Pharmacotherapy III - جامعة نزوى · peritonitis or diabetic foot infection. ... [TB]...

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College of Pharmacy and Nursing

School of Pharmacy

Pharmacotherapy III

Course Code: PHCY 510

Spring Semester 2018-19

Dr. Ahmed A. Abusham Assistant Professor - Clinical Pharmacy

Revised Jan 2019

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“Knowing is not enough;

we must apply. Willing is not

enough; we must do”

Johann Wolfgang

Dr. Ahmed Abusham1/29/2018

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29-Jan-18 Dr. Ahmed A. Abusham 1

Dr. Ahmed Abusham

Learning Outcomes

By the end of this lecture you will be able to:

• Discuss the principles of establishing an infection

• Recognize the common causes and symptoms of infectiousdiseases

• Discuss the factors affecting selection of antimicrobial

• Monitor antimicrobial of therapy



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Introduction

• The selection process for an appropriate antimicrobialregimen involves efficacy, safety and cost effectiveness.First, the need for antimicrobial therapy must beestablished.

• It has been estimated that 60% of physician office visitsfor colds, bronchitis, These prescriptions representinappropriate use of antibiotics.

• Host defenses that protect against infection includenatural barriers (eg, skin, mucous membranes),nonspecific immune responses (eg, phagocytic cells[neutrophils, macrophages], and specific immuneresponses (eg, antibodies, lymphocytes).

Infection:Interaction of

Patient, Microorganism

and Pharmacologic

Factors


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Establishing Infection

• Fever is an elevated body temperature of 37.7°C or above.However, this symptom can be misleading because not allfebrile responses are infectious in origin.

• Some clinical signs may be more specific for a particularpathogen or site of infection. For example, a “stiff neck” isan important sign of meningitis.

• Laboratory markers: an increased white blood cell count,an increased erythrocyte sedimentation rate (ESR) andliver enzymes (LFTs). ESR and LFTs are nonspecific.

• When the collection of clinical and laboratory signs andsymptoms in a particular patient suggests infection, thenext step is to identify the causative pathogen.

Identifying the Pathogen

• Culture specimens are obtained from the suspected site to identifythe pathogen(s). For example, a sputum for pneumonia, a urine culture for cystitis (bladder) or pyelonephritis (kidney) infection, and cerebrospinal fluid (CSF) for meningitis.

• The Gram stain is a useful test for organism cell wall (gram-positive or gram-negative) and cell morphology [cocci (spheres) orbacilli (rods)]. It is performed on sputum, urine, CSF, and wound specimens.

• Other tests that are commonly used for rapid identification oforganisms include the acid-fast bacilli (AFB) stain formycobacteria, India ink and potassium hydroxide for fungalpathogens.

• Culture and sensitivity testing are the next steps after stainingtechniques. It requires at least 48 hours. Examples are diskdiffusion testing, Etesting and broth micro-dilution testing.


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Etest method. An Etest strip is placed on

a media plate containing growing

organism

Disk diffusion susceptibility test. See the varying zone sizes

that indicate sensitivity or resistance

The MIC for each antibiotic is the

concentration in the first well containing no visual

growth

Infection: Identifying the Pathogen

Selecting Antimicrobial Therapy• Some infectious diseases can be passed from person to

person. Some are transmitted by bites from insects oranimals. And others are acquired by ingestingcontaminated food or water or being exposed toorganisms in the environment.

• In the case of serious infections, waiting for results mayworsen the patient's condition or cause death.

• Empiric antibiotics are started before the results ofculture and sensitivity tests are available.

• Definitive or directed therapy is determined for eachpatient when the pathogenic organisms have beenidentified and susceptibility is known.


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Patient Factors Influencing Empiric Drug Selection

• Renal function and hepatic function are important patientcharacteristics to consider before drug selection, becausethese are the main routes of drug elimination

• Concomitant drugs may interact with some antimicrobialagents; fluconazole may be a better choice thanketoconazole in a patient taking an H2-blocker such asranitidine, because ketoconazole absorption is influencedby gastric pH,

• Pregnancy and other conditions may influence antibioticselection. Sulfonamide antibiotics are not recommendedin the last trimester of pregnancy because they canincrease bilirubin leading to neonatal brain damage.

Pharmacologic Factors Influencing Drug Selection

• Pharmacokinetic factors: A drug with a longer half-life maybe selected to enhance compliance. Tissue penetration andprotein binding are important because adequateconcentration must be achieved at the site of infection.

• When treating meningitis, it is imperative to evaluate drugpenetration into the CSF. Generally, drugs that are highlyprotein-bound do not penetrate well enough into the CSF.

• With the pharmacokinetics of aminoglycoside and quinoloneantibiotics have concentration-dependent activity. Moreconcentration = more bactericidal activity.

• Cell-wall-active antibiotics such as the β-lactams displaytime-dependent activity. More time above the MIC of theorganism = more bactericidal activity.


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Selecting Combination Therapy

• Aerobic and anaerobic coverage is needed in patients with peritonitis or diabetic foot infection.

• β-lactam antibiotics in combination with aminoglycosides display synergy against Enterococcus sp. and Pseudomonas aeruginosa,

• Tuberculosis, which is always treated with at least three drugs to prevent the development of resistance.

• Some disadvantages of combination therapy include the increased cost and the potential for increased frequency of side effects.

Monitoring Response• Therapeutic (clinical) failure may occur because of bacterial

resistance, inadequate dosage, noncompliance, or superinfection with another organism.

• In certain cases, antibiotic administration alone is inadequate for cure and a surgical debridement or drainage procedure is necessary for a successful outcome.

• A patient's renal function should be closely monitored because many antimicrobials are eliminated by the kidneys. Serum levels of certain antibiotics, such as aminoglycosides, may be measured

• For patients receiving antibiotics in the outpatient setting, patient and family education is important for successful treatment.


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Basis of use of

Antimicrobials


Learning Outcomes

By the end of this presentation you will be able to:

1. Identify principles of antimicrobial use

2. Recognize classification of infectious organisms

3. Discuss optimization of antimicrobial therapy

4. Apply antibiotic selection cascade

5. Recognize the basis of Antibiograms



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Bacterial shapes and arrangements


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Classification of Infectious OrganismsMicroorganism Class and subclass examples

Bacteria

Aerobic

Gram +veCocci:

Streptococcus pneumonia,

Streptococcus viridans

Staphylococcus aureus,

Staphylococcus epidermidis

Enterococcus

Rods (bacilli):

Corynebacterium

Listeria

Gram -veCocci:

Neisseria meningitides.

Neisseria gonorrhoeae.

Rods (bacilli):

Escherichia coli, Klebsiella pneumonia,

Pseudomonas aeruginosa

Helicobacter pylori

Haemophilus influenzae

Enterobacter, Citrobacter, Proteus,

Serratia, Salmonella, Shigella)

Campylobacter, Legionella

Bacteria

Anaerobic

Gram +veCocci:

Peptostreptococcus

Rods (bacilli):

Clostridium tetani,

Clostridium difficile

Gram -veCocci:

None

Rods (bacilli):

Bacteroides fragilis,

Fusobacterium29-Jan-18 17

Mycobacteria

[TB]

Mycobacterium tuberculosis

Mycobacterium avium

Acid-Fast Stain (AFB)

Fungi Aspergillus fumigatus, Candida Albicans, Cryptococcus

neoformans, Histoplasma capsolatum, Tinea ringworm,

Trichophyton ,

Viruses Influenza, hepatitis A, B, C, D, E; human immunodeficiency

virus (HIV); rubella; herpes; cytomegalovirus (CMV);

rhinovirus, adenovirus Colds and Flu

Chlamydiae Chlamydia trachomatis

Chlamydia pneumonia

Classification of Infectious Organisms



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Basis of Use

Therapeutic (directed) treatment:

known pathogen.; sensitivity data are usually available.

Monitoring for resistance is necessary.

Prophylactic treatment: For purpose of preventing an infection Mainly to avoid complication of another treatment/surgery.

Empiric treatment:

Absence of an identified site or organism

Typically in association with more severe clinical illness.

Start only after specimen collection.

Duration should be carefully defined and limited.

Antibiotic Common ADRsAntibiotic ADRs

Co-AmoxclavFlucloxacillin

Cholestatic jaundice

LinezolidTrimethoprim

Myelo-suppression (blood disorder)

Chloromphenicol Bone marrow depression (aplastic anaemia)

Rifampicin, Isoniazid, tetracyclines, Sodium fucidate, Metronidazole

Hepatotoxicity

AminoglycosidesVancomycin

Nephrotoxicity



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Optimizing Antimicrobial Rx

Education - reinforcing the essential educational methods

Antibiotic control program – order form, auto stop, restriction

Sufficient linkage between prescribers and ID team:consultants – microbiologists - clinical pharmacists

Point of care decision and recommendations e.g. shifting fromIV to PO - TDM.

Clinical guidelines considering local resistance pattern

Audit and feedback – multidisciplinary team


Dr. Ahmed A. Abusham WHO29-Jan-18 22


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Educate patients through practice posters and leaflets as antimicrobial prescribing is greatly influenced by patients’ expectations.

Patients’ Education


Prescribers’ Education

Don't prescribe a prolonged course based on “just in case”.

Don't select a potent broad spectrum antimicrobial for management of simple UTI “use a hammer to kill a fly”.

Don't add on antimicrobials regardless of culture and sensitivity data “machine-gun strategy”.



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Dr. Ahmed A. Abusham

Decision Pathway

Diagnosis

Likely Pathogen

Local Susceptibility

Route of Admin

Dose & Freq

Duration

Is ABX required?

EfficacyClinical benefit

ToxicityPatient safety

costEconomic benefit

Possible Antibiotic

Amphotericin B conventional Amphotericin B lipid complex Amphotericin B liposomal

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4080

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Why IV2PO?

40-50% of Intravenous Rx could be switched to per oral Rx:

– Eliminates ADRs e.g. phlebitis (70% of cases)

– Reduces catheter related infections (60% of cases). Catheters should be removed within 72 h.

– Decreases the occurrence of nosocomial infections

– Maintains patient’s comfort and motility

– Reduces nursing and administration time

– Facilitates sooner discharges / Reduce hospital stay

– Reduces overall treatment cost



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Learning Outcomes


Define the upper respiratory tract infections (URTIs),

Discuss etiology, pathophysiology, clinical manifestations of URTI

Describe the pharmacological management and prevention of URTI.

Educate patient on proper management of his infection.


Respiratory System



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Respiratory Infections

• Upper respiratory tract infections (URTI) include:

– Colds and flu

– Influenza

– Sore throat (pharyngitis)

– Otitis media

– Sinusitis

• Lower respiratory tract infections (LRTI) include:

– Bronchitis and chronic obstructive pulmonary disease (COPD)

– Pneumonia

– Cystic fibrosis (CF)


Colds and Flu

Viral infection causing rhinitis, pharyngitis and laryngitis (coryzal symptoms)

Caused by rhinovirus, coronavirus , adenovirus , influenza and parainfluenza virus

Mild infections called “colds” while severe infections called “flu”

Management: symptomatic consists of rest, adequate hydration and simple analgesics antipyretics

Anti-virals and anti-bacterials are not indicated



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Influenza (H1N1)

Oseltamivir and zanamivir are used for treatment and prevention of Influenza A (H1 N1; Swine & Avian) and B.

Amantadine was used for influenza A virus (? Resistance)

Individual at risk and eligible for treatment are:

Asthma and COPD patients

Cardiovascular disease patients

Chronic kidney disease patients

Diabetic patients

Immunosuppressed patients (HIV, Cancer)

Those who are over 65 years


Sore Throat (Pharyngitis)

• Most infection are viral (Epstein-Barr virus)

• The common bacterial cause is Streptococcus pyogenes

• Clinical features: sore throat, fever and common cold symptoms.

• Marked inflammation of the pharynx with white exudates, tender cervical lymph nodes

• Diagnosis: to distinguish streptococcal from viral infection using a throat swab for culture.

• Treatment: viral: symptomatic treatment

• Bacterial: culture, give antibiotics (penicillins, cephalosporins, macrolides) and monitor treatment



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Otitis Media

Common infection in children under 3 years

Causative organisms: Streptococcus pneumonia (s. pneumonia),

S. pyogenes and Haemophilus influenzae (H. influenzae)

Clinical features include severe ear pain, purulent discharge,hearing impairment, fever

Diagnosis: a causative organism is rarely to be identified andtreatment has to be empirical

If treatment is to be given, it should be effective against thethree microorganisms

Co-amoxiclav or cefixime are effective treatments


Acute Sinusitis Occurs following viral URT/dental infection

Causative organisms: Streptococcus pneumonia (s.

pneumonia), S. pyogenes and Haemophilus influenzae (H.influenzae) and Staphylococcus aureus (S. aureus).

Clinical feature: facial pain and tenderness, headache,purulent nasal discharge. Complications includemeningitis, brain abscess and osteomyelitis.

Diagnosis: culture for sinus washout

Treatment: co-amoxiclav, cephalosporins, doxycycline. +metronidazole to cover anaerobes if any.



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Learning Outcomes


Define the lower respiratory tract infections (LRTIs),

Discuss etiology, pathophysiology, clinical manifestations of LRTI

Describe the pharmacological management and prevention of LRTI.

Educate patient on proper management of pneumonia infection.



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Pneumonia

Inflammation of the lung parenchyma (alveoli),

Of infective origin and characterized by consolidation(pus, bacteria, WBC and exudates filling alveoli and appear on chest x-ray as opaque shadow).

Classified according to the nature of its acquisition as community acquired (CAP) or hospital acquired pneumonia (HAP)

Causative Organisms: Typical: Streptococcus pneumonia and Haemophilus

influenzae Atypical: ligionella pneumophila, Mycoplasma pneumonia,

Chlamidophila pneumonia


chest x-ray showing severe,

bilateral pneumonia



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Community Acquired Pneumonia (CAP)

Diagnosis: sputum culture, bronchoscope lavage fluid formicroscopy and culture. Atypical pneumonia is determinedby serology

Targeted Treatment: Pneumococcus pneumoniabenzylpenicillin, amoxicillin, erythromycin. Combination of abeta-lactam and a macrolides may reduce mortality

Chlamedophila pneumonia: doxycycline and quinolones

Staphylococcus spp.: flucloxacillin, vancomycin

Legionella (legionnaire’s disease): rifampicin, quinolones,azithromycin

Moderate to severe disease: hospital admission, combinationof a beta-lactam and a macrolide/doxycycline, moxifloxacin


Hospital Acquired Pneumonia (HAP)(Nosocomial Pneumonia)

Causative organisms:

gram –ve bacilli (Enterobacter, Pseudomonas spp. andAcinetobacter spp.) and..

gram +ve cocci (S. aureus including MRSA)

Usually acquired in intensive care units (ICU) (50%) wherebroad spectrum antibiotics are used resistance

Clinical Features: nosocomial pneumonia accounts for 10-15%of acquired infections sepsis, respiratory failure

Predisposing factors include: stroke, mechanical ventilation,COPD, surgery, immunosupression and previous antibiotic use.



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Diagnosis: sputum, bronchoalveolar lavage and blood culture.

