AETCOM Module 2.5 - 5 Mark Notes

Bioethics Continued: Case Studies on Patient Autonomy and Decision Making

Background / Introduction

Competency Addressed

"Identify, discuss and defend medicolegal, sociocultural and ethical issues as they pertain to patient autonomy, patient rights, and shared responsibility in health care."

Key Concepts

1. Patient Autonomy

• Autonomy = the right of a patient to make decisions about their own health care without being overridden by others.
• Derived from the ethical principle of respect for persons.
• Includes the right to accept or refuse treatment, even when refusal may be harmful.
• Requires that the patient is competent to make that decision.

2. Paternalism vs. Autonomy

• Paternalism: The doctor (or family) overrides the patient's wish, believing they know what is "best."
• Soft paternalism: Acceptable - intervening only when patient's autonomy is impaired (e.g., unconscious, coerced).
• Hard paternalism: Overriding a competent patient's wishes - generally considered unethical.
• Modern medicine leans strongly toward autonomy over paternalism.

3. Shared Decision Making (SDM)

• A collaborative process between doctor and patient where both parties contribute to the clinical decision.
• Doctor's responsibilities: provide full, accurate, and understandable information; present all options; respect patient values.
• Patient's responsibilities: engage actively, ask questions, communicate values and preferences, take responsibility for choices.
• SDM balances beneficence with autonomy.

4. Full and Reasonable Disclosure

• The doctor must disclose:
  • The diagnosis and nature of the illness
  • The proposed treatment and alternatives
  • Risks, benefits, and complications
  • What happens if treatment is refused
• Disclosure must be in simple language the patient understands.
• Failure to disclose constitutes a medicolegal risk (basis for negligence claims).

5. Decision-Making Capacity vs. Competency

• A patient with intact capacity can: understand information, appreciate consequences, reason, and communicate a choice.
• Factors impairing capacity: acute illness, pain, drugs, psychiatric disorders, delirium, dementia, extreme fear/anxiety.

6. Surrogacy in Decision Making

• When a patient lacks decision-making capacity, a surrogate makes decisions on their behalf.
• Surrogate hierarchy (generally): spouse > adult children > parents > siblings.
• The surrogate must apply the substituted judgment standard (what would the patient want?), not their own preferences.
• If no surrogate is available, legal/ethical processes apply.
• Advance directives (living wills, DNR orders) allow patients to specify wishes in advance.

7. Do Not Resuscitate (DNR) Orders

• A DNR is a medical order to withhold CPR/resuscitation in event of cardiac/respiratory arrest.
• Must reflect the patient's informed wish or, if incapacitated, surrogate's decision based on patient's prior wishes.
• Has legal, ethical, and social dimensions.
• Involves balancing autonomy (patient's right not to be resuscitated) vs. beneficence (doctor's duty to preserve life).

Points for Discussion (from NMC book)

1. Extent of patient autonomy
2. Elements of decision making - Competency vs. Capacity
3. Surrogacy in decision making
4. Autonomy vs. Beneficence
5. How much do family wishes count?
6. Legal, ethical and social aspects of 'Do Not Resuscitate'

Assessment Short Questions (Summative)

1. Define patient autonomy - patient's right to make informed decisions about their own healthcare.
2. Contrast autonomy and paternalism - autonomy respects patient choice; paternalism overrides it "for the patient's good."
3. Responsibilities of patients and doctors in shared decision making.
4. What is full and reasonable disclosure? - complete information about diagnosis, treatment options, risks, and alternatives.

Learning Experience Format

• Introduction of case - 1 hour
• Self-directed learning - 2 hours
• Anchoring lecture - 1 hour
• Discussion and closure of case - 1 hour
• Total: 5 hours

Clinical/Ethical Scenario Application

Summary Table for Quick Revision

H. pylori in Peptic Ulcer Disease - Pharmacology (5-Mark Notes)

1. Role of H. pylori in PUD

• Helicobacter pylori is a gram-negative, spiral, urease-producing bacterium that colonises the gastric mucosa.
• Found in ~60-70% of gastric ulcers and ~90% of duodenal ulcers.
• Causes ulcers by: damaging the mucous layer, stimulating acid secretion, triggering inflammation (IL-1, TNF, IL-8).
• Without eradication: ulcer recurrence rate is ~59% (gastric) and ~67% (duodenal) per year.
• With eradication: recurrence drops to <10-20%.
• Also implicated in gastric MALT lymphoma - eradication causes complete remission in 60-90% of cases.

