After completing this note you will be able to describe the clinical approach to prescribing safely in the Kenyan hospital setting, recognise common pharmacological hazards in patients with HIV, TB, malaria, rheumatic disease, sickle‑cell disease and other tropical conditions, and outline the steps for rational drug selection, monitoring and documentation. Always verify doses and local protocols against the Kenya MoH guideline and your hospital formulary.
Definition
Clinical pharmacology is the science of how drugs act in humans, encompassing absorption, distribution, metabolism, excretion and the relationship between drug concentration and therapeutic or adverse effect. Rational prescribing is the systematic process of selecting the right drug, at the right dose, for the right duration, for the right patient, while minimizing harm and cost.
Anatomy and physiology you need
| System | Key structures/functions relevant to prescribing |
|---|---|
| Gastro‑intestinal | Gastric pH, motility, surface area – affect oral absorption |
| Hepatic | Cytochrome P450 enzymes (CYP3A4, CYP2C9, CYP2D6) – major site of metabolism |
| Renal | Glomerular filtration, tubular secretion – primary route of excretion for many drugs |
| Cardiovascular | Cardiac output, plasma protein (albumin) – influence distribution |
| Central nervous system | Blood‑brain barrier – limits entry of many agents |
| Immune system | Cytokine milieu, CD4 count – alters drug‑drug interactions in HIV/TB |
| Hematologic | Sickle‑cell disease (hemolysis, vaso‑occlusion) – impacts drug safety (e.g., analgesics) |
Causes and risk factors
- Polypharmacy in chronic HIV/TB co‑infection, malaria prophylaxis, rheumatic disease, and sickle‑cell disease.
- Renal or hepatic impairment common in advanced HIV, TB‑associated hepatitis, or malaria‑related organ dysfunction.
- Genetic polymorphisms affecting CYP enzymes (e.g., CYP2B6 in efavirenz metabolism).
- Nutritional deficiencies (protein‑energy malnutrition) altering plasma protein binding.
- Drug‑resistant organisms prompting use of second‑line, more toxic agents.
- Limited laboratory monitoring (e.g., lack of therapeutic drug monitoring for aminoglycosides).
- Traditional/herbal medicines that induce or inhibit metabolic pathways.
Pathophysiology
Infection or disease → organ dysfunction (hepatic, renal, cardiac) → altered drug ADME → sub‑therapeutic or toxic plasma levels → clinical adverse events or therapeutic failure → further organ injury → vicious cycle.
Example for HIV/TB co‑infection:
HIV infection → CD4 depletion → opportunistic infections → TB therapy (rifampicin) → rifampicin induces CYP3A4 → reduced plasma levels of protease inhibitors → virologic failure → increased viral load → further immune compromise.
Example for malaria:
Plasmodium infection → hemolysis & hepatic congestion → reduced albumin → higher free fraction of highly protein‑bound drugs (e.g., quinine) → increased toxicity risk.
Example for sickle‑cell disease:
Vaso‑occlusive crisis → tissue hypoxia → renal papillary necrosis → impaired excretion of NSAIDs → accumulation → nephrotoxicity → worsening renal function.
The next sections (investigations, diagnosis, management, monitoring) will be covered in parts 2 and 3.
Clinical features
| Domain | Key questions / findings | Why it matters |
|---|---|---|
| Presenting complaint | Onset, duration, pattern of symptoms (e.g., pain, dyspnoea, fever, rash, dizziness). | Determines acute vs chronic process and guides urgency of review. |
| Medication history | All prescribed drugs, over‑the‑counter meds, traditional/herbal remedies, recent changes, adherence, self‑medication for malaria, TB prophylaxis, HIV ART. | Polypharmacy and drug‑drug interactions are common sources of prescribing errors; herbal products may affect metabolism. |
| Co‑morbidities | HIV status, TB treatment, malaria episodes, rheumatic disease, sickle‑cell disease, renal or hepatic impairment, pregnancy, age‑related frailty. | Co‑morbid conditions alter pharmacokinetics, increase risk of adverse drug reactions (ADRs) and dictate dose adjustments. |
| Allergies / previous ADRs | Type of reaction, drug involved, severity, timing. | Prevent repeat exposure to offending agents; informs choice of safer alternatives. |
| Social & environmental factors | Occupation, travel, nutrition, alcohol use, smoking, access to health care, health‑literacy level. | Influences drug metabolism (e.g., alcohol‑induced liver injury) and adherence potential. |