Treatment: broad spectrum empiric therapy is indicated.

Influenced by previous antibiotics, surgery and duration of admission

Combination therapy include:

Aminoglycoside + penicillin / cephalosporin

Aminoglycoside + clindamycin

Vancomycin / linezolid + ciprofloxacin



Prevention:

postoperative mobilization, physiotherapy, and rational antibiotic use.

Administration of aerosolized antibiotics for prevention of ventilator-associated pneumonia.




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Urinary Tract Infections(UTI)


Learning OutcomesBy the end of this lecture you will be able to:

• Define the urinary tract infection (UTIs),

• Discuss etiology, pathophysiology, clinical manifestations of UTI

• Describe the pharmacological management and prevention of UTI.

• Educate patient on proper management of his infection.



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Introduction

• Infection of the bladder (cystitis) and kidney (pyelonephritis) are the most frequently involved.

• Complicated UTI can be acute or chronic and occur with metabolic, functional, or structural abnormalities of the urinary tract or kidneys.

• Metabolic factors: diabetes mellitus, renal failure, transplantation

• Functional abnormalities: neurogenic bladder

• Structural abnormalities: stones, tumors, catheters, stents.

• Urosepsis is a serious condition in which the bacterial species found within the urinary tract and in the blood.



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Etiology/Microbiology

• UTI is prevalent in females because the urethra in women is shorter and closer to the anus

• Sexual intercourse, use of diaphragm and spermicides can increase the risk of infection

• E coli is the most common causative organism (80%). In uncomplicated cystitis and pyelonephritis in women, Staphylococcus saprophyticus is the next most common causative organism.

• In complicated UTI, common organisms are Candida spp., Pseudomonas aeruginosa and Enterococci.


Risk Factors

• The most common risk factor is sexual activity

• Lower estrogen levels in postmenopausal women

• Pregnancy-induced changes, such as decreased peristalsis and dilation of the ureter, allow bacteria easier access

• Neurogenic bladder, and glucosuria in diabetics

• Obstruction of the ureters by stones, strictures, or tumors also increases susceptibility to pyelonephritis.



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Signs and Symptoms

• Acute, uncomplicated cystitis occurs in young patients with pain or burning on urination (dysuria), frequent voiding of small amounts of urine (frequency), and needing to urinate immediately (urgency).

• On positive dipstick or urinalysis, nearly all patients will have pyuria and 40% will have hematuria

• In acute uncomplicated pyelonephritis: fever, chills, nausea, vomiting, loin pain, tenderness, weakness, malaise, or headache.


Signs and Symptoms

• Urine bacterial counts of 104 CFU (colony-forming units per mL) = diagnosis of acute pyelonephritis

• The clinical presentation of complicated UTIs may include the dysuria, frequency, and urgency. headache, temperature instability, and irritability

• For patients with known or suspected complicated UTIs, a urinalysis, urine culture, blood count, and serum creatinine should be performed. Colony counts are usually 105 CFU or more per mL



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Nosocomial UTI

• The majority of nosocomial UTIs are associated with urinarycatheters. Symptoms are confusion and fever.

• the incidence of bacteriuria among catheterized patientsincreases with time at a rate of 6% per day of catheterization.

• For patients who have symptoms, a urinalysis and culture ofurine and blood should be obtained.

• Antimicrobial treatment of catheter-associated UTI has highfailure and relapse rates. Removing the catheter increasescure rates


Treatment

• Antimicrobials currently considered first-line treatment are co-trimoxazole, trimethoprim, or fluoroquinolones.

• Fluoroquinolones are relatively contraindicated in young childrenand pregnant women due to reports of cartilage abnormalities

• The oral first-generation cephalosporins and nitrofurantoin havehigher relapse and reinfection rates.

• Gentamicin has long demonstrated clinical efficacy, but the riskof renal toxicity and ototoxicity have limited its use.



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Treatment Regimens for Bacterial Urinary Tract Infections

Condition Usual Pathogens Special Circumstances Recommended Empirical Treatment

Acute

uncomplicated

cystitis in

women

E. coli,S. saprophyticus, P. mirabilis,Klebsiella pneumoniae

None 3-day regimen: oral co-trimoxazole, trimethoprim,

fluoroquinolone; 7-day regimen: nitrofurantoin

Locations with high co-trimoxazole E.coli resistance 3-day regimen: oral ciprofloxacin; 7-day regimen:

nitrofurantoin

Diabetes, symptoms for >7 days, recent UTI, age >65

years

Consider 7-day regimen: oral co-trimoxazole, trimethoprim,

ciprofloxacin

Pregnancy Consider 7-day regimen: oral amoxicillin, nitrofurantoin,

cefuroxime,

Acute

uncomplicated

pyelonephritis

in women

E. coli,K. pneumoniae,S. saprophyticus

Mild to moderate illness, no nausea or vomiting—

outpatient therapy

Oral co-trimoxazole (if organism is susceptible),

ciprofloxacin for 7–10 days

Severe illness–hospitalization required Parenteral extended-spectrum cephalosporin, ciprofloxacin,

or gentamicin until fever is gone; then oral co-trimoxazole or

fluoroquinolone for 10–14 days

Pregnancy–hospitalization recommended Parenteral extended-spectrum cephalosporin, gentamicin

until fever is gone; then oral amoxicillin, a cephalosporin, for

14 days

Complicated

UTI

E. coli, Proteus spp.,

Klebsiella spp.,

Pseudomonas spp.,

Serratia spp.,

enterococci,

staphylococci

Mild to moderate illness, no nausea or vomiting—

outpatient therapy

Oral ciprofloxacin for 7–10 days

Severe illness or possible urosepsis—hospitalization

required

Parenteral ampicillin and gentamicin, fluoroquinolone,

ceftriaxone, until fever is gone; then oral co-trimoxazole,

ciprofloxacin, as per culture results for 10–14 days


Treatment Goals & Patient Education

• Eradicate pathogenic strains of bacteria or fungi from the urinary tract andresolve or alleviate associated symptoms

• Achieve successful clinical outcome with a treatment regimen that iseffective, of less ADRs and low cost.

• ciprofloxacin 125 mg has been shown to be as effective as a single-dosepostcoital prophylaxis.

• Prevent recurrent infection by prophylaxis and through patient education.

• Photosensitivity reactions are common with co-trimoxazole as well as withsome fluoroquinolones, and patients should be cautioned about sunexposure and the use of sunscreens.

• Patients prescribed ciprofloxacin should be warned to avoid taking iron orother minerals / antacids at the same time to prevent treatment failurefrom decreased absorption.



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TUBERCULOSIS (TB)



• Define the tuberculosis infection (TB),

• Discuss etiology, pathophysiology, clinical manifestations of TB

• Describe the pharmacological management and prevention of TB.

• Educate patient on proper management of his TB infection.



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The Bacterium

The Infection


Epidemiology

• In 1993 the WHO declared tuberculosis as a global emergency

• Resistance is attributed to inadequate treatment and HIVinfection

• Infects 4 million cases and causes 2 million deaths worldwideeach year



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Aetiology

• Caused by tubercle bacilli that belong to the genus Mycobacterium

• The three obligates that can cause tuberculosis are:

– Mycobacterium tuberculosis

– Mycobacterium bovis

– Mycobacterium africanum


Aetiology

• Infection occurs in the vast majority of cases by the respiratory route (pulmonary TB)

• Infants, adolescents and immunosuppressed people are more susceptible to the serious form of tuberculosis such as miliaryor meningeal TB



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Aetiology

• Progressive pulmonary TB arises from exogenous reinfection or endogenous reactivation of a latent focus remaining from the initial infection

• About 65% of untreated TB patients will die within 5 years

• Completion of effective therapy always results in a cure of TB even with HIV infection

• Symptoms include:

– Early: fatigue, fever, night sweats and weight loss

– Late: cough, chest pain, haemoptysis and hoarseness

• Pulmonary infiltration, cavitation and fibrosis can occur before clinical manifestation/symptoms.


Aetiology

• Transmission: occurs through exposure to air-born droplets by people with pulmonary TB during coughing or sneezing

• About 90% cases of TB in children are non-infectious

• Incubation period from infection to occurrence of primary lesions ranges from 2 to 10 weeks

• Latent infection may persist for lifetime

• TB can not be acquired from people with latent TB infection



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Etiology

• Patient consider infectious if they have sputum smear positive. Patient with smear negative (3 samples) are less infectious than those with smear positive

• Risk groups for latent TB infection include:

– Close contacts of patients with smear positive TB

– Working colleagues (if they are immuno-suppressed)

– People from countries with high incidence of TB

– HIV (common), drug users, leukemia, lymphoma and haemodialysis patients - This was attributed to the poor general health and reduced immunity.


Diagnosis

• Early diagnosis and prompt treatment can reduce the period of infectivity to other people

• Also, strict attention to infection control procedures will prevent transmission of infection to others

• People from risk groups having lower respiratory symptoms should be carefully investigated for TB infection

• TB is a notifiable communicable disease. Suspected cases should be notified to Ministry of Health immediately.

• Latent TB infection is not notifiable



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Investigations

• Tuberculin test (Mantoux test - purified protein derivative (PPD)) is used to detect latent TB infection. It consists of intradermal injection of 2TU (tuberculin units) in 0.1 ml. A positive result (after 48-72 h) shows an induration of at least 6 mm.

• Radiography (X-ray): unilateral or bilateral opacities and patchy shadowing usually indicates the disease is active

• In HIV patient TB occurs early and may be diagnosed before HIV. Newly diagnosed HIV patient should be tested for TB and prophylaxis is recommended.


Treatment

• Anti-TB medications have 2 main purposes:

– To cure patients with TB

– To control TB by prophylaxis or by reducing the period of infectivity

• Rifampicin (450-600 mg) + isonizid (300 mg) + pyrazinamide (1.5-2 g) + ethambutol (400-800 mg) daily

• Isoniazid is a bactercidal against intracellular organisms

• Rifamicin is a bactercidal against dividing organisms

• Combination is always used and selection of therapy based on resistance and patient adherence to regimen



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Treatment

• Respiratory TB: active TB affecting lungs usually 6 month regimen of rifampicin, isoniazid, pyrazinamide and ethambutol

• Intermittent directly observed therapy (DOT) regimens: To be considered when non-adherence to drug therapy might be a problem.

• DOT regimen: rifampicin-isoniazid-pyrazinamide-ethambutol given daily for 2 months followed by rifampicin-isonizid 2-3 times weekly for 4 month

• Doses are increased when given intermittently as DOT


Treatment

• TB meningitis: Rifampicin-isoniazid for 12 months with pyrazinamide-ethambutol for at least 2 months

• Pregnant and breast feeding women should be given standard therapy but not streptomycin (ototoxic)

• Ethambutol: dose reduction and serum creatinine monitoring are required in patients with renal disease

• Ethambutol: may cause visual disturbances mainly in elderly patients

• Rifampicin, isoniazid or pyrazinamide: liver enzymes should be monitored in patient with liver disease



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Treatment

• Drug resistant TB is a worldwide problem. It is recommended that treatment is only carried out by expert physician in conjunction MOH authority.

• Pyridoxine (vitamin B6) is added to combat the peripheral neuropathy caused by isoniazid.


TB Control

• Prophylaxis: isoniazid alone for 6 months or isoniazid + rifampicin for 3 months

• BCG (Bacillus Calmette-Guérin) is alive attenuated vaccine derived from M. bovis. It prevents infection with serious TB forms



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Patient Care / Education

• Adherence is affected by the number of tablets per day andpatient may stop treatment after feeling better!!!

• Once daily regimen, one hour before breakfast wheneverpossible (use combination preparation)

• Verbal plus written information as appropriate

• Inform patient about expected adverse effects (blurred vision,discoloration of urine, etc…)

• Patient may report to the treating doctor in case of severeadverse effects.


Infective Meningitis



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• Define the meningitis infection,

• Discuss etiology, pathophysiology, clinical manifestations of meningitis

• Describe the pharmacological management and prevention of meningitis.





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Introduction

• It is the inflammation of arachnoid and pia mater associated with the presence of bacteria, viruses, fungi or protozoa in the cerebrospinal fluid (CSF)

• Associate with significant mortality and serious morbidity


Aetiology & Epidemiology

• Organism: Neisseria meningitidis (infancy to middle age) and Streptococcus pneumonia (adults > 45 years & children < 5 years)- account for 75% of cases

• Almost 50% of all cases occurring in the first 4 years of life

• Vaccine is available for Mmeningicoccal, Pneumococcal and Haemophilus influenzae B as well.



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N. meningitidis


Aetiology & Epidemiology

• Meningicoccal disease is highly infective

• Infection can also occur as a complication of surgery

• May also be a feature of diseases like syphilis, liprosy and tuberculosis meningitis

• Enteroviruses account for 70% of all viral meningitis. Others include herpes virus and HIV.

• Cryptococcus neoformans causes HIV fungal meningitis



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Pathophysiology

Microorganism can reach the meninges by:

– Direct spread for nasopharynx

– Blood-born spread

– Abnormal contact with skin or mucous e.g. skull fracture

– Spread from brain abscess or middle ear infection


Pathophysiology

• Most bacteria and fungi causing meningitis are encapsulatedwhich help them in resisting antibiotics and phagocytosis.

• Bacterial cell wall components are potent inducer of inflammatory response

• Cerebral oedema, obstruction of blood vessels, impaired CSFflow and an increase in intracranial pressure



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Clinical Manifestations

• Acute: headache, neck stiffness, photophobia, fever and vomiting

• Resistance of the leg movement (Kernig’s sign)

• Septic shock if there is septicaemia

• Haemorrhagic skin rash

• Untreated patients may develop seizures, loss of consciousness and death

• In viral meningitis patient usually remain alert and conscious


Kernig’s sign



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Diagnosis

• Cerebrospinal fluid (CSF) is obtained by lumbar puncture (LP)

• It contains 0.4 g/L protein and 2.2-4.4 mmol/L glucose

• CSF protein is usually raised above 1 g/L in bacterial, tuberculousand cryptococcal meningitis and above 0.5 g/L in viral meningitis

• CSF glucose is usually less than 50% of blood glucose in bacterial, tuberculous and cryptococcal meningitis but normal in viral meningitis. This is due to impaired CNS glucose transport and consumption of glucose by microorganisms.

• CSF white blood cells are usually raised above 1000 cell/mm3 in bacterial meningitis

• CSF gram stain; CSF culture; blood culture

• PCR (polymerase chain reaction): microorganism antigen detection.


Lumbar puncture



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Drug Treatment

• Because of clinical urgency, empirical antibiotic therapy maybe indicated (take specimens first!!)

• Require adequate level of bactericidal agent within the CSF

• Passage into CSF depends on:

– The degree of meningeal inflammation

– Integrity of blood brain barrier (BBB)

– Drug concentration in the serum,

– Lipid solubility,

– Protein binding,

– Molecular size of the drug.


