Intra-cranial pressure plasma osmolarity

Intra-ocular pressure plasma osmolarity

Given iv Onset – 0.5hr DoA: 2-3hr Excretion – glomelular filtrate

Water/electrolyte imbalance – Dehydration/Hypernatraemia

ECF volume – Hyponatraemia; (nausea, vomiting, pulmonary oedema)

Acetazolamide Carbonic anhydrase inhibitors

Prevent the reabsorption of HCO3

- and Na+

o H2O reabsorption is therefore reduced

Intra-ocular pressure (glaucoma) Renal stones – Uric Acid Metabolic Alkalosis – HCO3

- loss

Given oral Onset – 0.5hr DoA: 12hr Excretion – tubular secretion

K+ loss – Balance HCO3- in

collecting duct Metabolic acidosis

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o delivery of HCO3- to

distal tubule K+ loss tubular fluid

osmolarity ¯ H2O reabsorption in the collecting duct

( Na+/ K+/ HCO3- loss)

Furosemide

Loop diuretics Inhibit Na+ and Cl-

reabsorption in ascending limb

tubular fluid osmolarity/ ¯ osmolarity of medullary interstitium = ¯ H2O reabsorption in the collecting duct

Large in urine volume and Na+, Cl- & K+ loss (& Ca2+ & Mg2+ loss)

Acute pulmonary oedema – Heart failure, pulmonary, renal, hepatic, cerebral

Acute renal failure Hypercalcaemia Hyperkalaemia

Given oral Onset – 1hr DoA: 4-6hr Excretion – tubular secretionN.B. 50% unchanged, 50% metabolised

Hypovolaemia & Hypotension K+ loss (Ca2+/Mg2+), Metabolic

Alkalosis

Bendrofluazide

Thiazides Inhibit Na+ and Cl-

reabsorption in early distil tubule

delivery of Na+ to collecting duct activates N+/K+ exchange mechanism ↓es water reabsorption urine volume is increase [ K+ loss ( Na+/K+ exch)]

Moderate in urine volume & Na+, Cl- , K+ & Mg2+ (but reduced loss of Ca)

Cardiac Heart failure Hypertension – initially ¯ blood

volume/long-term = vasodilation Severe resistant oedema Idiopathic hypercalciuria – stone

formation Nephrogenic diabetes insipidus

(paradoxical)

Given oral Onset – 1-2hr DoA: 8-12hr Excretion – tubular secretionN.B. competes with uric acid

K+ loss, Metabolic Alkalosis Diabetes Mellitus – Inhibits insulin

secretion

Spironolactone

Potassium sparing diuretics

Block aldosterone receptors

Block of Na+/K+ exchange– ↑ed Na+ & ↓ed K+ loss

Small ↑in urine

Primary & secondary hyperaldosteronism Given oral Onset – days DoA: canrenone Excretion – glomeular filtrateN.B. competes with uric acid

Hyperkalaemia, Metabolic Acidosis Spironolactone – Gynaecomastia,

Menstrual Disorders, Testicular Atrophy

AmilorideNa channel blockade

With K+ losing diuretics to prevent K+ loss Given oral Onset – 6hr DoA: 24hr

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volume Excretion – tubular secretionN.B. unchanged with urine

Anti-emetics – treatment for nausea & vomiting

Promethazine

Phenothiazine derivative

Competitive antagonist at histaminergic (type H1), cholinergic (muscarinic, M) & dopaminergic (type D2) receptors: H1> M > D2

Acts centrally (labyrinth, NTS, vomiting centre) to block vomiting centre

Motion sickness Disorders of the labyrinth e.g Meniere’s

disease Hyperemesis gravidarium Pre- & post-operatively (sedative & anti-

muscarinic action are also useful)Other uses: Relief of allergic symptoms Anaphylactic emergency Night sedation; insomnia

Administer orally Onset of action 1-2 hours Maximum effect circa 4 hours Duration of action 24 hours

Dizziness Tinnitus Fatigue Sedation Excitation in excess Convulsions (children more

susceptible) Antimuscarininc side-effects

Metoclopramide

Dopamine receptor antagonist

Order of antagonistic potency: D2 >> H1 >>> Muscarinic receptors

Acts centrally (CTZ) Acts in the GI tracto ↑es smooth muscle

motilityo ↑ed GI emptying

Uraemia (severe renal failure) Radiation sickness Gastrointestinal disorders Cancer chemotherapy (high doses) e.g.