| System review | Cardiovascular (palpitations, edema), respiratory (cough, wheeze), GI (nausea, diarrhoea), neuro (confusion, seizures), skin (rashes, bruising). | Detects organ‑specific toxicity or disease that may mimic drug effects. |
| Examination – vital signs | Blood pressure, heart rate, respiratory rate, temperature, oxygen saturation, weight. | Hypertension, tachycardia or hypotension may signal drug toxicity or under‑treatment; weight informs dosing in obesity or cachexia. |
| Cardiovascular exam | Heart sounds, peripheral pulses, edema. | Fluid overload or cardiomyopathy can be drug‑induced (e.g., β‑blocker overdose) or disease‑related. |
| Respiratory exam | Breath sounds, use of accessory muscles. | Pulmonary infiltrates may be due to TB drugs, malaria, or drug‑induced pneumonitis. |
| Abdominal exam | Hepatomegaly, tenderness, ascites. | Hepatic enlargement suggests drug‑induced hepatitis; ascites may reflect heart failure from inappropriate prescribing. |
| Neurological exam | Level of consciousness, focal deficits, reflexes. | Confusion or seizures may be from anticholinergic toxicity, quinine, or ART interactions. |
| Skin exam | Rashes, urticaria, jaundice, bruising. | Cutaneous eruptions are common ADRs; jaundice signals hepatic injury. |
| Musculoskeletal | Joint swelling, tenderness, sickle‑cell vaso‑occlusive pain. | Rheumatic disease flares may be precipitated by NSAID withdrawal or steroid tapering. |
Differential diagnosis
| Condition | Points toward it | Distinguishing feature |
|---|---|---|
| Drug‑induced hepatotoxicity | Recent start of anti‑TB, ART, antimalarials; jaundice, right‑upper‑quadrant pain | Elevated transaminases >5× ULN, temporal relation to drug |
| Acute kidney injury from nephrotoxic drugs | Use of aminoglycosides, NSAIDs, contrast; oliguria | Rising creatinine with drug exposure, urine sediment |
| Malaria relapse vs drug failure | Recent travel, fever spikes, chills, recent antimalarial use | Parasitaemia on thick smear, response to alternative regimen |
| TB treatment failure / resistance | Persistent cough, weight loss, sputum positive after 2 months | Positive culture/sensitivity, radiographic progression |
| HIV‑related opportunistic infection | Low CD4 count, new systemic symptoms, ART non‑adherence | Specific pathogen identified (e.g., PCP on BAL) |
| Sickle‑cell vaso‑occlusive crisis | Known sickle‑cell disease, severe bone pain, precipitated by infection or dehydration | Pain pattern, sickle cell screen, response to analgesia |
| Rheumatic flare | Joint swelling, morning stiffness, recent steroid taper | Synovitis on exam, elevated ESR/CRP, serology (RF, anti‑CCP) |
Investigations
| Test | What it answers | Interpretation |
|---|---|---|
| Full blood count | Anaemia, leukopenia, thrombocytopenia | Cytopenias suggest bone‑marrow suppression from drugs (e.g., zidovudine) |
| Liver function panel | Hepatocellular vs cholestatic injury | ALT/AST >5× ULN → hepatocellular; ALP/ bilirubin ↑ → cholestatic |
| Renal profile (creatinine, urea, electrolytes) | Glomerular function, electrolyte balance | Creatinine rise >0.3 mg/dL in 48 h → acute kidney injury |
| Therapeutic drug monitoring (e.g., antiretroviral trough levels) | Adequacy of drug exposure | Sub‑therapeutic → risk of resistance; supra‑therapeutic → toxicity |
| Sputum microscopy/culture & GeneXpert | Presence of Mycobacterium tuberculosis, resistance | Positive smear/culture confirms active TB; rifampicin resistance on GeneXpert |
| Malaria rapid diagnostic test + thick smear | Parasite species, density | Positive test → active infection; parasite count guides severity |
| CD4 count & viral load | Immune status, ART effectiveness | CD4 <200 cells/µL → high infection risk; viral load >1000 copies/mL → treatment failure |
| ECG | Cardiac conduction, QT interval | Prolonged QT suggests risk with certain antimalarials or antipsychotics |
| Urinalysis (dipstick + microscopy) | Hematuria, proteinuria, casts | Proteinuria + RBC casts → glomerulonephritis; may be drug‑related |
| Imaging (CXR, ultrasound) | Pulmonary infiltrates, organomegaly, effusions | CXR consolidation → pneumonia vs drug‑induced pneumonitis; US liver size |
Diagnosis and severity
- Identify the primary pharmacological problem – e.g., drug‑induced hepatotoxicity, therapeutic failure, adverse drug reaction, or drug‑drug interaction.