Drug Treatment

• Drugs that penetrate into CSF even if the meninges are not inflamedinclude: metronidazole, chloromphenicol, isoniazid

• Those penetrate only when meninges are inflamed: beta-lactams,quinolones, rifampicin

• Those penetrate poorly in all cases: aminoglycosides, vancomycin,erythromycin

• Direct intraventricular administration of antibiotics in meningitis isimportant for drugs that penetrate CSF poorly e,g, vancomycin andaminoglycosides

• The most common situation is in shunt associated meningitis where thereis a resistant coagulase-negative staph (staphylococcus epidermidis)



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Prophylaxis

• Oral drugs:

– Rifampin 600mg orally twice daily for two days

– Ciprofloxacin 500mg orally as a single dose (stat).

• Vaccines:

– meningococcal, pneumococcal, Haemophilus influenza B (Hibvax).


Intra-ventricular Catheter



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Drug Treatment

• Neonates: amoxicillin/cefotaxime/ ceftazidime/ gentamicin/bezylpenicillin

• Infants: amoxicillin/cefotaxime/ ceftrioxone

• children: cefotaxime/Ceftrioxone/ chloromphenicol/ benzylpenicillin

• Adults: cefotaxime/ceftrioxone/amoxicillin/ benzylpenicillin/chloramphenicol

• Steroids: reduce the risk of complications, such as brain swelling and seizures.


Fungal Infections



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Learning Outcomes


• Define the fungal infections

• Discuss etiology, pathophysiology, clinical manifestations of fungal

infections

• Describe the pharmacological management and prevention of fungal

infections



Introduction/Types

• Yeast: unicellular, oval cells: Cryptococcus neoformans meningitis

• Yeast-like: like yeast but produce pseudohyphae e.g. Candida albicans, C. flavus or C. niger. superficial or deep seated candidal infections

• Molds: produce hyphae as in rotten food, Aspergillusfumigatus. pulmonary infections

• Dimorphic fungi: exists either as yeast at body temp, or as mold at room temp. e.g: Penicillium spp.

• Fungi may cause superficial or deep human infections



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Common Types of

Fungi


Fungi vs Bacteria

Fungi differ from bacteria in the following:

• Fungi cells have true nuclei which bacteria do not

• Different cell wall and cell membrane constituents

• Produce hyphae which are long branching tubular structure

• Reproduce by budding while bacteria reproduce by binary fusion

• Fungi cells are closer to human cells compared to bacteria and are resistant to anti-bacterials.



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Superficial Fungal Infections

• Thrush: Candida - oral and vaginal infection

• Dermatophytosis (Tinea ringworm)

• Pityriasis versicolour (Tinea versicolour)


Epidemiology

Candida albicans:

• Common yeast-like fungi

• Part of the GIT normal flora

• The infection is usually endogenous

• Other species include: C. glabrata, C. krusi and C. tropicalis



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Epidemiology

• Superficial infection is common as oral and vaginal thrush andoccasionally nail infection

• Predisposing factors include:

• Presence of dentures

• Use on steroid inhalers

• Use of anti-bacterials

• Diabetes, pregnancy, and use of oral contraceptives

• Immuno- suppressed patients


Clinical Presentation

• Thrush – oral and vaginal:– Sore mouth with white patches of fungus on the mucosa

and tongue.

– Vaginal discharge which is thick and creamy andaccompanied by itching

• Esophageal candidiasis: in immuno-compromisedpatients.

• Nails: infection of subcutaneous tissue around andunder the nail. Inflamed pustules, itching andfissuring of the skin



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Vaginal Candidiasis

Nail Candidiasis

GIT Candidiasis

Oral Candidiasis


Diagnosis

• Microscopy: large yeast cells with pseudohyphae

• Culture should always be considered in nail and skininfections because of resistance.

• Sensitivity testing is required in immuno-suppressedpatients or those who had been previously exposed toanti-fungals.



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Treatment

• Polyenes: insoluble, not absorbed from GIT e.g. nystatin, amphotericin B

• Imidazoles: topical: econazole, clotrimazole

• triazoles: systemic: fluconazole and itraconazole

• For treatment of oral or vaginal candidiasis (thrush), these agents are applied:– Topically ( nystatin, econazole, clotrimazole)

– Orally (nystatin, fluconazole )


Dermatophytosis

Pityriasis versicolour

Dermatophytosis



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Dermatophytosis (Tinea ringworm)

• Caused by molds: trichophyton and epidermophyton

• Usually infect skin, nails and hair

• Acquired from soil, animals or humans

• Clinical feature: • Skin: Ringworm - a circular inflamed lesion

• Nail: thick discoloured nail

• Scalp: scaling, itching, inflammation, and hair loss

Treatment:

• Topical (for small areas): imidazoles, terbinafine

• Systemic (for large areas, nails and hair): Griseofulvin.


Pityriasis versicolour (Tinea versicolour)

• Caused by Malassezia furfur: requires fatty acids present in sebum (oily or fatty secretion of sebaceous glands)

• Clinical Features: scaly, pigmented patches scattered over the trunk, neck and shoulders + dandruff

• Diagnosis: microscopy of scraping from the patches

Treatment:

• Topical: 2% selenium sulfide, terbinafine or imidazole

• Oral: Itraconazole for 7 days in severe cases



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Deep-Seated Fungal Infections in immuno-suppressed patients


Aspergillosis

Epidemiology

• Urinary tract: common in catheterized patients

• Patients on Total parenteral nutrition (TPN)

• Neutropenic patients: candida, aspergillus

• The most common causative fungi are candida and aspergillus

• HIV infection: Cryptococcus neoformans


Cryptococcosis


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Clinical Presentation

• Neutropenic with Candidaemia (fungi in blood)

• Fever

• Low blood pressure

• Septic shock (in severe infections)


Diagnostic Features

• Culture from blood or cerebrospinal fluid

• Sputum for aspergillus (rarely diagnosed from blood culture)

• Lung biopsy for pulmonary aspergillosis



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Drug Treatment

• Amphotericin B: bind to ergosterol in the fungi cell wall causing leakage of the cell contents and death.

• Should never be diluted in sodium chloride 0.9% ppt

• Conventional Amphotericin B (Fungizone):

Usual dose = 1mg/kg iv infusion in dextrose 5% (1-6 wks)

Can be given as a bladder wash-out as 50mg/L

Contraindicated in renal impairment

Causes hypokalaemia


Drug Treatment

Amphotericin B lipid formulations:

I. Encapsulated in liposomes (Ambisome):

Dose: 3-7 mg/kg iv infusion in dextrose 5%

can be used for patient with impaired renal function

Causes hypokalaemia

II. As a complex with lipid molecules (Abelcet):

Dose: 5 mg/kg iv infusion in dextrose 5%

can be used for patient with impaired renal function

Causes hypokalaemia and infusion reaction



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Drug Treatment

Triazoles:

• Inhibit synthesis of ergosterol

• Fluconazole: PO, IV

– treatment of yeasts and yeast-like infections(Crytococcal and candidal infections)

– Commonly given for preventive purposes

– not affected by reduction in gastric acidity

• Itraconazole: PO, IV

– Against yeast, dermatophyte and aspergillus

– Oral alternative to amphotericin B

– Useful in fluconazol resistant cases

– Absorption is affected by reduction in gastric acidityDr. Ahmed A. Abusham

Drug Treatment

• Voriconazole: PO, IV

– More GIT absorption, not affected by reduction ingastric acidity

– Main indication is invasive aspergillosis

– Interact with many drugs (check BNF)



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Drug Treatment

Caspofungin: IV only

– The first of echinocandin antifungals

– Inhibit cell wall synthesis

– Does not inhibit the cytochrome P450 system lessrange of drug interaction

– Active mainly against all types on candida

– Does not pass the blood brain barrier (BBB)


Practice Points

• Nephrotoxicity and Infusion related toxicity areassociated with amphotericin B

• Hepatotoxicity is associated with azoles (ketoconazole)and flucytosine

• Bone marrow suppression: flucytosine

• Drug interactions: azoles (voriconazole)

• To avoid precipitation of amphotericin B in IV infusion itshould only be diluted in dextrose 5%.

• Itraconazole absorption is impaired when given withantacids or omeprazole.



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Infections in the Immuno-compromised Patient


Learning Outcomes


– Define febrile neutropenia

– Discuss etiology, pathophysiology, clinical manifestations of infections in

immunocompromised patients

– Describe the pharmacological management and prevention of infections

in immunocompromised patients

– Educate patient on proper management of his infection.



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Definition of Febrile Neutropenia

Febrile Neutropenia:Single oral temp > 38.30C OR ≥ 38.00C over 1 hour and

absolute neutrophil count (ANC) < 0.5 i.e. < 500 cells/mm3


Introduction

• Infection remains the most difficult complication encountered in immuno-compromised patients.

• Infection is the result of a negative balance between the capacity of hostimmune defenses and the toxicity of invading microorganisms

• An immuno-compromised state arises when these defenses/protective barriers are broken or essential immune cells are absent or impaired.

• The most common factors leading to defective immune cell responsesinclude AIDS, cancer, infections and drugs e.g. cytotoxics and immuno-suppressives.



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Introduction

• Immuno-compromised patients often present with multiple infections that may not be initially detectable by laboratory and radiographic studies.

• Broad empiric therapy with combinations of antibacterial, antifungal, and antiviral agents, may be necessary.

• Patients on chemotherapy/cytotoxic regimen:

• have prolonged drug-induced myelo-suppression (neutropenia lasting >27 days)

• are high risk for death due to bacterial or fungal infection.


Neutropenia• Gram-negative bacteria represent over 70% of infections associated with

neutropenic fever (P. aeruginosa, K. pneumonia, H. influenzae)

• The widespread treatment/prophylaxis against gram-negative bacteria, shifted the bloodstream pathogens towards gram-positive.

• In early phase of neutropenia (<10 days), bacteraemia arises from the central venous catheter (CVC) and/or damaged GIT (mucositis)

• S. aureus, S. epidermidis, and streptococci are the main Gram+ve bacteria isolated in neutropenic patients.



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Neutropenia

• During the second and third weeks of neutropenia, candida/yeastsemerge as a prominent cause of infection.

• Therefore, empiric antifungal therapy is recommended in persistent fever and neutropenia lasting more than 10 days.

• As neutropenia extends beyond the third week, invasive aspergillosis (mold), become more prominent.

• Mortality rates of invasive aspergillosis infections approach 100% in patients who do not recover from neutropenia.


Components of Immune Dysfunction and Infection

• Chemotherapy- and radiation-induced damage to mucosal barriers can also induce infection and ulceration,

• The prolonged central venous access using CVC poses an increased risk of bloodstream infection with skin flora.

• The risk of infection after stem cell engraftment (BMT) e.g. graft versus host disease (GVHD) depends on the type of transplant and the level of risk.



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Hickman’s

CVC


Catheter Related Bloodstream Infection (CRBSI)

MRSE=Methicillin-Resistant Staphylococcus epidermidisMRSA=Methicillin-Resistant Staphylococcus aureusPNSP =Penicillin Non-susceptible Streptococcus PneumoniaeVRE =Vancomycin-Resistant EnterococciVRSA =Vancomycin-Resistant Staphylococcus aureus



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Clinical Presentation and Diagnosis

• Suspected bloodstream infections should be evaluated by blood culture.At least two specimens are sent for culture.

• Patients with CVC should have blood samples taken through each lumento rule out the possibility of CRBSI.

• Meningitis and encephalitis generally require Computed tomography (CT)and/or Magnetic resonance imaging (MRI) scans of the brain.

• The upper and lower respiratory tract is the most common site ofinfection in immuno-compromised patients.

• Fever is non-specific. It is common once a patient is receiving more thanthree antimicrobials.


Treatment

• Empiric antimicrobial therapy is indicated to prevent death from infection.

• Antimicrobial therapy is selected on the basis of the most likely pathogensand local antimicrobial susceptibility patterns.

• Antimicrobials used should be broad-spectrum, convenient to administer andavailable as intravenous.

• Consider prophylaxis against opportunistic infections

• For specific therapies see the following tables.



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Common Antimicrobial Treatment Regimens

Pathogen (bacteria) Intravenous Therapies

Gram-positive cocci S. aureus, S. epidermidis, S. pneumoniae, S. Viridans

Empiric: Vancomycin 0.5–1 g q6–12h; Cloxacillin 1–2 g q4–6h if MRSA rates are low

Enterococcus faecalis , E. faecium

Definitive: According to culture and sensitivity results

Gram-negative aerobic bacilli (Pseudomonas aeruginosa, Haemophilus influenzae)

Empiric: piperacillin/tazobactam 3.5–4.6 g q6h, meropenem 1 g q8h; with or without aminoglycoside; ciprofloxacin 400 q8–12h or with or without aminoglycoside in penicillin-allergic patients

Legionella spp. Azithromycin 500 mg q24hmoxifloxacin 400 mg q24h

Listeria monocytogenesNocardia spp

Cotrimoxazole 7.5 mg/kg q12h;



Pathogen (fungi / parasites) Intravenous Therapies

Candida Caspofungin 70 mg day #1, then 50 mg q24hFluconazole 6–12 mg/kg q24h

Aspergillus spp. Voriconazole 6 mg/kg q12h for 48 h, then 4 mg/kg q12h; lipid amphotercine B 5 mg/kg q24h

Pneumocystis jirovecii Co-trimoxazole 5 mg/kg q6h; pentamidine 4 mg/kg q24 hours; dapsone orally 100 mg/day

Toxoplasma gondii Oral pyrimethamine 50–100 mg daily + sulfadiazine 1 g q4–6h;

Strongylide stercoralis Thiabendazole 25 mg/kg q12h (max 3 g/day)



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Pathogen (virus) Intravenous Therapiesa

Cytomegalovirus (CMV) Ganciclovir 5 mg/kg q12h; foscarnet 60 mg/kg q8h;

Varicella-zoster virus Acyclovir 10 mg/kg q8h; foscarnet 40 mg/kg q8h

Herpes simplex virus Acyclovir 5–10 mg/kg q8h; foscarnet 40 mg/kg q8h


Prophylaxis

• Fluoroquinolones are typically the preferred for prophylaxis of gram –veorganisms

• Fluconazole 200 to 400 mg per day for superficial and invasive candidiasis

• Co-trimoxazole is recommended for prophylaxis and treatment of Pneumocystis jirovecii opportunistic infection.

• Prophylaxis with acyclovir (200 to 400 mg orally two to four times a day) to prevent viral infection

• Ganciclovir prophylaxis is often reserved for patients at extremely high risk for cytomegalovirus (CMV) infection.



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Practice Points• Identify the most common bacterial, viral, and fungal pathogens.

• Describe the opportunistic infections in febrile neutropenia and after solid organ or BM transplantation.

• Understand general principles of anti-infective therapy in the immuno-compromised patient.

• Early empiric broad-spectrum IV antibiotic therapy results in a significant reduction of mortality and morbidity rates

• Provide modification of empiric antibacterial, antifungal, or antiviral therapy.


HIV INFECTION I

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LEARNING OUTCOMES


Define the AIDS/HIV infection

Discuss etiology, pathophysiology and clinical manifestations of HIV infection

Discuss the opportunistic infections encountered in AIDS patients.

Describe the pharmacological management and prevention of HIV infection

Educate patient on proper management of his/her infection.