Cisplatin (intractable vomiting)

May be administered orally; rapidly absorbed; extensive first pass metabolism

May also be given i.v. Crosses BBB Crosses placenta

In CNS: Drowsiness; Dizziness; Anxiety Extrapyramidal reactions;

(parkinsonian-like syndrome: rigidity, tremor)

In the endocrine system: Hyperprolactinaemia Galactorrhoea Disorders of menstruation

Hyoscine

Anti-muscarinic Antagonistic: musc. >>>D2 = H1 receptors

Acts centrally (vestibular nuclei, NTS, vomiting centre) to block activation of vomiting centre

Prevention of motion sickness Has little effects once nausea/emesis is

established In operative pre-medication

Can be administered orally (peak effect in 1-2 hours), i.v., transdermally

Drowsiness Dry mouth Cycloplegia Mydriasis Constipation

Ondansetron

5HT3 receptor antagonist

Block transmission in visceral afferents & CTZ

Main use in preventing anticancer drug-induced vomiting, especially cisplatin

Radiotherapy-induced sickness Post-operative nausea & vomiting

Administer orally; well absorbed, excreted in urine

Headache Sensation of flushing and warmth ↑ed large bowel transit time

(constipation)Treatment of Gastric & Duodenal Ulcers

MetronidazoleAntibiotics for treatment of Helicobacter pylori

Active against anaerobic bacteria & protozoa

Used in combination with “triple therapy” 1st Example:

o Metronidazole or amoxycillino Clarithromycino Proton pump inhibitor, PPI

(omeprazole)

Compliance Development of resistance Adverse response to alcohol,

especially with metronidazole (interferes with alcohol metabolism) Amoxycillin

Broad spectrum antibiotic

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2nd Example:o H2 receptor antagonistso Clarithromycin o Bismuth

Clarithromycin

Macrolide structure – inhibits translocation of bacterial tRNA

Omeprazole

Inhibitors of Gastric Acid secretion

PPIs: Inhibit gastric acid

secretion from the parietal cell by >90%

Irreversible inhibitors of H+/K+ ATPase

Accumulates in cannaliculi of parietal cells & prolongs its DoA (2-3 days)

Component of triple therapy Peptic ulcers resistant to H2 antagonists Reflux oesophagitis

Orally active Administered as enteric coated

slow-release formulations

(rare)

Ranitidine HISTAMINE TYPE 2 (H2) R ANTAGONISTS – inhibit gastric acid secretion

Healing ulcers (although less effective than PPIs)

Orally administered Well absorbed

Rare (relapses likely after withdrawal of treatment)

Cimetidine

Sucralfate

CYTOPROTECTIVE DRUGS – enhance mucosal protection mechanisms and/or build a physical barrier over the ulcer

Polymer containing aluminium hydroxide & sucrose octa-sulphate Acquires a strong negative charge in an acid environment Binds to positively charged groups in large molecules These coat & protect the ulcer, limit H+ diffusion and pepsin

degradation of mucus Increases PG, mucus & HCO3

- secretion & ↓the number of H. pylori

Most of orally administered drug remains in GI

May cause constipation Reduces absorption of some other

drugs (e.g. antibiotics and digoxin)

Bismuth chelate Like sucralfate Used in triple therapy (resistant cases)

Misoprostol

Stable prostaglandin analogue – mimics the action of locally produced PG to maintain the GI mucosal barrier

May be co-prescribed with oral NSAIDs when used chronically NSAIDs block the COX enzyme for PG synthesis from arachidonic acid Therefore, there is a reduction in the natural factors that inhibit gastric

acid secretion & stimulate mucus & HCO3- production

Diarrhoea, abdominal cramps, uterine contractions

Caution in pregnancy

“Ant-acids” Mainly salts of Al3+

& Mg2+

Neutralises acid, ↑ gastric pH, ↓ pepsin activity

Primarlity used in non-ulcer dyspepsia Reducing duodenal ulcer recurrence rates

Treatment of Gastro-Oesophageal Reflux Disease (GORD) – treat with PPIs (drugs of choice) or H2 antagonists (less effective) &c ombine with drugs that increase gastric motility & emptying of the stomach e.g. DA2 receptor antagonists (metoclopramide)Anxiolytics & Sedatives/Hypnotics