- Classify severity (adapted from WHO‑UMC and CTCAE concepts):
| Severity | Clinical picture | Management urgency |
|---|---|---|
| Mild | Asymptomatic lab abnormality, ≤2× ULN transaminases, no organ dysfunction | Close monitoring, possible dose adjustment |
| Moderate | Symptomatic (e.g., nausea, mild jaundice), 2–5× ULN, mild renal rise, no life‑threatening signs | Prompt drug review, consider substitution, supportive care |
| Severe | Life‑threatening manifestations (e.g., hepatic failure, acute kidney injury requiring dialysis, severe arrhythmia, anaphylaxis) | Immediate drug cessation, intensive care, specific antidotes where available |
| Critical | Multi‑organ failure, shock, severe haemolysis, status epilepticus | Emergency resuscitation, multidisciplinary team, possible transfer to tertiary centre |
- Document the diagnosis using a structured format:
- Problem: e.g., “Probable isoniazid‑induced hepatotoxicity”.
- Causality: based on temporal relationship, de‑challenge, alternative causes.
- Severity: moderate (ALT 4× ULN, mild right‑upper‑quadrant pain).
- Plan: stop isoniazid, switch to alternative regimen, monitor LFTs every 48 h, counsel patient on signs of worsening, report ADR to national pharmacovigilance centre.
- Rational prescribing principles applied:
- Right drug – choose agents with proven efficacy for the disease (e.g., rifampicin for drug‑sensitive TB).
- Right dose – dose adjusted for renal/hepatic function, weight, age; avoid fixed mg statements.
- Right duration – complete full course to prevent resistance (e.g., 6 months for TB).
- Right patient – consider comorbidities (HIV, sickle‑cell) and potential interactions (e.g., protease inhibitors with rifampicin).
- Right monitoring – schedule labs and clinical review according to drug safety profile.
By systematically gathering history, performing targeted examination, ordering focused investigations, and applying severity grading, the junior doctor can make a precise diagnosis, mitigate harm, and prescribe safely in the complex Kenyan clinical environment.
Management
Immediate stabilisation
- Airway, breathing, circulation – give supplemental O₂ if SpO₂ < 94 %; establish IV access; treat hypotension with fluid bolus (crystalloids) before any drug that may lower blood pressure.
- Identify drug‑related emergencies – anaphylaxis (epinephrine auto‑injector), severe hypersensitivity to antiretrovirals or anti‑TB drugs (stop offending agent, give antihistamine and steroids), drug‑induced QT prolongation (review ECG, correct electrolytes, avoid further QT‑prolonging drugs).
Definitive treatment – rational prescribing principles:
| Step | Action | Rationale |
|---|---|---|
| 1 | Confirm indication (e.g., bacterial infection, hypertension, pain) | Avoid unnecessary exposure |
| 2 | Choose drug class with best efficacy‑safety profile for local resistance patterns | E.g., first‑line β‑lactam for community pneumonia; artemisinin‑based combination for malaria |
| 3 | Check patient‑specific factors (age, renal/hepatic function, comorbidities, pregnancy, HIV/TB co‑therapy) | Prevent toxicity and drug‑drug interactions |
| 4 | Start at lowest effective dose, titrate as needed | Minimise adverse effects |
| 5 | Provide clear instructions on timing, food‑effects, adherence | Improves therapeutic outcome |
| 6 | Document allergies, previous ADRs, and monitoring plan | Facilitates safe follow‑up |
Monitoring & follow‑up
- Therapeutic drug monitoring (TDM) where available (e.g., aminoglycosides, antiepileptics, some antiretrovirals).
- Laboratory checks: baseline CBC, liver enzymes, renal function; repeat 48‑72 h for drugs with known organ toxicity (e.g., isoniazid, pyrazinamide, fluoroquinolones).
- Clinical review: symptom resolution, side‑effect screen, adherence check at each visit.
- Pharmacovigilance: report any suspected ADR to national centre; educate patient on red‑flag symptoms (e.g., rash, jaundice, visual changes).
Contra‑indications & safety
- Absolute: known hypersensitivity to drug class, severe hepatic failure for hepatotoxic agents, QTc > 500 ms for macrolides/fluoroquinolones.
- Relative: pregnancy (e.g., avoid tetracyclines), renal impairment (adjust dosing of renally cleared drugs), co‑administration with strong CYP inducers/inhibitors (e.g., rifampicin with protease inhibitors).
Complications and prognosis
- Adverse drug reactions (ADRs) – ranging from mild GI upset to life‑threatening Stevens‑Johnson syndrome; early detection improves outcome.
- Drug‑drug interactions – can cause therapeutic failure (e.g., rifampicin reducing protease inhibitor levels) or toxicity (e.g., co‑trimoxazole with sulfonamide allergy).
- Medication‑related resistance – inappropriate empiric therapy or poor adherence in TB/HIV leads to multidrug‑resistant organisms, worsening prognosis.
- Polypharmacy – common in chronic disease clusters (HIV + TB + hypertension) → higher risk of falls, renal injury, cognitive impairment.
- Long‑term sequelae – chronic kidney disease from repeated nephrotoxic agents, ototoxicity from aminoglycosides, cardiomyopathy from anthracyclines.