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EPIDEMIOLOGY

The acquired immune deficiency syndrome (AIDS) is the state of immuno-suppression produced by chronic infection with the human immuno-deficiency virus (HIV)

Described in homosexuals, IV drug users, infected blood transfusion,mother to child transmission

Resistance to therapy is about 20% and increasing

The virus has been isolated from blood, semen, vaginal secretions, saliva,tears, urine, CSF and breast milk.

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EPIDEMIOLOGY

Predominant routes of transmission:

1. Sexual intercourse (anal or vaginal)

2. Sharing of unsterilized needles or syringes

3. Unscreened blood or blood products

4. During labour or through breast feeding (vertical transmission)

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The surface glycoprotein molecule has strong affinity for the CD4 receptor protein on the T-helper lymphocytes

After entry, the virus releases its genetic material . The viral RNA converted to DNA using nucleosides

DNA integrated in the host cell producing new viral protein

New virus assembled, moved out of the host cell and matured as infectious influenced by protease enzyme

Immediately after infection there is a very high turn over (10000 million virus per day)

Adsorption Entry Replication Assembly Release ….

PATHOGENESIS

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PATHOGENESIS29

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PATHOGENESIS

The affected T-helper lymphocytes will be depleted and patient becomes susceptible to infections and cancers

Outside the body HIV is inactivated by:

Hydrogen peroxide

Alcohol / sodium hypochlorite

Glutaraldehide

Heat (50 C for 10 minutes)

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CLINICAL MANIFESTATIONS

Opportunistic infections: infections that would not cause disease in immuno-competent host e. g. pneumocystis pneumonia (PCP), toxoplasmaand cytomegalovirus (CMV).

Infections that are severe and common in HIV patients include TB, herpes simplex, Salmonella infections .

HIV myelopathy, HIV encephalopathy and HIV enteropathy

70% of patients develop a flu-like illness

The primary infection characterized by fever, rash, arthralgia, lymphadenopathy and oropharyngeal candidiasis

according to their clinical status, Patients can be classified into:

Asymptomatic

Symptomatic with fever, night sweats, lethargy, weight loss

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AIDS PATIENTS

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INVESTIGATIONS AND MONITORING

HIV antibody: it may take 3 months after infection for antibody to be detected.

Patient is usually tested for diseases like PCP, CMV etc.

CD4 count (CD4 in T-lymphocytes in peripheral blood = 500-1500 cell/mm3). Itestimates the level of immno-suppression.

As the disease progresses the number of cells falls. If CD4 count is less than200, patient should be offered prophylaxis against opportunistic infections

Viral load (measurement of plasma HIV RNA) predicts disease progressionand help adjusting therapy.

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HIV INFECTION II

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DRUG TREATMENT

Goals of therapy in HIV-positive individuals are to:

1. Improve the quality and duration of life

2. reducing viral load and restoring immune function

3. Treat / prevent opportunistic infections

4. Relieve symptoms

The triple therapy is highly active antiretroviral therapy (HAART) and superior to dual or mono-therapy

Treatment of opportunistic infections require induction phase of high dose therapy followed by indefinite maintenance therapy and prophylaxis using lower dose

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DRUG TREATMENT -- NRTIS

Nucleoside and nucleoside analogues reverse transcriptase inhibitors (NRTIs):

Inhibit the virus reverse transcriptase enzyme by acting as false substrate after phosphorylation

Examples:

Zidovudine - didanosine

Lamivudine - stavudine

Tenofovir - abacavir

Available as combination therapy to reduce the number of tablets per day

The first line combination therapy = abacavir + lamivudine

Triple NRTIs therapy is no longer recommended because it is associated with treatment failure

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DRUG TREATMENT -- NNRTIS

Non-nucleoside reverse transcriptase inhibitors (NNRTIs):

Inhibit the virus reverse transcriptase enzyme by binding to its active site.

They do not need phosphorylation.

Examples: - efavirenz - nevirapine

Resistance to NNRTIs is rapid. They should be prescribed with at least two NRTIs or NRTIs + protease inhibitor

Have much longer half-life than protease inhibitors and NNRTIs

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DRUG TREATMENT

PROTEASE INHIBITORS

Bind to the active site preventing the maturation of the new virus

Examples:

Atazanavir Darunavir

Indinavir Ritonavir

Saquinavir

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DRUG TREATMENT

General principles of retroviral therapy:

Select triple therapy based on treatment history and resistance pattern

One drug should penetrate BBB to protect against HIV relatedencephalopathy

Regimen should suit patient life style for sake of adherence to therapy.

Post exposure prophylaxis:

3-5 days of 2 nucleotide analogues (NRTIs) and a protease inhibitor (PI)followed by 4 weeks triple therapy.

May reduce possibility of infection by 80 %.

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OPPORTUNISTIC INFECTIONS

Pneumocystis jirovecii (carinii) pneumonia - PCP:

Fungal infection, one of the most common causes of morbidity andmortality in the HIV +ve patients.

Diagnosis confirmed by immuno-fluorescence or silver staining ofsputum or broncho-alveolar lavage

Symptoms include fever, nonproductive cough, shortness of breath,anorexia and weight loss

Treatment: oxygen, cotrimoxazole (120 mg/kg/day IV in divideddoses). Alternatives include:

dapsone 100 mg daily + trimethoprim 5mg/kg 6 hourly,

clindamycin 600 mg 6 hourly + primaquine 30 mg once daily,

pentamidine 600 mg given through nebulizer

Prophylaxis with cotrimoxazole 960 mg every other day will reduceincidence and severity of disease.

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Oropharyngeal Candidiases:

Frequent fungal infection that occurs early in the disease course and appears as white patches on the oral mucosa

It may involve esophagus causing dysphagia (difficult swallowing)and odynophagia (painful swallowing)

Treatment: nystatin suspension or lozenges and good oral hygiene.For severe cases oral fluconazole 50 mg dally or itraconazole 200 mg daily is recommended

In case of esophageal candidiasis higher doses for longer durationsare recommended e.g. fluconazole 200 mg daily for 2 weeks

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Cryptococcus neoformans:

Fungal infection with meningeal involvement

Symptoms: fever, headache (no neck stiffness or photophobia)

Diagnosis: PCR, CSF and blood culture

Treatment: IV amphotericin + flucytosine for 2 weeks followed by fluconazole 400 mg daily PO for 10 weeks

Renal/liver function and serum potassium should be monitored

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Toxoplasmosis: Toxoplasma gondii

Protozoal infection involves central nervous system and presents with headache, fever, confusion, seizures

Diagnosis: lesions on computed tomography (CT scan) and brain biopsy

Treatment: sulphadiazine and pyrimethamine for several weeks + folinic acid to prevent myelosuppression

Treatment during pregnancy: spiramycin 6 to 9 mega units per day to prevent transmission from mother to fetus

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Mycobacteria (TB):

Bacterial infection characterized by reactivation of latent disease and severity of infection

Diagnosis: specimen culture

Treatment: usually empirical. Prophylaxis may be required

Cytomegalovirus (CMV):

It is a herpes virus infection acquired by 90% of homosexual men and reactivated in immuno-suppressed individuals

Mainly affect retina and GIT with neurological involvement

Treatment: ganciclovir (to be handled as cytotoxic agent).

Ganciclovir ADRs include neutropenia and thrombocytopenia. Alternative: valganciclovir.

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PATIENT CARE

AIDS is a multisystem disorder that challenges the infected individuals, their families and the healthcare providers

Monitor regularly for signs of treatment failure, low adherence and drug toxicity

Provide appropriate advice regarding prevention of transmission of infection (safer sex, safer drug use?)

Give regular prophylactic therapy to avoid complications of opportunistic infections

Pharmaceutical care plan should include polypharmacy, new drugs, drug interactions, adverse drug reactions and adherence to medication use.

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Malignancy & Chemotherapy



– Discuss the pathophysiology and clinical manifestations of

malignancy

– Describe the classes of chemotherapeutic/cytotoxic agents

– Discuss the handling/common adverse drug reactions of

chemotherapeutic/ cytotoxic agents

– Discuss the management of colorectal and breast cancers

– Educate patient on proper management of his/her disease



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Malignancy

• The term malignancy refers to cancerous cells that tend to havefast, uncontrolled growth

• Malignant cells have the ability to spread (metastasis), invade,and destroy tissues.

• Malignant cells that are resistant to treatment may return afterbeing removed or destroyed.


MalignancySome types of malignancies:

• Carcinoma: Cancers derived from epithelial cells. This group iscommon and include breast, prostate, lung, pancreas, and colon.

• Sarcoma: Cancers arising from connective tissue (i.e. bone, cartilage,fat, nerve), originating outside the bone marrow.

• Lymphoma and leukemia: Arise from hematopoietic (blood-forming)cells that leave the marrow and mature in the lymph nodes and blood

• Germ cell tumor: Cancers derived from pluripotent cells, most oftenpresenting in the testicle or the ovary.



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Cytotoxic Drugs

• Cytotoxic drugs have both anti-cancer cells activity and the potentialto damage normal cells.

• Chemotherapy may be given to cure the cancer, to prolong life, or topalliate symptoms.

• Chemotherapy may be combined with radiotherapy or surgery orboth as adjuvant treatment



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Groups of

Cytotoxic Drugs


Alkylating Agents

• They act by damaging DNA, thus interfering with cell replication.

• prolonged usage can severely affect the reproductive system (sterility) and may cause acute leukaemias.

• Examples: Cyclophosphamide Chlorambucil, Melphalan Busulfan. In treatment of leukemia



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Antimetabolites

• Combine irreversibly with vital cellular enzymes preventing their division.

• Example: Methotrexate: causes myelosuppression, mucositis. (Check renal and hepatic function).

• Folinic acid following methotrexate helps to prevent ADRs.

• Example: Capecitabine, which is metabolised to fluorouracil (5FU), for treatment of metastatic colorectal cancer and advanced gastriccancer


Anthracyclines

• Antibiotic cytotoxics act as radiomimetics and simultaneous use of radiotherapy should be avoided.

• Examples: Daunorubicin, doxorubicin, epirubicin and idarubicin are anthracycline antibiotics.

• Treatment of lymphomas and leukaemias

• May cause severe cardiotoxicity



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Vinca Alkaloids

• Are used to treat a variety of cancers including leukaemias, lymphomas, and some solid tumors (e.g. breast and lung cancer).

• Neurotoxicity (reversible), occurs with all vinca alkaloids and is a limiting side-effect of vincristine

• Myelosuppression is the dose-limiting side-effect of vinblastine, vindesine, and vinorelbine but not vincristine

• The vinca alkaloids may cause extravasation and reversible alopecia.

• Examples: Vinblastine, vincristine, vindesine, and vinorelbine injections


Hydroxycarbamide

• Hydroxyurea

• Orally active drug used mainly in the treatment of chronic myeloid leukaemia (CML).

• Myelosuppression, nausea, and skin reactions are the most common toxic effects.

• It is teratogenic.



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Platinum Compounds

• Carboplatin is widely used in the treatment of advanced ovariancancer and lung cancer

• Oxaliplatin is licensed in combination with fluorouracil and folinicacid, for the treatment of colorectal cancer

• Cisplatin is the most toxic, causing nephrotoxicity, ototoxicity,peripheral neuropathy, and myelosuppression.


Protein Kinase Inhibitors

• Imatinib, a tyrosine kinase inhibitor, is licensed for the treatment ofnewly diagnosed CML

• Dasatinib, is licensed for the treatment of CML in those who haveresistance to or intolerance of imatinib.

• Erlotinib, is licensed in combination with gemcitabine for thetreatment of metastatic pancreatic cancer.



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Taxanes

• Paclitaxel is considered for inoperable ovarian cancer and in thetreatment of metastatic breast cancer

• Docetaxel is licensed for use in locally advanced or metastaticbreast cancer

• Side-effects include hypersensitivity, myelosuppression, peripheralneuropathy, alopecia, persistent fluid retention (commonly withDocetaxel) .

• Dexamethasone by mouth is recommended for reducing fluidretention and hypersensitivity reactions.


Dr. Ahmed A. Abusham

Example Cytotoxic Agents

• Alkylating agents: cyclophosphamide, melphalan

• Antimetabolites: methotrexate, mercaptopurine, 5-fluorouracil (5FU)

• Anthracyclines: doxorubicin, epirubicin

• Vinca alkaloids: vincristine, vinblastine

• Platinum compounds: cisplatin, carboplatin

• Protein kinase inhibitors: dasatinib, imatinib

• Taxanes: Paclitaxel, Docetaxel

• Monoclonal antibody: Rituximab, alemtuzumab

• Hormones:Tamoxifen

• Interferon Alpha / Beta

• Hydroxyurea

• Thalidomide !? Phocomelia (malformation/missing of thelimbs).

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Adverse Effects of Cytotoxics



The Thalidomide Tragedy


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• Extravasation of intravenous drugs: A number of cytotoxic drugswill cause severe local tissue necrosis if leakage into theextravascular compartment occurs:

– Vesicant drug: causes blistering, local or extensive tissuenecrosis with or without ulceration

– Irritant drug: causes burning sensation, pain, tightness, with orwithout inflammation. No tissue necrosis or ulceration




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• Alopecia: reversible hair loss is a common complication. Nopharmacological methods of preventing this effect.

• Oral mucositis: A sore mouth is a common complication ofcancer chemotherapy (fluorouracil, methotrexate, and theanthracyclines). Good mouth care (rinsing the mouth andbrushing of the teeth with a soft brush) will help.




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• Tumour lysis syndrome (TLS): occurs as a result of massive cell breakdown following treatment of cancer. Features include hyperkalaemia, hyperuricaemia, and hyper-phosphataemia with hypocalcaemia. Renal damage and arrhythmias may follow.

• Hyperuricaemia: associated with acute renal failure. Allopurinolshould be started 24 hours before treating such tumors and patients should be adequately hydrated.

• Reduce mercaptopurine or azathioprine dose if allopurinol needs to be given concomitantly


Adverse Effects of CytotoxicsNausea and vomiting:

• Nausea and vomiting cause distress to many patients and it may lead to refusal of further treatment.

• Those affected more often include women, patients under 50 years of age, anxious patients, and those who experience motion sickness. Symptoms may be:

– Acute (occurring within 24 hours of treatment): use 5hydroxy-tryptamine 5HT3 or serotonin antagonists e.g. Granisetron)

– Delayed (first occurring more than 24 hours after treatment). Use Dexamethasone alone or with metoclopramide

– Anticipatory (occurring prior to subsequent doses). Use Lorazepam



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Adverse Effects of CytotoxicsNausea and vomiting:

Drugs may be divided according to their emetogenic potential:

• Mildly emetogenic treatment— radiotherapy, fluorouracil, vincaalkaloids, and low dose methotrexate.

• Moderately emetogenic treatment— taxanes, doxorubicin, and high dose methotrexate .

• Highly emetogenic treatment—cisplatin, dacarbazine, and high dose cyclophosphamide.



Bone-marrow suppression

• All cytotoxic drugs except vincristine and bleomycin cause bone-marrow suppression: neutropenia, thrombocytopenia.

• Fever in a neutropenic patient requires immediate broad-spectrum parentral antibacterial therapy.