Sodium Valporate

Anti-compulsive; Anti-epileptic (very useful in seizures)

Vigabatrin Selective GABA-T inhibitorGABA GABAA receptor

agonistsMuscimol Selective GABAA receptor

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Bicuculline GABAA receptor antagonists

CompetitivePicrotoxin Non-competetive) – blocks flow of Cl- ions

GABA GABAB receptor agonistsBaclofen Muscle relaxant in sp. cord & spasmolytic drug

Phaclofen GABAB receptor antagonistsSaclofen Competitive

Diazepam

Anxioltyics Benzodiazepines Bind to GABAA receptor Cl- influx

hyperpolarisation ↑ frequency of

openings of channels

Long-acting anxiolytic Anti-convulsants Anti-spastics

Administration: Well absorbed P.O. Peak [plasma] = 1hr I.v. versus status epilepticus Distribution: Bind to plasma proteins strongly Highly lipid soluble wide

distributionMetabolism – extensive in the liver: Diazepam – t1/2 = 32hr Oxazepan – t1/2 = 8hrExcretion – urine – glucoronide conjugatesDuration of Action (vary): short/long

Sedation, confusion, ataxia (impaired manual skills)

Potentiate other CNS depressants (alcohol, barbs)

Tolerance (less than BARBs; ‘tissue’ only)

Dependence: withdrawal syndrome similar to BARBs (lessintense) so imp. to withdraw slowly

free [plasma] by e.g. aspirin, heparin

Oxazepam

Long-acting anxiolytic – if there is hepatic impairment

Short-acting sedative/hypnotics

Buspirone 5HT1A agonist Anxiolytic Slow onset of action (days/weeks) Few side-effects

Propranolol Non-selective β-blocker Improves physical symptoms – tachycardia (β1) or tremor (β2)

Temazepam/Clonazepam

Sedatives/Hypnotics

Benzodiazepines (above) Short-acting sedative/hypnotics Anti-convulsants

(see above for Benzodiazepines) Temazepam – t1/2 = 8hr

(see above for Benzodiazepines)

Amobarbitol/Phenobarbitol

Barbiturates Bind to GABAA receptor Cl- influx

hyperpolarisation ↑ duration of openings

of channels

General Anaethetics Anti-convulsants – Phenobarbitol Sedatives/Hypnotics – Amobarbitol

Amobarbitol – t1/2 = 20-25hr Low safety margins: (↓ respiration or overdosing – alkaline dieresis)

Alter natural sleep (¯ REM) Enzyme inducers Potentiate depressants (alcohol) Dependence: withdrawal

syndrome insomnia, anxietyChloral Hydrate Liver conversion trichloroethanol (a BARB) Wide margin of safety – in children & elderly

Antiparkinsonian/NeurolepticsL-DOPA Ant-Parkinson’s

Disease DOPA – precursor to

dopamine, converted to dopamine in brain

DOPA decarboxylase also present in peripheral tissues

Parkinson’s Disease Rigidity – stiffness, limbs feel heavy/weak Bradykinesia – slowness of movement Postural abnormality Pill-rolling rest tremor Difficulty with fine movements –

Acute: Nausea – prevented by Doperidone (peripheral acting antagonist) Hypotension Psychological effects – schizophrenia like syndrome with delusions,

hallucinations, also confusion, disorientation & nightmares Chronic:

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cause side effects of nausea & vomiting

macrophagia Monotomy of speech & loss of volume of

voice Disorders of posture – flexion of the neck

& trunk Lack of arm swing Loss of balance – lack of righting reflex,

retropulsion Short steps, shuffling gait

Dyskinesias (54%) – abnormal movements, which affect the face & limbs On-off oscilations (64%) – rapid fluctuations in clinical state, where

hypokinesia & rigidity may suddenly worsen

Bromocriptine D2 Receptors Longer DoA of L-DOPA

Common – confusion, dizziness, nausea/vomiting Rare – constipation, headache, dyskinesias, drowsiness & hallucinations

Carbidopa DOPA decarboxylase

inhibitor Combination of L-DOPA

Prevent DOPA decarboxylase for converting DOPA dopamine side-effects (nausea & vomiting)