2. Diagnosis of H. pylori (for context)

3. Indications for H. pylori Eradication

• All patients with documented PUD (whether active or in remission, first episode or recurrent)
• Patients with gastric MALT lymphoma
• Long-term NSAID users with prior PUD history
• First-degree relatives of gastric cancer patients
• Post-endoscopic resection of early gastric cancer
• Patients aged <60 years with uninvestigated dyspepsia (ACG guidelines)

4. Treatment Regimens

A. Standard Triple Therapy (First Line - where clarithromycin resistance <15%)

• If penicillin allergy: replace amoxicillin with metronidazole 500 mg BD.
• Eradication rate: 70-85%.
• Avoid if prior macrolide antibiotic exposure or clarithromycin resistance >15%.

B. Bismuth Quadruple Therapy (First Line in high resistance areas / Second Line)

• Eradication rate: >90%.
• Preferred first-line when clarithromycin resistance is unknown or >15%, or in developing countries.
• Bismuth acts locally - coats ulcer base, anti-H. pylori, and promotes mucus secretion.

C. Concomitant (Non-Bismuth) Quadruple Therapy

• PPI + Amoxicillin + Clarithromycin + Metronidazole - all four given simultaneously for 10-14 days.
• Superior to standard triple therapy in meta-analyses.

D. Sequential Therapy

• 5 days: PPI + Amoxicillin, THEN
• 5 more days: PPI + Clarithromycin + Tinidazole (or Metronidazole)
• Total: 10 days. Rationale: amoxicillin reduces bacterial load first, then targeted antibiotics finish the job.

5. Role of Individual Drugs

Proton Pump Inhibitors (PPIs)

• Mechanism: Irreversibly inhibit H⁺/K⁺-ATPase (proton pump) of parietal cells.
• Increase gastric pH → enhances antibiotic stability and efficacy (especially clarithromycin, which is acid-labile).
• Examples: Omeprazole 20 mg, Lansoprazole 30 mg, Pantoprazole 40 mg, Rabeprazole 20 mg, Esomeprazole 40 mg.
• Are prodrugs - activated in acidic environment of parietal cell canaliculus.

Clarithromycin

• Macrolide antibiotic; inhibits 50S ribosome (protein synthesis).
• Most active anti-H. pylori agent but resistance is rising (13-16% in the US).
• Main cause of triple therapy failure.

Amoxicillin

• Beta-lactam; inhibits cell wall synthesis.
• Resistance rare (<1%) - backbone of most regimens.
• Replaced by metronidazole in penicillin allergy.

Metronidazole

• Nitroimidazole; forms free radicals that damage bacterial DNA.
• Resistance common (up to 30% in North America, 80% in developing countries) but still partially effective.

Bismuth Subsalicylate

• Not an antibiotic but has direct anti-H. pylori activity.
• Disrupts bacterial cell wall; inhibits urease, phospholipase, and adhesion to gastric mucosa.
• Adds mucosal protection (forms a protective layer over ulcer base).
• Also used as adjunct to prevent antibiotic resistance being the sole reason for failure.

Tetracycline

• Inhibits 30S ribosome; resistance is very rare (<2%).
• Used in bismuth quadruple regimens.

6. Salvage / Second-Line Therapies

7. Confirming Eradication

• Test with urea breath test or stool antigen test at least 4 weeks after completing therapy and 2 weeks after stopping PPI.
• Serology is NOT useful for confirming eradication (remains positive for months after).