• In selected patients, the duration and the severity of neutropenia can be reduced by the use of recombinant human granulocyte-colony stimulating factors (GCSF).

• Symptomatic anaemia is usually treated with red blood cell transfusions or Erythropoetin administered subcutaneously.



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Reproductive function:

• Most cytotoxic drugs are teratogenic and should not beadministered during pregnancy, especially during the first trimester.

• Regimens with an alkylating drug carry the risk of causingpermanent male sterility (there is no effect on potency). Pre-treatment counseling and consideration of sperm banking may beappropriate.



Anthracycline-induced cardiotoxicity:

• The anthracycline cytotoxic drugs are associated with dose-related,cumulative, and potentially life-threatening cardiotoxicity.

• Dexrazoxane is licensed for the prevention of chronic cumulativecardiotoxicity caused by doxorubicin or epirubicin treatment



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Haemorrhagic cystitis:

• is a common manifestation of urothelial toxicity which occurs withthe cyclophosphamide and ifosfamide; it is caused by themetabolite acrolein.

• Mesna reacts specifically with this metabolite in the urinary tract,preventing toxicity. Mesna is used routinely in patients receivingthese drugs.


Leukemias & Lymphomas



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Leukemias

• Leukemia and lymphoma are the main haematological malignancies

• Characterized by improvement of prognosis with the use of chemotherapy

• Leukemia is divided into 4 groups:

– Acute myeloblastic (AML)

– Acute lymphoblastic (ALL)

– Chronic myelocytic (CML)

– Chronic lymphocytic (CLL)



Chronic Leukemia:

• CML: 30% asymptomatic. malaise, weight loss and night sweats, hepato-splenomegaly

• CML is a triphasic disease : the initial phase (months to years), the median phase (5 years) and the accelerated phase (progressive)

• CLL: night sweats, weight loss, hepato-splenomegaly, lymph-adenopathy,. Survival varies from 2 to 20 years

• CLL: Patients are of increased risk of infection, haemolytic anaemia, thrombocytopenia, non-Hodgkin’s lymphoma



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Bone Marrow Aspiration


Treatment

• Induction therapy: ablation of bone marrow followed by recovery of normal haemopoiesis Remission = absence of all clinical and microscopic signs of disease

• Consolidation therapy: intensive post remission therapy to sustainthe remission

• Maintenance therapy: to sustain a complete remission . Milder than induction or consolidation but for longer duration

• Supportive therapy: is vital to manage the disease and the complications of therapy e.g. ADRs, pain, infection etc.



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Treatment

• Patients with ALL affecting brain are treated with intrathecalmethotrexate (MTX) or cranial irradiation because cytotoxicspoorly pass the BBB

• ALL treatments generally include: methotrexate, cytorabine,prednisolone, vincristine, 6-mercaptopurine

• AML treatment generally include: daunorubicin, etoposide,mitoxantrone, fludarabine


Treatment

• CML treatment include: hydroxycarbamide (hydroxyurea) (brings theWBC under control within 1-2 weeks), interferon, imatinib, BMT

• CLL: there is no cure. All treatments are palliative specially inlymph-adenopathy. Drugs include: chlorambucil, cyclophosphamide,prednisolone, fludarabine



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Treatment

BMT = bone marrow (stem cell) transplantation:

• Life-saving technique start with conditioning therapy including high dose cyclophosphamide or melphalan or busulpham (ablative therapy)for 2-3 days followed by infusion of harvested stem cells.

• Allogenic (Allograft) BMT: uses donor bone marrow, ablative therapy and infusion

• Autologus (Autograft) BMT: uses own patient bone marrow, ablative therapy and infusion




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BMT Complications

• Acute graft versus host disease (GVHD)

• Caused by T-lymphocytes in the donated marrow

• Life threatening disease. May lead to multi-organ failure with a high mortality rate (infection)

• Risk increases with age (>45 years)

• Occurs within 100 days of BMT

• Fever, rash, diarrhoea and liver dysfunction

• Prophylaxis: ciclosporin, Methotrexate for 6-12 months post BMT

• Treatment: high dose methylprednisolone + ciclosporin


Lymphomas

• Cancer of the lymphatic system. It account for 3% of cancer cases annually

• There are 2 main categories, Hodgkin’s (HL) and non-Hodgkin’s (NHL) lymphomas

• The main site is the lymph nodes but NHL may involve skin, GIT and CNS

• They are aggressive diseases and fatal if not treated.



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Hodgkin (HL) and Non-Hodgkin (NHL) Lymphomas

• Characterized by enlarged abnormal lymph nodes with anaemia

• Risk factors for HL include glandular fever, HIV and genetic link

• Etiology for NHL may include malaria infection, use of immuno-suppressants, insecticides, Crohn’s disease

• High grade NHL is fatal within months, but very responsive to therapy

• Symptoms: painless lymph-adenopathy, hepato-spleno-megaly, weight loss, fever, sweats

• Diagnosed by CBC, BMA, lymph node biopsy,

• Medications include: doxorubicin, vincristine, etposide, procarbazine, prednisolone, cyclophosphamide, fludarabine,


Patient Care

• Patient and family must be aware of long term treatment complications, success rate and ADRs

• Common complications: mucositis, febrile neutropenia, GVHD, cancer, cardiotoxicity

• RBCs for anaemia and platelets for thrombocytopenia and bleeding

• Renal, hepatic and other concomitant diseases

• Endogenous infections from gut respiratory tract and skin are prevented by giving prophylactic anti-infectives and encourage oral hygiene.

• Neutropenia: managed by GCSF therapy.



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Colorectal Cancer


World Health Organization – Oman Cancer Country Profiles, 2014


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WORLWIDE: Annual cancer cases will rise from 14mn in 2012 to 22 within the next twodecades

2011: 1,289. Of these 1,187 were Omanis and 102 were non-Omanis. (50% F/M)

Oman had recorded a 25 per cent increase in 2011 as compared to 2010, - Ministry ofHealth.

The success of treatment is less as 50 per cent of the patients are in the advanced stages.

There has been a remarkable improvement in health, and life expectancy (beyond the ageof 70)

Eighty seven cases were reported among children aged 14 years and below.

The incidence rate per 100,000 of the population was found to be the highest in Dhofargovernorate at 75.1, followed by Muscat with 73.4. The incidence in Dakhliyah was 41.6,

Cancer in Oman. Feb 8, 2016

Oman Cancer association


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malignancy







Colorectal Cancer



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PATHOPHYSIOLOGY

• Colorectal cancer is a malignant neoplasm involving the colon, rectum, and anal canal.

• Development of a colorectal neoplasm is a multistep process of genetic alterations of normal bowel epithelium structure and function leading to unregulated cell growth, proliferation, and tumor development.

• Adenocarcinomas account for more than 90% of tumors of the large intestine.


CLINICAL MANIFESTATIONS

• Patients with early-stage colorectal cancer are often asymptomatic,and lesions are usually detected by screening procedures.

• Blood in the stool is the most common sign; however, any change in bowel habits, vague abdominal discomfort, or abdominal distention may be a warning sign.

• Approximately 20% of patients with colorectal cancer present with metastatic disease. The most common site of metastasis is the liver, followed by the lungs and then bones.



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PREVENTION AND SCREENING

• Primary prevention is aimed at preventing colorectal cancer in at-risk population = Chemoprevention with celecoxib is one of the preventive measures.

• Secondary prevention is aimed at preventing malignancy in a population that has already manifested an initial disease process

• Screening: Digital rectal examination and annual occult fecal blood testing starting at age 50 years and examination of the colon every 5 or 10 years depending on the procedure.


TREATMENT

• The goals of treatment are to eradicate micrometastatic disease, prevent recurrence and alleviate symptoms.

• Chemotherapy is the primary treatment modality for metastaticcolorectal cancer.

• Surgical removal of the primary tumor is the treatment of choice for most patients with operable disease

• Fluorouracil (5-FU) and Capecitabine are the most widely used chemotherapeutic agents.



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Breast Cancer




malignancy








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Breast Cancer


PATHOPHYSIOLOGY

• The strongest risk factors are female gender and increasing age. Additional risk factors include:

– endocrine factors (e.g., late age at first birth, estrogen therapy),

– genetics (e.g., personal and family history, mutations of tumor suppresser genes)

– environment (e.g. radiation exposure).

• Breast cancer spreads via the bloodstream early in the course of the disease, resulting in relapse and metastatic disease after local therapy.

• The most common metastatic sites are lymph nodes, skin, bone, liver, lungs, and brain.



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CLINICAL PRESENTATION

• The initial sign in more than 90% of women with breast cancer is apainless lump that is typically solitary, unilateral, solid, hard,irregular, and nonmobile.

• Less common initial signs are pain and nipple changes. Moreadvanced cases present with prominent skin edema, redness,warmth, and induration (rigid breast).

• Symptoms of metastatic breast cancer include bone pain, difficultybreathing, abdominal enlargement, jaundice, and mental statuschanges.

• It is common to detect breast cancer during routine screeningmammography in asymptomatic women.


DIAGNOSIS

• Initial workup should include a careful history, physical examinationof the breast, mammography, and possibly ultrasound.

• Breast biopsy is indicated for a mammographic abnormality thatsuggests malignancy or a mass that is palpable on physicalexamination.

• Stages of breast cancer:

– Stages 0 – II: Early Breast Cancer

– Stage III: Locally Advanced Breast Cancer

– Stage IV: Advanced or Metastatic Breast Cancer



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TREATMENT

• The goal of therapy with early and locally advanced breast cancer iscure. The goals of therapy with metastatic breast cancer are toimprove symptoms, improve quality of life, and prolong survival.

• Surgery alone can cure most patients with localized cancers andapproximately half of those with stage II cancers.

• Doxorubicin-containing regimens are popular. Taxanes are a newerclass against metastatic breast cancer.

• Tamoxifen is the gold standard for adjuvant endocrine therapybecause of decreased recurrence and mortality.

• Prevention: Tamoxifen, 20 mg daily, reduced the incidence by 48%.


Cancer Treatment

• Induction therapy: ablation of bone marrow followed by recovery ofnormal haemopoiesis Remission = absence of all clinical andmicroscopic signs of disease

• Consolidation therapy: intensive post remission therapy to sustainthe remission

• Maintenance therapy: to sustain a complete remission . Milder thaninduction or consolidation but for longer duration

• Supportive therapy: is vital to manage the disease and thecomplications of therapy e.g. ADRs, pain, infection etc.



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Guidelines on handling cytotoxic drugs

1. Trained personnel should reconstitute cytotoxics

2. Reconstitution should be carried out in designated areas

3. Personal protective equipment (PPE) should be used

4. Face and eyes should be protected

5. Adequate care should be taken in the disposal of waste material, including syringes, containers etc..

6. Pregnant staff should not handle cytotoxics

7. Staff dealing with cytotoxics should be monitored



Personal protective equipment (PPE)


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ANAEMIA


Learning Outcomes


– Recognize the blood components

– Discuss the etiology, pathophysiology and clinical manifestations of anaemia

– Discuss the common inherited haemoglobinopathies in Oman

– Describe the management of anaemias/blood disorders

– Educate patient on proper management of his anaemia



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Components of Blood• The majority of blood is plasma which is a water based solution

containing plasma proteins, electrolytes and other dissolved constituents.

• The remainder of blood is cellular consisting of

– Red blood cells (Erythrocytes) Anaemias– White blood cells & lymphatic system (Leucocytes, Lymphocytes,)

infections, malignancies

– Platelets (Thrombocytes) coagulation profile

• Blood bank transfusion - BMT transplantation


Components of Blood



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Introduction• Generally anaemia means a lowering of haemoglobin

concentration, red cell count, or packed cell volume(Haematocrit) to below `normal' values

• WHO's suggested definition of anaemia:– Adult: a haemoglobin concentration below 13 g per 100 mL in men

and below 12 g per 100 mL in women;

– Children: below 12 g per 100 mL (6 to 14 years), or below 11 g per100 mL (6 months to 6 years)

• Symptoms of anaemia are variable: fatigue, pallor, dyspnoea,palpitations, faintness, anorexia, tachycardia, heart failure


Introduction

• Reduction in overall haemoglobin concentrations may be due to:– reduced red cells in size (microcytic), enlarged (macrocytic), or normal in

size (normocytic).

– reduced red cells in number with the cells retaining normal amounts ofhaemoglobin (normochromic anaemia)

– reduced amount of haemoglobin in the cells (hypochromic anaemia).

• The immediate cause of anaemia could be:– decreased red cell production (due to defective proliferation and/or

maturation of red cells from their precursors in bone marrow),

– increased red cell destruction (i.e. haemolysis), or loss of red cells fromthe circulation (haemorrhage)

• These conditions may occur due to underlying disease,nutritional deficiency, congenital disorders, or drug toxicity.



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Haemolytic anaemia

• Defined as a reduction in the mean life span of RBC (120days) due to premature destruction of red cells ----- haemolysis

• Haemolytic anaemias may be either congenital or acquired:

– The congenital disorders include: sickle-cell disease, beta-thalassaemia and Glucose-6-phosphate dehydrogenasedeficiency (G6PD deficiency) anaemia.

– The acquired disorders include: The immune type e.gpenicillin allergy and the non-immune type e.g. malaria orsnake venoms



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Haemolytic anaemia

• In patients with G6PD deficiency (congenital), treatment consists essentially of avoidance of drugs or foodstuffs likely to provoke haemolysis (dapsone, fava beans).

• Acquired haemolytic anaemia is best treated by eliminationof any underlying cause. Most drug-induced haemolytic anaemias respond rapidly to discontinuation of the drug.


Haemolytic anaemia G6PD

Drugs with definite risk: • Dapsone

• Niridazole

• Methylene blue

• Nitrofurantoin

• Primaquine

• Quinolones

• Sulphonamides

• Naphthalene

• Food: Fava beans Favism

Drugs with possible risk:• Aspirin

• Chloroquine

• Quinine

• Quinidine

• Menadione



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Iron-deficiency anaemia • If loss is increased, and/or intake decreased, a negative iron-balance may lead to

depletion of body iron stores, iron deficiency, and eventually to anaemia.

• Iron requirements are increased during infancy, puberty, pregnancy, and during menstruation. Iron-deficiency anaemias are most common in women and children;

• Iron deficiency usually results in a microcytic, hypochromic anaemia, but the diagnosis of iron deficiency should be confirmed by measurement of serum ferritin and total iron binding capacity (transferrin).

• Almost all iron-deficiency anaemias respond readily to treatment with iron. The treatment of choice is oral administration of a ferrous salt.

• Many iron compounds have been used for this purpose, but do not offer any real advantage over the simple ferrous sulfate, fumarate, or gluconate salts.

• The usual adult dose is about 100 to 200 mg of elemental iron daily.


Iron-deficiency Anaemias (IDA)



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Iron-deficiency anaemia

Adverse effects of Iron:

• Gastro-intestinal irritation can occur with iron salts. Nausea and epigastric pain are dose-related

• Oral iron, particularly modified-release preparations, can exacerbate diarrhoea in patients with inflammatory bowel disease

• Iron preparations taken orally can cause constipation, particularly in older patients

• If side-effects occur, the dose may be reduced; or another iron salt may be used

• May cause urine discoloration


Megaloblastic anaemia

• Megaloblastic anaemia is a consequence of impaired DNA biosynthesis, usually due to a deficiency of B12 (cobalamins) or folate, both of which are essential for this process.