Tolocapone/Entacapone

COMT Inhibitors Tolocapone = CNS & peripheral Entacapone =peripheralCNS – prevents breakdown of dopamine Peripheral – COMT inhibitors stop 3-OMD formation, ↑ing bioavailability L-DOPA

Deprenyl MAO Inhibitors – selective for MAO-B,

In early stages of the disease or with L-DOPA, ↓ the dose of L-DOPA

Rare – hypotension, nausea/ vomiting, confusion & agitation

Chlorpromazine Schizophrenia – neuroleptics

All mentioned in the drugs table but NO information givenHaloperidol

Sulpiride

Clozapine

Antagonists to D2 receptors

Clozapine shows non-selectivity with D1 or D2

Block other receptors 5-HT

Schizophrenia Positive symptoms – delusions,

hallucinations, thought disorders Negative symptoms – withdrawal,

flattening of emotional responses Drugs tend to treat the positive

symptoms – neuroleptics are D2 antagonists correcting the over activity of dopamine in the mesolimbic system & striatum

No effect on the forebrain where negative symptoms are produced

Anti-emetic effect: Blocking dopamine receptors in the chemoreceptor trigger zone Phenothiazine , effective at controlling vomiting & nausea induced by drugs Many neuroleptics also have blocking action at histamine receptors –

effective at controlling motion sicknessExtrapyramidal side effects – blockade of dopamine receptors in the nigrostriatal system can induce “Parkinson” like side effects dyskinesisDyskinesias:Endocrine Effects: DA is involved in Tuberoinfundibular system – regulated prolactin secretion Neuroleptics increase serum prolactin concentrations which can lead to

breast swelling (men & women) and sometimes lactation in womenBlockade of cholinergic muscarinic receptors – typical peripheral anti-muscarinic side effects e.g. blurring vision, ↑ed intra-ocular pressure, dry mouth, constipation, urinary retention

General Anaesthetics

Propofol

Intravenous G.A. Potentiate GABAA receptor function

Activation ↑ed inhibitory effect of GABAA receptor ↑ed Cl- into other

Has many different subunits: Β3 – suppression of reflex responses α5 – amnesia

Loss of consciousness at low concn – (e.g. isoflurane - 100μM)o Depress excitability of thalamo-

cortical neuronso Influences reticular active

neurons i.e. Reticular Formatn

INHALATION ANAESTHETIC – given for maintenance of anaesthesia Rapidly eliminated Rapidly control of depth of

anaesthesiaEtomidate

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neurones hyperpolarisation of nerves around their de-activation

Suppressn of reflexes at high concn – (e.g. isoflurane - 300μM)o Depression of reflex pathways

in the sp cord Relief of pain (analgesia) – opioid

(e.g. i.v. fentanyl)o Synaptic transmission in

hippocampus (new memory formation)/amygdala

Muscle relaxation – Neuro-mus blocking drugs (e.g. suxamethonm)

Amnesia – Benzodiazepines (e.g. i.v. midazolam)

Nitrous OxideInhalation G.A. Poteniate GABAA receptor function (and glycine receptors)

Nitric oxide – Reduced NMDA receptor function (altered synaptic function) – least toxic but least potent (for children)

Inhibits nicotinic acetylcholine receptors (altered synaptic function) – for amnesia & relief of pain

Facilitate TREK (background leak) potassium channel opening (reduced neuronal excitability) – slow hyperpolarisation – for suppression of reflex responses

INTRAVENOUS ANAESTHETIC – given for initiation of anaesthesia Fast Induction Less coughing/excitatory

phenomenaHalothane

Enflurane

Local Anaesthetics

Lidocaine

Amide L.A.

N.B.All L.A. have aromatic region; basic amide side chain; ester or amide bond

Bock of voltage-sensitive Na+ channels in sensory neurones

Use dependant – more L.A used more effect

May also influence:oChannel gating – bind

in the inactivated state ↑ed effect

oLowers surface tensn Block nocioceptor –

small diameter fibres & non-myelinated fibres

Are weak bases Infected Tissue: is

acidic ↑ ionisatn less effect of L.A. (cannot cross memb)