Quick Summary Table

Antitussives - Pharmacology Notes

Definition

"An ideal antitussive would suppress the hypersensitive component of cough in disease yet allow the protective cough reflex to remain active." - Murray & Nadel's Respiratory Medicine

Cough Reflex Arc (basis for drug action)

Classification

I. Centrally Acting Antitussives

A. Opioid (Narcotic) Antitussives

• Prototype centrally acting antitussive - the standard against which all others are compared.
• Mechanism: Mu-opioid receptor agonist; depresses sensitivity of the cough centre in the medulla to peripheral stimuli. (Note: the antitussive action may not be entirely opioid-receptor mediated.)
• Dose: 10-30 mg orally every 4-6 hours.
• Advantages: Effective for pathologic cough; also has mild analgesic and anxiolytic effects.
• Adverse effects: Constipation, sedation, dysphoria, fatigue, addiction potential (limits long-term use), respiratory depression at high doses, histamine release (may worsen wheeze).
• Efficacy: Active against pathologic cough and cough in normal volunteers; limited activity in COPD patients or acute cough of common cold.

• Reserved for palliative control of cough in terminal cancer patients.
• Slow-release morphine: partially effective for severe chronic idiopathic/refractory cough.
• Also relieves anxiety and pain.

• Opioid used in combination cough preparations.
• Higher addiction potential; schedule II in USA.

B. Non-Opioid Centrally Acting

• Most widely used OTC antitussive; synthetic D-isomer of morphine derivative (3-methoxy-N-methylmorphinan).
• Mechanism:
  • Acts centrally to elevate cough threshold in medullary cough centre.
  • Also blocks NMDA (N-methyl-D-aspartate) excitatory receptors in the CNS - unlike codeine.
  • Does NOT bind to mu-opioid receptors → no analgesia, no addiction at therapeutic doses.
• Dose: 10-20 mg every 4 hours OR 30 mg every 6-8 hours; max 120 mg/day. Extended-release form available for twice-daily use.
• Advantages: Equal efficacy to codeine; fewer subjective and GI side effects; does not inhibit mucociliary clearance; antitussive effect lasts 5-6 hours.
• Adverse effects:
  • At therapeutic doses: minimal.
  • At high doses: dizziness, nausea, vomiting, headaches.
  • Drug of abuse - at very high doses causes hallucinations, euphoria, dissociation, motor impairment (via NMDA blockade).
  • Serotonin syndrome if combined with MAO inhibitors (inhibits neuronal serotonin reuptake) - avoid in patients on MAOIs.
  • Avoid in children due to risk of adverse effects and overdose.
• Use: Acute debilitating cough, OTC cough preparations (often combined with antihistamines, decongestants, expectorants).

• Structurally related to morphine; does not bind to opioid receptors.
• At least as effective as codeine as antitussive.
• Long t½ - can be given once or twice daily.
• Used in many countries outside the USA.

II. Peripherally Acting Antitussives

• Chemically related to local anaesthetics (tetracaine, benzocaine).
• Mechanism: Anaesthetises stretch receptors (RAR - rapidly adapting receptors) in respiratory passages, lungs, and pleura → blocks afferent input to cough centre.
• Dose: Taken as whole capsules with water - must NOT be chewed (causes numbness of tongue, mouth, throat; topical toxicity).
• Adverse effects: Dizziness, oral numbness if capsule broken, CNS depression in overdose.

• Non-opioid; peripheral inhibition of sensory cough receptors (C-fibre afferents).
• Favorable benefit/risk profile compared with dextromethorphan.
• Used in children and adults.

III. Neuromodulators (for Chronic/Refractory Cough)

Quick Comparison Table

Important Clinical Points

1. Treat the cause first - cough is a defence reflex; identify and treat the underlying cause (infection, asthma, GERD, postnasal drip, ACE inhibitor use) before suppressing it.
2. ACE inhibitor cough: Switch to ARB (angiotensin II receptor blocker) - antitussives are not the solution.
3. Avoid in children: DXM-containing preparations and opioid antitussives should be avoided in children < 6 years.
4. Productive cough: Should generally NOT be suppressed with antitussives - use expectorants/mucolytics (guaifenesin, acetylcysteine) instead.
5. Serotonin syndrome: Both codeine and dextromethorphan inhibit serotonin reuptake - dangerous with MAOIs.
6. Opioid antitussives work at doses lower than those required for analgesia.