• For immediate treatment, combined therapy for both deficiencies (B12 + Folic) may be started. The patient may be converted to the appropriate treatment once the cause of the anaemia is known.



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• Vitamin B12 deficiency anaemia may be due to:– malabsorption following gastrectomy, or lack of the intrinsic factor

essential for B12 absorption (pernicious anaemia)

– dietary deficiency (mainly in strict vegetarians),

• vitamin B12 deficiency may result in neurological damage,including peripheral neuropathy and effects on mentalfunction.



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• The treatment is with vitamin B12, almost always by theintramuscular since in most patients absorption from thegastrointestinal tract is inadequate.

• Hydroxocobalamin is preferred to cyanocobalamin since itneeds be given less often.

• Hydroxocobalamin 1 mg every 2 to 3 months for life is used toprevent a recurrence of the deficiency as in pernicious anaemia,total gastrectomy .


Megaloblastic anaemia • Folate-deficiency anaemia may be due to:

– inadequate diet, or malabsorption syndromes

– increased utilisation as in pregnancy,

– increased urinary loss or loss due to haemodialysis, or to an adverseeffect of alcohol or anti-epileptics

• Deficiency may be associated with neural tube defects if it occurs inpregnancy.

• Drugs which act as inhibitors of dihydrofolate reductase, such asmethotrexate, may produce severe megaloblastic anaemia. This may beprevented or reversed by therapy with folinic acid



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Spina bifida "split spine” is a developmental birth defect caused by the incomplete closure of the embryonic neural tube



• Women in the high risk group who wish to become pregnant should take folic acid 5 mg daily to continue until week 12 of pregnancy

• Women with sickle-cell disease should continue taking their normal dose of folic acid 5 mg daily throughout pregnancy.



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Haemoglobinopathies

• Haemoglobinopathies are clinical abnormalities due to altered structure, function, or production of haemoglobin.

• Examples: Sickle-cell disease and beta-thalassaemia


Prevalence



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Sickle-cell disease • Sickle-cell disease is a formation of an abnormal haemoglobin SS, making the

red cell sickle in shape.

• The sickle-cell trait (haemoglobin AS), is generally asymptomatic

• In addition to shortened survival, the decreased flexibility of the deformederythrocytes can lead to vaso occlusive crisis (VOC).

• This may produce pain due to infarction with no blood supply to the bones,lung (ACS), liver, kidney, penis (priapism), and brain (stroke).

• Occasionally a large proportion of red cell mass may become trapped inspleen or liver (sequestration crisis) with death due to anaemia.


Sickle Cell Anaemia - VOC



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Sickle-cell disease

• Treatment of sickle-cell disease is essentially symptomatic.

• Young children should receive prophylactic penicillin and pneumococcal vaccine, to reduce the risk of infection

• Infection should be treated early,

• Folate supplementation given because of increased erythropoiesis (RBCs production)

• Sickle-cell crisis requires hospitalisation, with rehydration and analgesia(including morphine) for pain.

• Blood transfusion is also important to avoid fatal anaemia.


Sickle-cell disease

• Studies reported that therapy with hydroxycarbamide (hydroxyurea) caused a 44% reduction in the rate of painful crises.

• Bone Marrow Transplantation is curative in some patients.



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Sickle Cell Anemia Rx

Phenoxymethyl penicillin (pen V) 125 mg 12 hourly

Folic acid 5 mg OD

Mefenamic acid 250 mg / Ibuprofen 200 mg TDS / prn..

Morphine BD / Tramadol / co-codamol 2-4 times daily prn

Hydroxycarbamide (hydroxyurea) 500 mg BD ………………….. can reduce the frequency of crises in sickle-cell disease and reduce the need for blood transfusions


Beta-Thalassaemia

• Thalassaemia major: Due to a deficiency in beta globin production and interference with red cell maturation

• The RBCs are trapped and destroyed in the spleen.

• The condition is characterised by a hypochromic, microcytic anaemia accompanied by haemolysis.

• In thalassaemia trait/minor where only one of the beta globin genes is affected, the anaemia is mild and clinically insignificant.



127

TH

AL

AS

SA

EM

IA

Alpha Thal

alpha chain =

beta chain =Alpha ppt

On the walls

Of the RBCs

RBCs damage

Bone marrow

Liver

Spleen (enlargement)

Beta Thal (anaemia)

Thalassaemia Minor (trait) Thalassaemia Major

SQUH Patients = 230

Beta Thal



Liver and spleen enlargement Bone changes – jaw, forehead

Arrhythmias Pain, lack of appetite, fatigue Haemoglobin < 8 (10-11g/dL)



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beta-Thalassaemia

• The anaemia stimulates erythropoietin production, and if not corrected it will result in recurrent bone fractures, deformity of the skull, splenomegaly and increased susceptibility to infection.

• If untreated, death in patients with thalassaemia major usually occurs by the 2nd or 3rd year.

• Treatment includes regular blood transfusion to correct the anaemia. Transfusions should be started as early as possible in life.


beta-Thalassaemia

• Repeated transfusion results in iron overload , leading eventually to haemochromatosis.

• The consequences of haemochromatosis include liver dysfunction, endocrine dysfunction, hypogonadism, diabetes and hypothyroidism, arrhythmias and heart failure.

• If unchecked, the iron build-up usually leads to death (mainly through heart failure or arrhythmia).

• The accumulation of iron can be retarded by the use of the chelating agent desferrioxamine injection.

• Deferiprone and deferasirox have been used as an oral alternative to desferrioxamine,



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Desfrrioxamine Pump


Thalassaemia Rx

• Inj. Desferrioxamine 0.5 - 2 g daily, 5 days a week + Deferiprone 500 mg OD,5 days a week.

• Water for injection

• Emla cream

• Folic acid 5 mg OD

• Ascorbic acid 100 mg OD

• Zinc 50 mg OD

• Mefenamic acid 250 mg OR Ibuprofen 200 mg TDS / prn..

• Hypoglycemics, biphosphonates, Ca, ACEI, aspirin…



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1

College of Pharmacy and Nursing

School of Pharmacy

Pharmacotherapy III

Course Code: PHCY 510

Spring Semester 2018-19

Dr. Ahmed A. Abusham Assistant Professor - Clinical Pharmacy

Revised Jan2019

University of Nizwa Pharmacy Practice Dr. Ahmed Abusham

Case Discussion

Scenario: Sara is a 25-year-old marketing executive. She is worried about her cough and hoarse voice, as she has to give a presentation to her company board next week. Sara says that she developed symptoms of cough with thick mucus sputum, running nose, mild fever and tiredness 5 days ago. She used ‘cough lozenges’ for her symptoms and felt ‘a bit better. She denies any sputum production or wheeze, or contact with anyone suffering from pertussis (whooping cough). Sara is single and lives with her parents. She is a non-smoker and drinks alcohol only at social functions. She underwent a tonsillectomy at age 13. She denies any history of asthma. She has no history of renal or hepatic disease and no known drug allergies. Her family history is unremarkable. Currently, she is not taking any medication. On examination, she looks anxious. Her blood pressure is 126/84 mmHg, pulse 90 beats/min, respiratory rate 15/min and temperature 37.8 ºC. There is no cervical lymphadenopathy or cyanosis. Throat examination reveals no exudates. Respiratory examination reveals no chest wall tenderness and auscultation reveals normal breath sounds. There were no other significant findings.

Questions:

1. Apply SOAP module to this scenario.

2. Sara is worried about her symptoms and requests an antibiotic prescription. She says shewas prescribed an antibiotic for similar symptoms in the past and felt better after taking it.Would you recommend an antibiotic for Sara at this visit? Why/why not? If yes, pleasespecify:

3. Would you recommend any over-the-counter medication(s) for Sara’s symptoms?Why/why not? If yes, please specify:

4. What advice will you give Sara about non-pharmacological strategies to manage hercurrent condition?

Patient‐centeredCare


Case Discussion

Scenario:

Mr Abdulla, a 42-year-old businessman, reported a seven-day history of extreme sleepiness and lack of energy (lethargy), sneezing, running nose and dry sore throat. He also reported that over the last two days he has also had facial pain and his nasal discharge is now green. He has been using a topical decongestant nasal spray and paracetamol for the past two days with partial symptom relief. Examination is unremarkable except for fever and bilateral maxillary facial tenderness. He has no known drug allergies. Laboratory result revealed heavy growth of Streptococcus pyogenes.

Questions: 1. Apply SOAP module to this case

AcuteSinusitis


Case Discussion

Scenario: Amna, a 55-year-old female; Chief Complaint: Increased urinary urgency, frequency, fever, and lower back pain. She claims that she was OK until about 2 days ago, when she first noticed an increased frequency and urgency to use the bathroom. She attributed her symptoms to trying a different brand of coffee. She became more concerned when she began experiencing a slight fever and lower back pain (5/10) yesterday evening; Medical History: Hypertension (HTN) for 10 years; type 2 diabetes mellitus for 8 years; history of nephrolithiasis Family History: Father died of myocardial infarction (MI) age 70. Social History: Occasional alcohol use on weekends, no history of smoking

Medication History: Atenolol, 25 mg PO OD Metformin, 500 mg PO BID Enteric-coated aspirin, 125 mg PO OD Multivitamin, 1 tablet PO OD Calcium carbonate + Vitamin D, 500 mg PO BID Allergies: no known drug allergies

Physical Examination Pleasant woman in mild discomfort T 38°C, BP 146/90, HR 90, RR 24, Wt 58 kg, Ht 158 cm

Laboratory results: [study these results using ‘lab reference values’ handouts.]

Na: 140 Hct: 0.35 SCr: 88.4

K: 4.1 Hgb: 135 Glucose: 13.3

Cl: 100 Lkcs: 14.1 × 109

HCO3: 24 Plts: 330 × 109 Urinalysis: WBC 3 +, Gram (-) rods >105 CFU/mL (+) Hematuria, (+) Nitrite, Blood Cultures: Pending BUN: 4.99 HBA1c 7.8%

UrinaryTract

Infection


Questions: 1. Apply SOAP module for this scenario.

2. Which organism is the most prevalent in urinary tract infections (UTIs)?a. Klebsiella sppb. Proteus mirabilisc. Escherichia colid. Staphylococcus saprophyticus

3. What is the most common route of organism entry into the urinary tract?a. Via contaminated foodb. Via an ascending route from the urethra into the bladderc. Via a descending route from the kidney into the bladderd. Clearance of a systemic infection into the bladder

4. Amna most likely has what type of UTI?a. Acute uncomplicated cystitisb. Acute uncomplicated pyelonephrititsc. Acute complicated pyelonephritisd. Nosocomial UTI

5. Why did the medical team obtain blood cultures?

6. If Amna's medical team wanted to initiate treatment with Gentamicin, what would beyour advice in relation to dose, frequency and duration of gentamicin therapy?

7. Amna is discharged from the hospital and given a prescription for Levofloxacin 500 mgPO QD × 10 days. As the pharmacist dispensing this prescription to Amna, what are some important patient counseling points that you should mention to Amna?

8. If the medical team diagnosed Amna with a nosocomial UTI, which organism would bethe most concerning? a. E. colib. S. saprophyticusc. Pseudomonas aeruginosad. Klebsiella Spp,

9. Which of the following represents the best choice for the initial management of anosocomial UTI? a. Gentamicin IV + piperacill in/tazobactam IVb. Imipenem IVc. Oxacill in IVd. Vancomycin IV

10. Summarize therapeutic, pathophysiologic, and disease management concepts for thetreatment of UTI using the key points format.


Case Discussion

Scenario: Mr Khalid, a 19-year-old university student, presents to the clinic in the afternoon, complaining from severe headache, vomiting and added that he cannot tolerate direct sun light since early morning of the same day. On examination, the patient has fever and he is unable to touch his chin to his knees. He does not have a rash and is alert and oriented. The GP administered benzylpenicillin IV. 1.2 g and Khalid was transferred urgently by ambulance to A&E. Mr Khalid weighs 70 kg, is a smoker and has an unremarkable medical history. Khalid remembers that he occasional takes caffeine tablets prior to examinations and meningitis vaccine given at school. On arrival at A&E, his vital signs are recorded as follows: heart rate 124 bpm temperature 39.0°C respiratory rate 28 breaths per minute blood pressure 95/65 mmHg

Planned investigations include: lumbar puncture(LP) and cerebrospinal fluid (CSF) analysis CSF PCR for herpes simplex virus (HSV) blood cultures urea and electrolytes and full blood count

The following lumbar puncture cerebrospinal fluid (CSF) results are reported from the biochemistry and pathology laboratories within 4 hours of admission: White blood cells 1350 (<5 cells/mm3) CSF protein 1.31 (<0.4 g/L) CSF glucose 1.4 (2.2–4.4 mmol/L) Gram-negative diplococci identified in the CSF

The patient is diagnosed with suspected meningitis and the treatment plan is as follows: cefotaxime i.v. 2 g q.d.s. aciclovir i.v. 700 mg t.d.s. paracetamol p.o./p.r. 1 g q.d.s. cyclizine i.v. 50 mg t.d.s. p.r.n.

Discussion: 1. Apply SOAP module for this scenario.2. What are the signs and symptoms of meningitis?3. What is the significance of these laboratory findings?4. Which antibiotic regimens pass BBB and achieve therapeutic concentrations in the CSF?5. What is the rationale for prescribing aciclovir in cases of suspected meningitis? What is

your advice to the clinician/prescriber? 6. What are the goals of therapy in community-acquired bacterial meningitis?

Meningitis


Case Discussion

Scenario: A 4-year-old boy is brought to the clinic by his mother. She says that her son keeps scratching a spot on his arm for several days, and it appears that the spot is growing larger. No one else at home has anything similar. She added that he has not had a fever or any systemic signs of illness. There have been no recent exposures to new foods, medications, lotions, or soaps. He attends preschool during the day. On examination of his skin there was a circular, 25 BZ-sized-ring on his right forearm. It has a red, raised border. The remainder of his skin and his general physical examination are normal. The laboratory result revealed fungal epidermophyton. .

Questions: 1. Apply SOAP module for this scenario.2. Describe the common types of Fungi – give examples?3. List the antifungal drugs and describe their therapeutic uses.4. How do you prepare amphotericin B as an infusion?

Fungal Infection


Case Discussion

Scenario: Saleh is a 55-year-old male diagnosed with acute lymphocytic leukemia (ALL) 2 weeks back. He is currently receiving day 10 of his induction chemotherapy regimen. On day 7 of therapy, he became febrile, was cultured, and empirically started on ceftazidime 4.5 g 6 hourly and gentamicin 480 mg IV 24 hourly. Despite his aggressive antibiotic therapy, last evening he spiked a temperature to 39.8C. Saleh also complains of nose bleeds, fever and painful oral lesions

Past Medical History Saleh was diagnosed with rheumatoid arthritis (RA) 2 years ago and has been managed with non-steroidal anti-inflammatory drug (NSAID) therapy. He was healthy until the diagnosis of ALL.