Surface Anaesthesia: Spray or powder via mucosal surface – e.g. mouth, eye, brachial tree High concentrations needed for effect – risks systemic toxicity in high concnInfiltration Anaesthesia: Directly into tissues and sensory nerve fibres (subcutaneous) Used in minor surgery (e.g. removal of cysts) Adrenaline co-injection (not in extremities) causes vasoconstriction ↓ diffusion

away from target site – ↑ DoA & ↓ systemic toxicity & ↓ chances of bleedingIV Regional Anaesthesia: IV given distal to pressure cuff to prevent systemic toxicity (used in limb surgery) Systemic toxicity can occur is the pressure cuff is released prematurelyNerve Block Anaesthesia: Injected close to nerve roots – e.g. in dental surgery (slow onset, low dose) Vasoconstriction co-injection can also be givenSpinal Anaesthesia: (intra-thecal) & can be combined with glucose Used in abdominal, pelvic and lower limb surgery (L3-L4) ↓ BP due to blockade of pre-ganglionic sympathetic fibres prolonged headacheEpidural Anaesthesia: No side-effects of before (i.e. no hypotension & headaches) Injected into the fatty tissue of the epidural space to target the spinal roots For painless childbirth, abd, pelvic & lower leg surgery; slower onset & higher dose

CNS: restlessness, confusion, tremorCVS (Na blockade): v.dilation; ↓ bp

CocaineEster L.A. (symp actions)

CNS: euphoria; excitationCVS: ↑ CO; v.constriction; ↑ bp

Anti-ConvulsantsPhenytoin Interaction with

voltage-dependant sodium channels (inhibit firing) – phenytoin,

Partial epilepsy & acts via blockade of voltage gated Na channels

Pharmacokinetics: Half life 12-40+ hrs with large inter-individual variation (one daily dosage) Hepatic metabolism, hydroxylation and conjugation; excretion in the urine Highly protein bound (70-90%), can be displaced Start with low dose and increase with small increments until desired doseDrug Interactions:

Ataxia Dizziness Sedation Hypersensitivity reactions Fever Folate deficiency

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PropertyLocal Anaesthetic

Lidocaine (amide)

Cocaine (ester)

Absoprtion (mucus

membranes)

GoodUsed mostly for surface anaesthesia& used for all ROA’s

GoodOnly used as a surface anaesthetic

Protein Binding 70% 90%

Metabolism

Hepatic N-dealkylationAmides are slowly

Liver & plasma via non specific esterases

Plasma t1/2 2hrs 1hr

carbamzepine, sodium valporate

Direct/indirect enhancement of GABA mediated transmission (inhibition) – vigabatrin

Interaction with neuronal calcium channels

Blocking receptors for excitatory neuro-transmitters (glutamate mediated)

Aspirin and valoprate displaces Phenytoin from plasma proteins Causes initial increase in anticoagulation followed by decrease with warfarin Oestrogen containing COCP’s (combined oral contraceptive pill) ↓Phenytoin

efficacy P450 enzyme inducer

Depression

Carbamzepine

Partial and secondary generalised seizures by blockade of Na voltage sensitive channels

Pharmacokinetics: Long half life of 36hrs initially decreasing to 20hrs with chronic treatment 3x daily dosing Hepatic oxidation and conjugation Potent enzyme inducer – complex drug interactionsDrug Interactions: Susceptible to auto-induction with metabolism by hepatic enzymes (P450) Macrolide antibiotics (e.g. erythromycin) inhibit metabolism Ca channel blockers (e.g. verapamil) can double carbamezapine levels Phenytoin induces carbamezapine induction

Ataxia Dizziness Sedation Hypersensitivity reactions Depression

Sodium Valporate

(wide-spectrum) Partial & generalised epilepsy & acts via blockade of Na voltage sensitive channels & enhances GABA mediated inhibition

Pharmacokinetics: T1/2 = 9-18hrs Hepatic oxidation and conjugation – not metabolised by P450 Potent hepatic enzyme inhibitorA potent inhibitor of both oxidation and glucornidation

Sever hepatic toxicity –in children Pancreatitis Drowsiness Encephalopathy Tremor Weight gain

VigabatrinEnhancement of GABA mediated transmission – RARELY used

Relatively short half life (6-8h) but duration of action longer Retinopathy

Lamotrigine

(wide-spectrum) Partial & generalised epilepsy & acts via blockade of Na voltage sensitive channels

Pharmacokinetics: 29hr t1/2, 15hrs with enzyme inducing co-medication, 60hrs with valporate co-

administration Hepatic conjugation (no phase I metabolism) – inhibited by valporate 2% risk of hypersensitivity reaction, otherwise well tolderatedDrug Interactions COCP can lower levels by 1/3 Important drug interactions with valporate and other enzyme inducers (e.g.

