AETCOM Module 2.2 - The Foundations of Bioethics

1. Autonomy - Respecting the patient's right to make informed decisions about their own healthcare. The physician must share information, involve the patient, and honor their choices (shared responsibility). A patient cannot be forced into a procedure even if the doctor believes it is necessary.
2. Beneficence - The duty of the doctor to act in the best interest of the patient. Every clinical decision should aim at producing the maximum benefit for the patient.
3. Non-maleficence - "Primum non nocere" - "First, do no harm." Physicians must avoid actions or treatments that may cause unnecessary harm, side effects, or suffering.
4. Justice - Fair and equitable distribution of healthcare resources. All patients must be treated equally regardless of socioeconomic status, caste, religion, or gender.

• Describe and discuss the role of non-maleficence as a guiding principle in patient care
• Describe and discuss autonomy and shared responsibility in patient care
• Describe and discuss beneficence as a guiding principle
• Describe and discuss the role of justice in patient care and the physician's role in the health care system

AETCOM Module 2.3 - Health Care as a Right

1. Is health care a right? - Exploration of healthcare as a universal human right vs. a privilege. Students debate the constitutional, moral, and ethical basis for this claim.
2. Implications of health care as a right - What does it mean for a society to declare healthcare a right? Includes universal access, government responsibility, and equitable distribution of services.
3. Social and economic implications - The impact of poverty, geography, and socioeconomic status on healthcare access. Why do disparities exist between rural and urban populations, and between rich and poor?
4. Missing links in the healthcare system - Gaps in infrastructure, human resources, health insurance coverage, and policy implementation that prevent equitable access.
5. Implications for doctors - The role of the doctor as a key player in bridging these gaps. Doctors must be sensitive to systemic inequities and must not discriminate among patients based on ability to pay or social status.

• Describe and discuss the role of justice as a guiding principle in patient care (KH level)

• Formative: Active participation in debates
• Summative: Short questions on rights of patients, responsibilities of patients, duties of doctors, and the boundaries of the doctor-patient relationship.

Routes of Drug Administration

I. Enteral Routes

1. Oral (PO)

• Most common, convenient, and economical route.
• Drug is swallowed and absorbed through the GI mucosa.
• Advantages: Easy self-administration; antidotes (e.g., activated charcoal) can be used for overdose.
• Disadvantages: Variable absorption; low gastric pH inactivates some drugs; food interactions; subject to first-pass metabolism by the liver.
• Special preparations:
  • Enteric-coated: Protects acid-labile drugs (e.g., omeprazole) or stomach-irritating drugs (e.g., aspirin) - releases in the less acidic intestine.
  • Extended-release (ER/XR/SR/CR): Controls drug release for slower absorption, prolonged effect, fewer doses, improved compliance - useful for drugs with short half-lives (e.g., oral morphine ER requires only 2 doses/day vs. 6 doses for immediate-release).
• Examples: Paracetamol, amoxicillin.

2. Sublingual (SL) / Buccal

• Sublingual: Drug placed under the tongue.
• Buccal: Drug placed between the cheek and gum.
• Advantages:
  • Bypasses first-pass metabolism
  • Bypasses harsh GI environment
  • Rapid absorption into systemic circulation
  • Neutral salivary pH maintains drug stability
• Disadvantages: Limited to small doses; part of drug may be swallowed.
• Examples: Nitroglycerin (SL), buprenorphine.

II. Parenteral Routes

• Drug is poorly absorbed or unstable in the GI tract (e.g., heparin, insulin)
• Patient is unconscious or vomiting
• Rapid onset is needed

1. Intravenous (IV)

• Most common parenteral route; drug delivered directly into blood.
• Bolus: Immediate, full dose; rapid effect.
• IV infusion: Slower delivery, lower peak concentration, prolonged duration.
• Used in emergencies and for drugs requiring precise titration (e.g., rocuronium).
• Disadvantage: Risk of rapid toxicity; strict aseptic technique required; oily or insoluble substances cannot be given.

2. Intramuscular (IM)

• Drug injected into muscle (e.g., deltoid, gluteus).
• Aqueous solutions: Absorbed rapidly via diffusion.
• Depot preparations: Suspended in non-aqueous vehicle (oil/polyethylene glycol); drug precipitates at injection site and dissolves slowly - provides sustained release over days to weeks.
• Examples: Depot antipsychotics (haloperidol decanoate), benzathine penicillin.