A. Apply SOAP module to this scenario.. B. Answer the following Questions:

1. What is the role of antibiotics in the treatment of febrile neutropenia?2. Discuss the cascade of antimicrobial therapy in febrile neutropenic patients3. Discuss the etiology of neutropenia and thrombocytopenia in this patient4. What is the role of Co-trimoxazole in the treatment of immunocompromised patients?5. Should Saleh receive a colony-stimulating factor e.g. GCSF

Medication History Daunorubicin 100 mg IV D1-3 Vincristine 2 mg IV D1,8,15,22 Prednisone 50 mg PO BD D1-28 Asparaginase 10,000 U SC D17-28

Co-trimoxazole: 960 mg PO BD Fri, Sat, Sun Ranitldine: 50 mg IM OD Prochlorperazine:10 mg IM Q6h PRN Napraxen: 500 mg PO BD Allopurinol: 300 mg PO OD

Physical Examination: Thin, ill-appearing male Vitals: BP 110/72, HR 90, RR 28, T 39.8, Wt 57.0 kg, Ht 147 cm, BSA 1.68 m2. Conjunctival hemorrhage, White patches on oral mucosa Chest: clear Hickman catheter site: erythema Skin: Multiple ecchymosis and petechiae

Na 139 mmol/L K 4.1 mmol/L Glu 6.3 mmol/L Cr 88.4 mcmol/L AST 68 U/L ALP 532 U/L Uric 535 mcmol/L Hct 0.28% Hgb 12 mmol/L WBC 50X109 ANC 0.1 (100 cells/mm3) Plts 13X109

Laboratory results /investigation: WBC differential: promyeloblast present Bone marrow biopsy: +ve for ALL Blood culture: negative.? Oral culture> Candida albicans

Febrile Neutropenia


Case Discussion

Scenario: Mrs Wadha is a 25-year-old nurse, who has just been diagnosed HIV positive during routine antenatal screening. Her husband and their 3-year-old child have yet to be tested. She is 13 weeks pregnant and has a CD4 count of 450 cells/mm3 (500-1500) and a viral load of 15000 copies/ml. She has no HIV-related symptoms and is very shocked by the diagnosis.

Questions: 1. Apply SOAP module to this scenario.2. What are the predominant routes of HIV transmission3. Discuss the goals of therapy in HIV-positive individuals4. Outline the pharmaceutical care issues for Mrs Wadha during her pregnancy,

delivery, and for the care of her newborn baby? 5. 1f Mrs Wadha's husband tests negative for HIV, what advice should be given to

them regarding future family planning and HIV prevention?

HIV


Case Discussion

Scenario:

Fakhriya, a 70-year-old woman, reported that she has been feeling very tired. She informs her GP that she has been getting out of breath when walking up stairs which she never had in the past. She also reported that she is a strict vegetarian. On examination Fakhriya has pallor of the skin, conjunctiva and nail beds and brittle nails. The GP performs microscopy and a peripheral smear and the results show the following:

Microcytic hypochromic RBCs Serum iron 30 mcg/dL Total iron-binding capacity (TIBC) 660 mcg/dL HCT 25%

Questions: Apply SOAP module to this scenario. What is anaemia? What typical blood results might you expect in a patient with iron-deficiency

anaemia? What symptoms does Fakhriya have that support the diagnosis of iron-

deficiency anaemia? What risk factors does Fakhriya have for developing this condition? What medication would you recommend for Fakhriya? (drug, dose and

frequency.) What are the common side-effects of iron preparations? Should modified-release iron preparations be used in the treatment of anaemia?

Justify your answer. How would you counsel Fakhriya about the medications you have

recommended? Fakhriya tells you that she takes Antacids for her indigestion. Can she continue

to take this? What follow-up should Fakhriya receive?

Iron-deficiency Anaemia


Case Discussion

Scenario: Raya is a gray-haired 58-year-old lady, admitted to the hospital through A&E. She claimed that she had fallen over and bruised herself. On examination she appeared pale, confused, has yellow skin, inflamed tongue. She also has paraesthesia of feet and fingers. Raya had past history of heart failure. Her medications include frusemide and amiloride. She is diagnosed as having macrocytic anaemia. Laboratory tests revealed the following:

RBCs --- Macrocytic normochromic MCV --- 180 µm3 Folate --- 160 mg/l (160 – 640 mg/l). B12 --- 70 (110-1500 pg/mL)

Questions: • Apply SOAP module to this scenario.• State the causes of B12 deficiency anaemia.• What are the evidences that may lead you to consider B12 deficiency anaemia as a

diagnosis? • Can Raya have a blood transfusion after samples have been taken for folate and

B12 levels?

MegaloblasticAnaemia


Monday, September 16, 2013

Essential Tools for Pharmacy Practice

NB: These formulas are intended for use in adult patients

Estimated Creatinine Clearance (CLcr) in mL/minute: (the Cockcroft and Gault formula)

= (140 – Age) x Weight x Constant Serum creatinine Age in years Weight in kilograms; use ideal body-weight Serum creatinine in micromol/litre Constant = 1.23 for men; 1.04 for women

Important note: Renal function in adults is increasingly being reported on the basis of estimated glomerular filtration rate (eGFR) normalised to a body surface area of 1.73 m2 and derived from the Modification of Diet in Renal Disease (MDRD) formula which can be used to determine dosage adjustments in place of creatinine clearance. Toxic drugs: For potentially toxic drugs with a small safety margin, creatinine clearance (calculated from the Cockcroft and Gault formula) should be used to adjust drug dosages in addition to plasma-drug concentration and clinical response. Patients at extremes of weight: In patients at both extremes of weight (BMI of less than 18.5 kg/m2 or greater than 30 kg/m2) the absolute glomerular filtration rate or creatinine clearance (calculated from the Cockcroft and Gault formula) should be used to adjust drug dosages. ------------------------------------------------------------------------------------------------- Estimated body mass index (BMI): Body Mass Index = Weight (kg) / Height (m)2

Adult values: < 18.5 = Underweight 18.5 – 24.9 = Normal weight 25 – 29.9 = overweight ≥ 30 = Obese ----------------------------------------------------------------------------------- Estimated Ideal body weight in kg (IBW): Males: IBW = 50 kg + 0.9 (Ht – 152 cm) Females: IBW = 45.5 kg + 0.9 (Ht – 152 cm) Ht = height in centimeters ------------------------------------------------------------------------------------ For aminoglycosides calculate the adjusted body weight: ABW = IBW + 0.4 (TBW - IBW)

ABW = adjusted body weight: IBW = ideal body weight TBW = total body weight ------------------------------------------------------------------------------------- Body surface area (BSA) - The Mosteller formula:

BSA (m²) = √ Height (cm) x Weight (kg) / 3600]

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ References: British National Formulary (BNF) No. 63 (March 2012) Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. National Heart, Lung and Blood Institute. June 17, 1998 Gehan EA, George SL, Estimation of human body surface area from height and weight. Cancer Chemother Rep 1970 54:225-35. Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 22;317(17):1098


Is it Bacterial or Viral Infection? Description Bacterial Infection – Antibiotic needed Viral infection- NO Antibiotic needed Characteristics of microorganism Most bacteria are harmless, and some

actually help by digesting food, destroying disease-causing microbes, fighting cancer cells, and providing essential nutrients. Fewer than 1% of bacteria cause diseases in people.

Viruses are smaller than bacteria and require living hosts to multiply. Otherwise, they can't survive. When a virus enters the body, it invades cells and takes over the cell machinery, redirecting it to produce the virus.

Examples Pneumonia, Tuberculosis, Sinusitis, etc. Upper respiratory infection like common cold, flue can typically be detected by runny nose, cough, low-grade fever, sore throat, aching muscles.

Common symptoms, signs and duration of infection

A bacterial illness notoriously causes afever (> 37.80 C)

Shortness of breath Confusion / decreased responsiveness Malaise, headache, dehydration Tenderness and pain, pus discharge Lymphadenopathy

Causes site-specific symptoms, e.g.sinuses, throat infection.

Typically causes coloured (green,yellow, bloody or brown) mucus.

A bacterial illness commonly will lastlonger than 10 days.

A viral infection may or may not causemild fever.

Running nose, Sneezing. Coughing, Rhinitis, sore throat. Malaise, headache, ? dehydration Muscle aches

Typically causes wide-spread symptoms.

May produce clear or cloudy mucous, ifany.

Most viral illnesses last 2 to 10 days.

Diagnosis Diagnosing bacterial infection includes CBC, swabs or blood culture.

In viral respiratory infections, the diagnosis depends mainly on symptoms and signs


Description Is it Bacterial or Viral Infection? Follow-up on respiratory infection

Possible bacterial rather than viral: Viral infection may be followed by a secondary bacterial infection e.g. in diabetes or

exacerbation of COPD/Asthma More than 2 weeks of uncontrollable whooping cough: pertussis. A runny nose that persists beyond 10 days: sinus infection/pneumonia. Ear pain and new onset fever after several days of a runny nose: ear infection.

Patient should watch out for symptoms of pneumonia, but if he/she has a fever (< 37.80

C), pulse rate less than 100, respiratory rate less than 24 breaths per minute, and no chestsounds with clear chest x-ray, bacteria pneumonia is unlikely.

If symptoms do not resolve within 7-10 days, or if at any time patient develops a severeheadache or neck pain, persistent nausea / vomiting or a fever, he must see a doctor ASAP.

Patient counseling, education and management

Common scenario that is often frustrating for patients/consumers: 1. Leaving a doctor’s office “empty handed,” without a prescription for an

antibiotic! 2. Have wasted their time!3. Not worth the money that they pay!

Provide advice to reduce antibiotic use: 1. Reassure the patient by providing information on the natural course of illness and

time for resolution.2. Emphasize the risks of unnecessary antibiotics such as side effects (allergy,

diarrhea) and potential for developing resistant organisms3. Discourage use of antibiotics from others or using antibiotics left over from a

previous infection4. Recommend specific symptomatic therapy5. Listing symptoms that warrant a return visit6. Provide patient-education materials

Example management: adequate rest use of analgesics (paracetamol or ibuprofen) for headache, fever or muscle ache. use of saline solution or steam inhalations to help clear mucus and ease chest tightness use of honey and lemon, as they are simple to use and cheapest

Extract information from references

Objective: 1. Understand how to extract information from references, e.g. BNF, BNF for children and medicinesfor children, etc.2. Distinguish between adult and pediatric general issues, e.g. different doses and method ofcalculation (age, weight, BSA).3. Introduce to the general information of relevent group of drugs at the beginning of each chapter orsection (e.g. Asthma guideline, antimacrobial tables)

Outcome: 1. Be able to use the right dosage references and extract the required information.2. Know how to use the refrence.3. Know the diffrent measurements (age, weight or BSA) to calculate the dose.

Books are going to be used in this session are: BNF, BNF for children,

How to use these books:

BNF & BNF for children The book is Divided into chapters based on the system of the body (e.g.

cardiovascular system) or to an aspect of the medicines (e.g. infectious) the chapter is divided into sections based on the pharmacological action of the

drugs (e.g. Calcium channel blocker) other sections at the beganing of the book (e.g. emergancy treatment for

poisoning) At the end of the chapters, 9 appendix included (e.g. interaction) Finally the index give you the words arranged alphapitaclly either searching for a

drug or a disease.

Completed by:…………………………………..Date:………………………….

Exercise:

Using the BNF, answer the following questions*

1. Search for the drug “ATENOLOL”

a. Which pharmacological group does this drug belong to?

b. What the therapeutic dose for the following indications: hypertension and angina?

2. Search for the drug “GLYCERYL TRINITRATE”a. What it can be used for?

b. What is the dose if the sublingual tablet preparation is prescribed?

c. What is the dose if the Aerosol spray preparation is prescribed?

3. Search for the drug “FUROSEMIDE”

a. Which system is this drug related to? And what its therapeutic indication?

b. What other type of diuretic available?

4. Search for the drug “PREDNESOLONE”

a. What its therapeutic indication?

b. What type of prednisolone formulation available?

5. Search for the drug “WARFARIN”a. Give 3 examples of drug can interact with warfarin? Explain the interaction and the effect

when both drugs are taken.

6. Renal and liver impairnmenta. What is the dose of ‘PROGUANIL” if the patients has a moderate renal impairment?

b. Can “CLOPIDOGREL” be prescribed for patient with liver impairment?

7. Cautionary and advisory labels for dispensinga. Check the dispensing advises for “PARACETAMOL”

b. Check the dispensing advises for “PHENOXYMETHYLPENICILLINE”

8. Pregnancy and Breast feedinga. Check if “METFORMIN” can be given during pregnany and breast-feeding

* Please state the edition of the BNF you are using*


Elements of the Problem Oriented Medical Record SOAP (subjective; objective, assessment, plan) note.

Problem name: Each “problem” is listed separately and given an identifying number. Problems may be a patient complaint (e.g., headache), a laboratory abnormality (e.g., hypokalemia), or a specific disease name if prior diagnosis is known. When monitoring previously described drug therapy, more than one drug-related problem may be considered (e.g., nonadherence, a suspected adverse drug reaction or drug interaction, or an inappropriate dose). Under each problem name, the following information is identified:

Subjective Information that explains or delineates the reason for the encounter. Information that the patient reports concerning symptoms, previous treatments, medications used, and adverse effects encountered. These are considered nonreproducible data because the information is based on the patient's interpretation and recall of past events.

Objective Information from physical examination, laboratory results, diagnostic tests, pill counts, and pharmacy patient profile information. Objective data are measurable and reproducible.

Assessment A brief but complete description of the problem, including a conclusion or diagnosis that is supported logically by the above subjective and objective data. The assessment should not include a problem/diagnosis that is not defined above.

Plan A detailed description of recommended or intended further workup (laboratory radiology, consultation), treatment (e.g., continued observation: physiotherapy, diet, medications, surgery), patient education (self-care, goals of therapy, medication use and monitoring), monitoring, and follow-up relative to the above assessment.


Drug-Related Problems

1. Drug Needed (also referred to as no drug) o Drug indicated but not prescribed; a medical problem has been

diagnosed, but there is no indication that treatment has been initiated (maybe it is not needed)

o Correct drug prescribed but not taken (nonadherence)

2. Wrong/Inappropriate Drug o No apparent medical problem justifying the use of the drug o Drug not indicated for the medical problem for which it has been

prescribed o Medical problem no longer exists o Duplication of other therapy o Less expensive alternative available o Drug not covered by formulary o Failure to account for pregnancy status, age of patient, or other

contraindications o Incorrect nonprescription medication self-prescribed by the patient o Recreational drug use

3. Wrong Dose o Prescribed dose too high (includes adjustments for renal and hepatic

function, age, body size) o Correct prescribed dose but overuse by patient (overadherence) o Prescribed dose too low (includes adjustments for age, body size) o Correct prescribed dose but underuse by patient (underadherence) o Incorrect, inconvenient, or less-than-optimal dosing interval (consider

use of sustained-release dosage forms) 4. Adverse Drug Reaction

o Hypersensitivity reaction o Idiosyncratic reaction o Drug-induced dis ease o Drug-induced laboratory change

5. Drug Interaction o Drug-drug interaction o Drug-food interaction o Drug-laboratory test interaction o Drug-disease interaction


Rahma has indicated that she is injecting insulin to treat her diabetes. What questions might be asked to evaluate Rahma's use of and response to insulin? The following types of questions, when asked of Rahma, should provide the practitioner with information on Rahma's understanding about the use of and response to insulin. Drug Identification and Use

What type of insulin do you use? How many units of insulin do you use? When do you inject your insulin in relationship to meals? Where do you inject your insulin? (Rather than the more judgmental question,

“Do you rotate your injection sites?”) Please show me how you usually prepare your insulin for injection. (This

request of the patient requires the patient to demonstrate a skill.) What, if anything, keeps you from taking your insulin as prescribed?