Phenytoin)

Mostly dose dependant Dizziness Sedation Diplopia Ataxia

Anti-Microbial Drugs – Antibiotics

Sulpha-methoxazole

ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OR ACTION OF FOLATE – SULPHONAMIDES

Sulphanilamide is a structural analogue of P-aminobenzoic acid & competes for dihydropteroate, in the synthesis of folate

Bacteriostatic

Give rise to several other drugs e.g. diuretics – thiazides

Readily absorbed in the GI tract and maximum plasma concn is reached within 4-6 hours

Mild/moderate: (do not warrant withdrawal) nausea & vomiting, headache, mental depression.

Severe: (warrant withdrawal) hepatitis, hypersensitivity reactions, bone marrow suppression

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Trimethoprim

ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OR ACTION OF FOLATE – FOLATE ANTAGONISTS

Folate is utilised in tetrahydrofolate by the enzyme dihydrofolate reductase as a co-factor in thymidylate synthesis (purines & pyramidines)

Dihydrofolate reductase is more sensitive to drug trimethoprim in bacteria

Urinary & Resp Infections Oral administration – fully absorbed from the GI tract

Widely distributed throughout the tissues and body fluids – high concentrations in the lungs and kidney

Nausea/vomiting & skin rashes

Co-trimoxazole

ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OR ACTION OF FOLATE – SEQUENTIAL BLOCKADE (combination of sulphamethoxazole &trimethoprim)

Infections with pneumocystis carinii, which causes pneumonia in patients with AIDS

Two-thirds of each drug is protein bound & about half of each is excreted within 24 hours

Hypersensitivity Reactions

Penicillin

ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OF PEPTIDOGLYCAN – β-LACTAM ANTIBIOTICS

Penicillin is composed of a 6-aminopenillanic acid, which consists of a thiazolidine ring linked to a β-lactam ring

Interfere with the synthesis of the bacterial wall peptidoglycan Inhibis transpeptidation enzyme that cross-links peptide chains

attached to the backbone of the peptidoglycan

RESISTANCE Production of β-lactamases (bacteria) – solution: β-lactamase inhibitors ↓ in permeability of the outer membrane decreasing ability of the

drug to penetrate to the target site. Occurrence of modified penicillin-binding sites

Orally Drugs are widely distributed in the

body fluids, passing into joints, pleural & pericardial cavities, into bile, saliva, milk & across placenta

Lipid insoluble – do not cross bbb unless meninges are inflamed

Renal excretion (tubular secretion)

Hypersensitivity reactions – breakdown products of penicillin combine with host protein and become antigenic (skin rashes & fever acute anaphylactic shock)

Gut bacterial flora resulting in GI tract disturbances

Cefotaxime

ANTIBACTERIAL AGENTS WHICH INTERFERE WITH THE SYNTHESIS OF PEPTIDOGLYCAN – CEPHALOSPORINS

(same as penicillin)

RESISTANCE All Gram -ve bacteria have the gene encoding for β-lactamase ↓ed penetration of drug – alterations to outer membrane proteins or

mutations of the binding site proteins

Given parenterally, i.m. or i.v. Widely distributed in the body as

before but can cross the bbb – useful for bacterial meningitis

Excretion is via the kidney (tubular secretion) but some by bile

Hypersensitivity reactions (very similar to penicillin) may be seen

Nephrotoxicity & diarrhoea can occur with oral cephalosprins

Tetracyclin

ANTIBACTERIAL AGENTS AFFECTING BACTERIAL PROTEIN SYNTHESIS

Active transported into bacteria and interrupt protein synthesis

Competition with tRNA for the A binding site

Bacteriostatic, not bactericidal

Used to prevent gram +ve & -ve bacteria

RESISTANCE Development of energy-dependent efflux

mechanisms which transport the tetracycline’s out of the bacterium

Alterations of the target, the bacterial ribosome, can occur)