Laxatives and Purgatives - Pharmacology Notes

Definition & Distinction

Classification (by Mechanism & Onset)

I. Bulk-Forming Laxatives (Onset: 1-3 days)

• Hydrophilic, indigestible plant fibers that absorb and retain water in the intestinal lumen.
• Increase stool bulk and weight → distend the colon → stimulate peristalsis reflexively.
• Some undergo bacterial fermentation in colon → short-chain fatty acids → additional prokinetic effect.

II. Osmotic Laxatives (Onset: 1 hour - 3 days)

A. Saline Laxatives (Onset: 1-3 hours - purgative effect)

B. Non-Absorbable Sugars & Alcohols

• Synthetic disaccharide (galactose + fructose); resistant to intestinal disaccharidases.
• Fermented in the colon → short-chain fatty acids → pH drops → osmotic water retention + stimulation of peristalsis.
• Dose: 15-30 mL at night; effect in 24-48 hours.
• Dual use: (1) Constipation; (2) Hepatic encephalopathy - acidic environment "traps" NH₃ as NH₄⁺, reducing ammonia absorption. Goal: 2-3 soft stools/day at pH 5-5.5.
• ADRs: Flatulence, bloating, abdominal distension.

C. Polyethylene Glycol (PEG-3350, MiraLAX)

• Large, inert polymer; poorly absorbed; not degraded by bacteria.
• Retains water in lumen purely by osmosis; no electrolyte disturbances.
• Available as lavage solution for colonoscopy prep (4 litres, e.g., GoLytely).
• Dose: 1 tablespoon/day for constipation; 68 g for reliable laxation within 24 hours.
• Superior to lactulose in RCTs; Grade A recommendation.
• ADRs: Bloating, nausea; no significant electrolyte changes.

III. Stimulant (Irritant) Laxatives (Onset: 6-12 hours)

A. Diphenylmethane Derivatives

• Requires hydrolysis by intestinal/colonic enzymes to active form.
• Oral tablets (enteric-coated to prevent gastric irritation): 10 mg/day adults; 5-10 mg children (6-12 years).
• Suppository form acts faster (15-60 minutes).
• ADRs: Abdominal cramps, fecal incontinence; electrolyte disturbances with overuse.

B. Anthraquinone (Anthracene) Derivatives

• Derived from Cassia species. Pro-drug - converted by colonic bacteria to active anthrones.
• Onset 6-10 hours; commonly used in opioid-induced constipation.
• Dose: 15-30 mg at bedtime.

C. Ricinoleic Acid (Castor Oil)

• Hydrolysed in small intestine by lipases to ricinoleic acid (the active form).
• Irritates small intestinal mucosa → massive fluid/electrolyte secretion → powerful purgation.
• Onset: 1-3 hours (most rapid of all laxatives).
• Uses: Bowel preparation, rarely constipation.
• ADRs: Severe griping, dehydration, electrolyte imbalance; avoid in pregnancy (stimulates uterine contractions).

IV. Stool Softeners / Emollients (Onset: 1-3 days)

• Anionic surfactant (detergent-like); lowers surface tension of stool → allows mixing of aqueous and fatty components → softens stool.
• Also stimulates intestinal fluid/electrolyte secretion via increased mucosal cAMP.
• Dose: Docusate sodium 100 mg BD; Docusate calcium 240 mg/day.
• Marginal efficacy in chronic constipation; better for prevention.

V. Lubricant Laxatives

• Indigestible aliphatic hydrocarbons; coats and softens stool; interferes with water reabsorption.
• Onset: 2-3 days.
• ADRs (preclude regular use):
  • Interferes with absorption of fat-soluble vitamins (A, D, E, K).
  • Foreign-body reactions in intestinal mucosa/lymph nodes.
  • Anal leakage/seepage.
  • Lipid pneumonitis if aspirated (especially at night - avoid at bedtime).
• Not recommended for routine use.