Assessment of Therapeutic Response

How do you know if your insulin is working? What blood glucose levels are you aiming for? How often and when during the day do you test your blood glucose

concentration? Do you have any blood glucose records that you could share with me? Would you show me how you test your blood glucose concentration? What is your understanding of the hemoglobin A1c blood test? When was the last time you had this test done? What were the results of the last hemoglobin A1c test?

Assessment of Adverse Effects

Do you ever experience reactions from low blood glucose? What symptoms warn you of such a reaction? When do these typically occur during the day? How often do they occur? What circumstances seem to make them occur more frequently? What do you do when you have a low blood glucose?

The patient's responses to these questions on drug use, therapeutic response, and adverse effects will allow a quick assessment of the patient's knowledge of insulin and whether she is using it in a way that is likely to result in blood glucose concentrations that are neither too high nor too low. The responses to these questions also should provide the practitioner with insight about the extent to which the patient has been involved in establishing and monitoring therapeutic outcomes. Based on this information, the practitioner can begin to formulate the patient's therapeutic plan.


1

Table 1 Blood Chemistry Reference Values

Laboratory Test

Normal Reference Values

Conversion Factor Comments

ConventionalUnits SI Units

Electrolytes Sodium 135–145

mEq/L 135–145 mmol/L

1 Low sodium is usually due to excess water (e.g., ↑ serum antidiuretic hormone) and is treated with water restriction. ↑ in severe dehydration, diabetes insipidus, significant renal and GI losses.

Potassium 3.5–5 mEq/L 3.5–5 mmol/L

1 ↑ with renal dysfunction, acidosis, K-sparing diuretics, hemolysis, burns, crush injuries. ↓ by diuretics, alkalosis, severe vomiting and diarrhea, heavy NG suctioning.

CO2 content 22–28 mEq/L 22–28 mmol/L

1 Sum of HCO3 and dissolved CO2. Reflects acid–base balance and compensatory pulmonary (CO2) and renal (HCO3) mechanisms. Primarily reflects HCO3.

Chloride 95–105 mEq/L

95–105 mmol/L

1 Important for acid–base balance. ↓ by GI loss of chloride-rich fluid (vomiting, diarrhea, GI suction, intestinal fistulas, overdiuresis).

BUN 8–18 mg/dL 2.8–6.4 mmol/L

0.357 End product of protein metabolism, produced by liver, transported in blood, excreted renally. ↑ in renal dysfunction, high protein intake, upper GI bleeding, volume contraction.

Creatinine 0.6–1.2 mg/dL

50–110 µmol/L

88.4 Major constituent of muscle; rate of formation constant; affected by muscle mass (lower with aging); excreted renally. ↑ in renal dysfunction. Used as a primary marker for renal function (GFR).


2

CrCl 75–125 mL/min

1.25–2.08 mL/sec

0.016 Reflects GFR; ↓ in renal dysfunction. Used to adjust dosage of renally eliminated drugs.

Glucose (fasting)

70–110 mg/dL

3.9–6.1 mmol/L

0.055 ↑ in diabetes or by adrenal corticosteroids. Important to obtain fasting glucose level.

Glycosylated hemoglobin

<5% <5% 1 Used to assess average blood glucose over 1–3 months. Helpful for monitoring chronic blood glucose control in patients with diabetes. Values >8% seen in patients with poor glucose control.

Calcium–total 8.8–10.2 mg/dL

2.20–2.55 mmol/L

0.250 Regulated by body skeleton redistribution, parathyroid hormone, vitamin D, calcitonin. Affected by changes in albumin concentration. ↓ by hypothyroidism, loop diuretics, vitamin D deficiency; ↑ in malignancy and hyperthyroidism.

Calcium–unbound

4.5–5.6 mg/dL

1.13–1.4 mmol/L

0.250 Physiologically active form. Unbound “free” calcium remains unchanged as albumin fluctuates. Total calcium ↓ when albumin ↓.

Magnesium 1.6–2.4 mEq/L

0.8–1.20 mmol/L

0.5 1 ↓ in malabsorption, severe diarrhea, alcoholism, pancreatitis, diuretics, hyperaldosteronism (symptoms of weakness, depression, agitation, seizures, hypokalemia, arrhythmias). ↑ in renal failure, hypothyroidism, magnesium-containing antacids.

Phosphatea 2.5–5 mg/dL 0.8–1.60 mmol/L

0.323 ↑ with renal dysfunction, hypervitaminosis D, hypocalcemia, hypoparathyroidism. ↓ with excess aluminum antacids, malabsorption, renal losses, hypercalcemia, refeeding syndrome.

Uric acid 2–7 mg/dL 0.12–0.42 mmol/L

0.06 ↑ in gout, neoplastic, or myeloproliferative disorders, and drugs (diuretics, niacin, low-dose salicylate, cyclosporine).


3

Proteins Prealbumin 15–36 mg/dL 150–360

mg/L 10 Indicates acute changes in nutritional

status, useful for monitoring TPN.

Albumin 4–6 g/dL 40–60 g/L

10 Produced in liver; important for intravascular osmotic pressure. ↓ in liver disease, malnutrition, ascites, hemorrhage, protein-wasting nephropathy. May influence highly protein-bound drugs.

Globulin 2.3–3.5 g/dL 23–35 g/L

10 Active role in immunologic mechanisms. Immunoglobulins ↑ in chronic infection, rheumatoid arthritis, multiple myeloma.

Enzymes CK 0–150

units/L 0–2.5 µkat/L

0.016 In tissues that use high energy (skeletal muscle, myocardium, brain). ↑ by IM injections, MI, acute psychotic episodes. Isoenzyme CK-MM in skeletal muscle; CK-MB in myocardium; CK-BB in brain. MB fraction >5%–6% suggests acute MI.

CK-MB 0–12 units/L 0–0.2 µkat/L

0.016

cTnI <0.03 ng/mL <0.03 µg/L

1 More specific than CK-MB for myocardial damage, elevated sooner and remains elevated longer than CK-MB. cTnI >2.0 suggests acute myocardial injury.

Myoglobin <90 µg/L <90 mcg/L

1 Early elevation (within 3 hr), but less specific for myocardial compared to CK-MB.

Homocysteine 4–15 µmol/L 4–15 µmol/L

1 Damages vessel endothelial, which may increase the risk for cardiac disease. Associated with deficiencies in folate, vitamin B6, and vitamin B12.

LDH 100–190 units/L

1.67–3.17 µkat/L

0.016 High in heart, kidney, liver, and skeletal muscle. Five isoenzymes: LD1 and LD2 mostly in heart, LD5 mostly in liver and skeletal muscle, LD3 and LD4 are non-specific. ↑ in malignancy, extensive burns, PE, renal disease.


4

BNP <100 pg/mL <100 ng/L

1 BNP >500 ng/L indicates left ventricular dysfunction. Released from heart with ↑ workload placed on heart (e.g., CHF).

CRP 0–1 mg/dL 0–10 mg/L

1 Nonspecific indicator of acute inflammation. Similar to ESR, but more rapid onset and greater elevation. CRP >3 mg/dL increases risk of cardiovascular disease.

Liver Function AST 0–35 units/L 0–0.58

µkat/L 0.016 Large amounts in heart and liver;

moderate amounts in muscle, kidney, and pancreas. ↑ with MI and liver injury. Less liver specific than ALT.

ALT 0–35 units/L 0–0.58 µkat/L

0.016 From heart, liver, muscle, kidney, pancreas. ↑ negligible unless parenchymal liver disease. More liver specific than AST.

ALP 30–120 units/L

0.5–2.0 µkat/L

0.016 Large amounts in bile ducts, placenta, bone. ↑ in bile duct obstruction, obstructive liver disease, rapid bone growth (e.g., Paget disease), pregnancy.

GGT 0–70 units/L 0–1.17 µkat/L

0.016 Sensitive test reflecting hepatocellular injury; not helpful in differentiating liver disorders. Usually high in chronic alcoholics.

Bilirubin–total

0.1–1 mg/dL 1.7–17.1 µmol/L

17.1 Breakdown product of hemoglobin, bound to albumin, conjugated in liver. Total bilirubin includes direct (conjugated) and indirect bilirubin. ↑ with hemolysis, cholestasis, liver injury.

Bilirubin–direct

0–0.2 mg/dL 0–3.4 µmol/L

17.1


5

Miscellaneous Amylase 35–120

units/L 0.58–2.0 µkat/L

0.016 Pancreatic enzyme; ↑ in pancreatitis or duct obstruction.

Lipase 0–160 units/L

0–2.67 µkat/L

0.016 Pancreatic enzyme, ↑ acute pancreatitis, elevated for longer period than amylase.

PSA 0–4 ng/mL 0–4 mcg/L

1 ↑ in benign prostatic hypertrophy (BPH) and also in prostate cancer. PSA levels of 4–10 ng/mL should be worked up. Risk of prostate cancer increased if free PSA/total PSA <0.25.

TSH 2–10 µunits/mL

2–10 m units/L

1 ↑ TSH in primary hypothyroidism requires exogenous thyroid supplementation .

Cholesterol Total <200 mg/dL <5.2

mmol/L0.025 Desirable = Total <200; LDL 70–160

(depends on risk factors); HDL >45 mg/dL; ↑ LDL or ↓ HDL are risk factors for cardiovascular disease. Consult NCEP and ATP guidelines for most current target goals and description of patient risk factors.

LDL 70–160 mg/dL

<3.36 mmol/L

0.025

HDL >45 mg/dL >1.16 mmol/L

0.025

Triglycerides (fasting)

<160 mg/dL <1.80 mmol/L

0.011 ↑ by alcohol, saturated fats, drugs (propranolol, diuretics, oral contraceptives). Obtain fasting level.

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATP, Adult Treatment Panel; BNP, brain natriuretic peptide; BPH, benign prostatic hypertrophy; BUN, blood urea nitrogen; CHF; congestive heart failure; CK, creatine kinase (formerly known as creatine phosphokinase); CrCl, creatinine clearance; CRP, C-reactive protein; cTnI, cardiac troponin I; ESR, erythrocyte sedimentation rate; GFR, glomerular filtration rate; GGT, gamma-glutamyl transferase; GI, gastrointestinal; HDL, high-density lipoprotein; IM, intramuscularly; LDH, lactate dehydrogenase; LDL, low-density lipoprotein; MI, myocardial infarction; NCEP, National Cholesterol Education Program; NG, nasogastric; PE, pulmonary embolism; PSA, prostate-specific antigen; SI, International System of Units; TPN, total parenteral nutrition; TSH, thyroid-stimulating hormone. aPhosphate as inorganic phosphorus.


6

Table 2 Hematologic Laboratory Values

Laboratory Test

Normal Reference Values

Comments Conventional Units SI Units

RBC count Male 4.3–5.9 ×

106/mm3 4.3–5.9 × 1012/L

Female 3.5–5.0 × 106/mm3

3.5–5.0 × 1012/L

Hct ↓ with anemias, bleeding, hemolysis. ↑ with polycythemia, chronic hypoxia.

Male 39%–49% 0.39–0.49 Ia

Female 33%–43% 0.33–0.43 Ia

Hgb Similar to Hct. Male 14–18 g/dL 140–180

g/L

Female 12–16 g/dL 120–160 g/L

MCV 76–100 µm3 76–100 fLb

Describes average RBC size; ↑ MCV = macrocytic, ↓ MCV = microcytic.

MCH 27–33 pg 27–33 pg

Measures average weight of Hgb in RBC.

MCHC 33–37 g/dL 330–370 g/L

More reliable index of RBC hemoglobin than MCH. Measures average concentration of Hgb in RBC. Concentration will not change with weight or size of RBC.

Reticulocyte count (adults)

0.1%–2.4% 0.001–0.024 Ia

Indicator of RBC production; ↑ suggests ↑ number of immature erythrocytes released in response to stimulus (e.g., iron in iron-deficiency anemia).

ESR Nonspecific; ↑ with inflammation, infection, neoplasms, connective tissue disorders, pregnancy, nephritis. Useful monitor of temporal arteritis and polymyalgia rheumatica .

Male 0–20 mm/hr 0–20 mm/hr

Female 0–30 mm/hr 0–30 mm/hr


7

WBC count 3.2–9.8 × 103/mm3

3.2–9.8 × 109/L

Consists of neutrophils, lymphocytes, monocytes, eosinophils, and basophils; ↑ in infection and stress.

ANC >2,000 mm3 ANC = WBC × (% neutrophils +% bands)/100; if <500 ↑ risk infection, if >1,000 ↓ risk infection.

Neutrophils 54%–62% 0.54–0.62 Ia

↑ in neutrophils suggests bacterial or fungal infection. ↑ in bands suggests bacterial infection.

Bands 3%–5% 0.03–0.05 Ia

Lymphocytes 25%–33% 0.25–0.33 Ia

Monocytes 3%–7% 0.03–0.07 Ia

Eosinophils 1%–3% 0.01–0.03 Ia

Eosinophils ↑ with allergies and parasitic infections.

Basophils <1% <0.01 Ia Platelets 130–400 ×

103/mm3 130–140 × 109/L

<100 × 103/mm3 = thrombocytopenia; <20 × 103/mm3 = ↑ risk for severe bleeding.

Iron Male 80–180

mcg/dL 14–32 µmol/L

Body stores two-thirds in Hgb; one-third in bone marrow, spleen, liver; only small amount present in plasma. Blood loss major cause of deficiency.

Female 60–160 mcg/dL

11–29 µmol/L

↑ needs in pregnancy and lactation.

TIBC 250–460 mcg/dL

45–82 µmol/L

↑ capacity to bind iron with iron deficiency.

ANC, absolute neutrophil count; ESR, erythrocyte sedimentation rate; Hct, hematocrit; Hgb, hemoglobin; MCH, mean corpuscular hemoglobin; MCHC, mean cell hemoglobin concentration; MCV, mean cell volume; RBC, red blood cell; SI, International System of Units; TIBC, total iron-binding capacity; WBC, white blood cell. aWith the SI, the concept of number fraction replaces percentage. Thus, for mass fraction, volume fraction, and relative quantities, the unit “I” is used to replace former units. bfL, femtoliter; femto, 10-15; pico, 10-12; nano, 10-9; micro, 10-6; milli, 10-3.

Reference: Applied Therapeutics: The Clinical Use of Drugs by Mary Anne Koda-Kimble, Lloyd Yee Young, Wayne A. Kradjan, and B. Joseph Guglielmo;2010

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