Orally or parenterally Tetracycline’s chelate metal ions

(e.g. iron) – non-absorbable complex

Wide distribution, entering most fluid compartments

Excretion via the bile & by glomerular filtration in the kidney

GI disturbances (direct irritation and later to modification of the gut flora)

They chelate calcium, tetracycline’s are deposited in growing bones & teeth staining & bone deformities

Chloramphenicol Inhibition of protein Bacteriostatic – Gram -ve and Gram +ve Given orally or parenterally – Depression of the bone marrow

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synthesis – binds to 50S subunit of the ribosome & inhibits transpeptidation

bacteria

RESISTANCEProduction of chloramphenicol acetyl-transferase (plasmid mediated)

reaches max cocn in 2 hrs Widely distributed in tissues &

body fluids including the CSF 30-50% plasma protein bound its

half life is approximately 2 hours 10% is excreted in the urine, and

remainder is inactivated by liver

pancytopenia New borns ‘grey-baby

syndrome’(vomiting, diarrhoea, flaccidity)

Hypersensititvity rxns GI disturbances – disruptions in

gut flora

Gentamycin

Inhibition of protein synthesis by binding to the 30S subunit of the ribosome alteration in codon:anticodon recognition misreading of the mRNA production of defective bacterial proteins

Effect is bactericidal; enhanced by agents that interfere with cell wall synthesis

Effective against many aerobic Gram -ve and some Gram +ve bacteria – given with penicillin in infections by Streptococcus, Listeria or Pseudomonas aeruginosa

RESISTANCE Inactivation by microbial enzymes, the

genes for which are carried on plasmids Failure of penetration Lack of binding due to mutations that

alter the binding-site on the 30S subunit

Given i.m. or i.v. – bnding to plasma proteins is minimal

The aminoglycosides are polycations & highly polar – not absorbed in the GI tract

They do not enter cells, nor cross the BBB into the CNS (plasma half life 2-3 hours)

Elimination is virtually entirely by glomerular filtration in the kidney

Ototoxicity – progressive damage to and destruction of sensory cells in the cochlea & vestibular organ of ear

Nephrotoxicity – damage to the kidney tubules (can be reversed if the use of the drug is stopped)

Isoniazid

ANTI-MYCOBACTERIAL AGENTS for tuberculosis & leprosy

Limited to mycobacteria – passes freely into mammalian cells & is thus effective against intracellular organisms (evidence suggests that it inhibits the synthesis of mycolicacids, important constituents of the cell wall and peculiar to mycobacteria)

Bacteriostatic

Absorbed from the GI tract or after parenteral injection (widely distributed throughout the tissues & body fluids, including the CSF)

Penetrates well into the necrotic tuberculous lesion Metabolism, involves largely acetylation, depends on genetic factors –

slow/fast

RifampicinBinds & inhibits DNA-dependent RNA polymerase in prokaryotic but not eukaryotic cells

Orally (widely distributed) Excretion – Urine & bile

(enterohepatic cycling)

Infrequent – skin eruptions, fever, GI disturbances

Pyrazinamide

Effective against the intracellular organism in macrophages, since after phagocytosis the organism will be contained in phagolysosomes in which the pH is low

Oral admin (wel absorbed) Widely distributed (meninges) Renal excretion by glomerular

filtration

Arthralgia GI tract upsets; malaise & fever

Anti-Microbial Drugs – Antifungal

Nystatin

Polyene macrolide – no absorption from the mucous membranes of the body or from skin

Binds to memb & interferes with perme and transport functions

Forms a pore in memb creating trans-membrane ion channel

Fungal infections of the skin and GI tract Drugs greater avidity for ergosterol (fungal membrane sterol) than for cholesterol, the main sterol in the plasma membrane in animal cells

Rare – nausea & vomiting

Miconazole Azole group of synthetic antimycotic agents

Azoles block the synthesis of ergosterol (main sterol in the fungal cell membrane, by interacting with the enzyme necessary for the conversion of lanosterol to ergosterol)

I.v. infusion for systemic infections and orally for infections of the GI tract

GI tract disturbances & blood dyscrasias

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Resulting depletion of ergosterol alters fluidity of the membrane and interferes with action of membrane associated enzymes

The overall effect is an inhibition of replication & inhibition of the transformation of candidal yeast cells into hyphae – the invasive and pathogenic form of the parasite