VI. Newer / Secretagogue Agents

Classification Summary Table (Goodman & Gilman)

Clinical Indications

Important Adverse Effects to Remember

Antiretroviral Therapy (ART) - Pharmacology Notes

HIV Replication Cycle & Sites of Drug Action

Classification of Antiretroviral Drugs

I. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

II. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Long plasma half-life (>24 hours) → once-daily dosing.
• 2nd-generation NNRTIs (doravirine, etravirine, rilpivirine) have higher potency, longer half-lives, reduced side effects, higher barrier to resistance vs 1st generation (efavirenz, nevirapine).
• All metabolized by CYP450 → many drug-drug interactions.
• Baseline genotypic resistance testing recommended (primary resistance 2-8%).

III. Protease Inhibitors (PIs)

• All require pharmacokinetic boosting with ritonavir (100 mg) or cobicistat (150 mg) - "boosted PI" - to increase plasma levels and extend dosing intervals.
• Extensive CYP3A4 metabolism → major drug-drug interactions.
• All PIs taken with food (except atazanavir requires separation from antacids).

IV. Integrase Strand Transfer Inhibitors (INSTIs)

• Currently preferred first-line drugs due to high efficacy, high barrier to resistance (dolutegravir, bictegravir), once-daily dosing, minimal drug interactions.
• Chelated by divalent cations (Mg²⁺, Al³⁺) - separate from antacids/polyvalent cations by ≥2 hours.

V. Entry/Fusion Inhibitors

A. Fusion Inhibitor

• Synthetic peptide (36 amino acids); binds to gp41 heptad repeat region → blocks conformational change needed for membrane fusion.
• Route: Subcutaneous injection only (not oral).
• ADRs: Local injection site reactions (almost universal - nodules, pain, erythema), pneumonia risk.
• Reserved for salvage therapy in multi-drug resistant HIV.

B. CCR5 Co-receptor Antagonist

• Binds CCR5 chemokine receptor on host CD4 cells → prevents gp120 binding → blocks viral entry.
• Only active against CCR5-tropic (R5) HIV - must perform tropism testing (viral genotyping) before use.
• If CXCR4-tropic (X4) or dual/mixed-tropic virus is present → drug will not work.
• Excellent CSF penetration; cervicovaginal levels 4x higher than plasma.
• ADRs: Hepatotoxicity (with allergic prodrome), cough, URI, dizziness, myocardial ischaemia.
• Substrate of CYP3A4 - dose adjustment with CYP3A inhibitors/inducers.

C. CD4 Post-Attachment Inhibitor

• Monoclonal antibody binding CD4 receptor → blocks HIV entry post-attachment.
• IV every 2 weeks; reserved for multidrug-resistant HIV.

D. gp120 Attachment Inhibitor

• Prodrug → temsavir; binds HIV gp120 → prevents attachment to CD4.
• For heavily treatment-experienced patients with multidrug-resistant HIV.

VI. Capsid Inhibitor

• Binds HIV capsid protein → disrupts multiple stages: nuclear import, viral assembly, uncoating.
• Long-acting: SC injection every 6 months (longest-acting ARV).
• Used in multidrug-resistant HIV and being studied for PrEP.

Recommended First-Line ART Regimen

TDF + 3TC (or FTC) + DTG (Tenofovir + Lamivudine/Emtricitabine + Dolutegravir)

• Two NRTIs as the backbone + one third agent (INSTI preferred > NNRTI > boosted PI).
• Aims for plasma viral load <50 copies/mL (undetectable) within 6 months.
• Goal: U=U (Undetectable = Untransmittable).

• ABC/3TC (if TDF contraindicated - requires HLA-B*5701 testing)
• AZT/3TC (used in PMTCT regimens)

Special Situations

Key Drug-Drug Interactions

Summary: Class ADRs at a Glance