- Prognosis improves markedly when prescribing follows evidence‑based algorithms, patients are counselled on adherence, and monitoring catches toxicity early.
High‑yield exam points
- Look‑alike conditions:
- Drug‑induced fever vs. infective fever – timing after drug start, absence of focal signs.
- Hyponatraemia from thiazides vs. SIADH – check volume status and medication list.
- Common wrong first step: prescribing a second‑line antibiotic before confirming culture results or local resistance data.
- Examiner bedside question: “Explain how you would choose an antihypertensive for a patient on efavirenz‑based ART.” (Answer: avoid calcium‑channel blockers metabolised by CYP3A4; prefer ACE‑inhibitor or thiazide with monitoring).
- Key rational‑prescribing principle: “Start low, go slow” – especially in the elderly and those with renal impairment.
- Safety check: always review the patient’s current drug chart for potential QT‑prolonging agents before adding a macrolide.
Clinical case
Case: 34‑year‑old male with known HIV (on tenofovir‑lamivudine‑efavirenz) presents with a 5‑day history of productive cough, night sweats, weight loss and a temperature of 38.5 °C. Chest X‑ray shows right upper‑lobe infiltrates. Sputum is positive for Mycobacterium tuberculosis; CD4 count 210 cells/µL.
Questions
- What is the initial anti‑TB regimen and why?
Answer: A four‑drug regimen (isoniazid, rifampicin, pyrazinamide, ethambutol) for the intensive phase because it provides rapid bactericidal activity, prevents resistance, and covers possible drug‑susceptible TB in an immunocompromised host.
- How will you modify his ART during TB treatment?
Answer: Switch efavirenz‑based regimen to a protease‑inhibitor‑based regimen (e.g., lopinavir/ritonavir) after the first two weeks of TB therapy to avoid rifampicin‑induced reduction of efavirenz levels and manage drug‑drug interactions.
- What monitoring is essential during the first two months?
Answer: Baseline and monthly liver function tests (isoniazid, pyrazinamide hepatotoxicity), visual acuity (ethambutol optic neuritis), renal function (pyrazinamide), and adherence counseling; also repeat CD4 count at 2 months to assess immune recovery.
Practice questions
Question 1
A 58‑year‑old woman with hypertension and newly diagnosed type 2 diabetes is started on a thiazide diuretic for blood pressure control. Two weeks later she develops mild hyponatraemia (Na⁺ = 130 mmol/L) but is asymptomatic. What is the most appropriate next step?
A. Stop the thiazide immediately
B. Restrict fluid intake to 1 L/day
C. Add a low‑dose potassium‑sparing diuretic
D. Observe and repeat electrolytes in 1 week
Answer: D. Observe and repeat electrolytes in 1 week
Explanation: Mild, asymptomatic hyponatraemia can be monitored; abrupt cessation may worsen blood pressure control.
Question 2
A 22‑year‑old male with severe malaria is started on an artemisinin‑based combination therapy (ACT). He is also on co‑trimoxazole prophylaxis for HIV. Which adverse effect should you watch for?
A. QT prolongation
B. Severe neutropenia
C. Hypoglycaemia
D. Hepatotoxicity
Answer: D. Hepatotoxicity
Explanation: Both ACT and co‑trimoxazole can cause liver enzyme elevation; monitoring LFTs is prudent.
Question 3
A patient on long‑term isoniazid for latent TB develops peripheral neuropathy. Which adjunct is indicated?
A. Vitamin B12 injection
B. Pyridoxine (vitamin B6) supplementation
C. High‑dose folic acid
D. Calcium carbonate
Answer: B. Pyridoxine (vitamin B6) supplementation
Explanation: Isoniazid interferes with pyridoxine metabolism; supplementation prevents neuropathy.
Question 4
A 45‑year‑old man with chronic hepatitis B is prescribed tenofovir for viral suppression. Which monitoring parameter is most critical?
A. Serum potassium weekly
B. Serum creatinine and phosphate every 3 months
C. Complete blood count monthly
D. Lipid profile annually
Answer: B. Serum creatinine and phosphate every 3 months
Explanation: Tenofovir can cause renal tubular dysfunction; renal function and phosphate should be checked regularly.
Question 5
During a ward round, a junior doctor plans to start a macrolide for community‑acquired pneumonia in a patient already receiving fluoroquinolone for a urinary tract infection. What is the safest action?
A. Proceed – no interaction exists
B. Replace fluoroquinolone with a β‑lactam
C. Add a potassium‑sparing diuretic to counter QT risk
D. Delay macrolide until fluoroquinolone course finishes
Answer: B. Replace fluoroquinolone with a β‑lactam
Explanation: Both macrolides and fluoroquinolones prolong QT; using a β‑lactam avoids additive cardiac risk.
Drafted with AI assistance from standard references and reviewed for structure. Check details against your lecture notes and the Kenya MoH guideline.