Short plasma half life and needs to be given every 8 hours

Anti-Microbial Drugs – Antiviral

Acyclovir

Guanosine derivative

Acyclovir is converted to monophosphate by thymidine kinase –virus carries out phosphor-ylation

Converted to the triphosphate by host cellthymadine kinases

Acyclovir triphosphate inhibits viral DNA-polymerase, terminating the chain

High specificity for herpes simplex (which cause glandular fever or shingles)

Acyclovir has reproducible effect against cytomegalovirus (CMV) which can cause glandular fever in adults or severe disease e.g. retinis, resulting in blindness in individuals with AIDS

RESISTANCEdue to changes in the viral genes coding for thymidine kinase or DNA ( pneumonia, encephalitis in immunocompromised pts)

Acyclovir triphosphate is fairly rapidly broken down within the host cells by cellular phosphatases

Given orally, i.v and topically The drug is widely distributed,

reaching concentrations in the CSF which are 50% of those in the plasma

It is excreted in the kidneys partly by glomerular filtration and partly by tubular secretion

Local inflammation can occur during i.v. injection

Renal dysfunction has been reported when acyclovir is given i.v.; slow infusion reduces the risk

Zidovudine (azidothymidine,

AZT)

Thymadine analogue

Phosphorylated to triphosphate form competes with triphosphates (essential for formation of proviral DNA by viral reverse transcriptase, viral RNA-dependant DNA polymerase)

Its incorporation into the growing viral DNA strand results in chain termination

In patients with AIDS: reduces the incidence of opportunistic infection; stabilises weight; reverses HIV-associated thrombocytopenia; stabilises HIV associated dementia; reduces viral load

Can prolong life If given to HIV +ve individuals before the onset of AIDS

In HIV +ve mothers it ↓ risk of transmissn of the virus to the foetus by 66%

In subjects accidentally exposed to HIV e.g. hospital worker, rape victims

RESISTANCE(mutations reverse transriptase)

Given orally or i.v. Bio-availability is 60-80 % due to

1st pass metabolism & peak plasma concn occurs at 30 mins

There is little plasma protein binding no drug interactions

Enters mammalian cells by passive diffusion (passes in to the CSF)

Metabolised to inactive glucuronide in the liver, only 20% being excreted in the urine

Anaemia & Neutropaenia

Cytotoxic DrugsCyclo-

phosphamide(mustard gas)

ALKYLATING AGENT

Highly reactive molecules that bind irreversibly to cell macromolecules, notably DNA, RNA and proteins

Covalently bond with nucleophiles Reactive group is a carbonium ion Most are bifunctional Guanine N7 is main target, also N1 & N3 of adenine and N3 of cytosine intra.interchain crosslinks & interfere with transcriptn & replicatn

N.B. immunopharmacology of these drugs

Myelotoxicity - ¯ leukocyte production ¯ resistance to infection

Impaired wound healing Depression of growth (children) Sterility Teratogenicity

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Loss of hair Nausea and Vomiting

Fast growing cells Inhibit cell division Cell cycle specific drugs: Bone

marrow, GI tract epithelium, Hair & nails, Spermatogonia

Slow growing cells Introduce DNA mutations Cell cycle independent (alkylating

agents) e.g. secondary tumours

MethotrexateANTIMETABOLITE Folate antagonist. Folate essential to synthesise purine nucleotides

(interfere with thymidylate synthesis)

Doxorubicin CYTOTOXIC ANTBIOTICS

Inhibits DNA and RNA synthesis. Mainly through inhibition of topoisomerase II action

Bleomycin Metal-chelating glycopeptide antibiotics that causes fragmentation of DNA chains. It can act on non-dividing cells

Vinca alkaloids (vincristine)

PLANT ALKALOIDS Inhibits mitosis at metaphase by binding to tubulin and inhibiting polymerisation into microtubules prevent spindle formation

Podophyllotoxins (etoposide)

Inhibits DNA synthesis by an action on topo-isomerase II/inhibits mitochondrial function & cell block at G2

Procarbazine MISCELLANEOUS (monoamine oxidase inhibitor) Inhibits DNA/RNA synthesis and interferes with mitosis at interphase

Cisplatin (similar action to alkylating agents) Interacts with DNA causing guanine intrastrand cross-links

UC


UC


Standard Drug List 2

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Transcript of Standard Drug List 2