3. Subcutaneous (SC)

• Injected into the loose connective tissue below the skin.
• Absorption by simple diffusion - slower than IV, similar to IM.
• Provides constant, slow, sustained drug levels.
• Contraindicated for tissue-irritating drugs (risk of pain and necrosis).
• Examples: Insulin, heparin.

4. Intradermal (ID)

• Injected into the dermis (the vascular layer below the epidermis).
• Used for diagnostic tests (tuberculin test, allergy testing) and desensitization.

III. Other (Miscellaneous) Routes

1. Inhalation / Nasal

• Delivers drug across the large surface area of respiratory mucosa/pulmonary epithelium.
• Onset is nearly as rapid as IV bolus.
• Useful for local effect in the lungs (asthma, COPD) - minimizes systemic side effects.
• Gases (anesthetic agents) and aerosols are given by inhalation.
• Nasal route: used for allergic rhinitis and for systemic delivery (e.g., desmopressin, sumatriptan nasal spray).

2. Intrathecal / Intraventricular

• Drug injected directly into the cerebrospinal fluid (CSF), bypassing the blood-brain barrier (BBB).
• Used when rapid CNS effects are needed (e.g., spinal anesthesia, intrathecal methotrexate in meningeal leukemia, antibiotics in meningitis).

3. Topical

• Applied to skin or mucous membranes for a local effect.
• Examples: Antifungal creams, eye drops, ear drops.

4. Transdermal

• Drug applied to skin via a transdermal patch for systemic absorption.
• Absorption varies with skin thickness and lipid solubility of the drug.
• Advantages: Avoids first-pass metabolism; sustained, controlled release; non-invasive.
• Examples: Nicotine patch, fentanyl patch, nitroglycerin patch.

5. Rectal

• Drug administered as suppository or enema via the rectum.
• 50% of rectal drainage bypasses portal circulation, reducing first-pass metabolism.
• Useful when patient is vomiting, unconscious, or oral route is unavailable.
• Disadvantages: Erratic and incomplete absorption; may irritate rectal mucosa.
• Examples: Diazepam rectal gel (status epilepticus in children), paracetamol suppository.

Summary Table

Skeletal Muscle Relaxants

Classification

Skeletal Muscle Relaxants
├── 1. Neuromuscular Blocking Drugs (NMBDs)
│       ├── A. Non-depolarizing (competitive) blockers
│       └── B. Depolarizing blockers
├── 2. Spasmolytics (for spasticity - upper motor neuron lesions)
│       ├── Baclofen
│       ├── Diazepam
│       └── Tizanidine
└── 3. Antispasmodics (for peripheral muscle spasm)
        ├── Cyclobenzaprine
        ├── Methocarbamol
        └── Carisoprodol

I. Normal Neuromuscular Transmission

1. Action potential arrives at motor nerve terminal → Ca²⁺ influx → ACh released
2. ACh crosses synaptic cleft and binds to nicotinic receptors (nAChR) at motor end plate (two ACh molecules bind to α-subunits)
3. Na⁺/K⁺ channel opens → end plate potential → muscle action potential → muscle contraction
4. ACh is rapidly destroyed by acetylcholinesterase

II. Neuromuscular Blocking Drugs (NMBDs)

A. Non-depolarizing (Competitive) Blockers

• No initial fasciculations (no activation)
• Response to tetanic stimulation: unsustained (fade)
• Post-tetanic facilitation: present
• Reversed by neostigmine (AChE inhibitor) - increases ACh to compete back
• Recovery: 30-60 min (depending on dose)

B. Depolarizing Blockers

• Binds nicotinic receptor → opens ion channel → persistent depolarization of motor end plate
• Initial fasciculations visible (transient muscle contractions)
• Membrane remains depolarized and unresponsive → flaccid paralysis
• Succinylcholine is NOT metabolized at the synapse (unlike ACh) → sustained depolarization
• Not reversed by neostigmine (AChE inhibitors make it worse - more ACh = more depolarization)
• Recovery: 4-8 minutes (rapid, metabolized by plasma pseudocholinesterase)

• Occurs with large doses or prolonged exposure
• End plate becomes repolarized but is desensitized - no longer responds to ACh
• Behaves more like non-depolarizing block
• Can be reversed by neostigmine at this stage

• Rapid sequence intubation (RSI) - fastest onset and recovery
• Short surgical procedures
• Electroconvulsive therapy (ECT)

• Hyperkalemia - dangerous in burns, crush injury, denervation (extrajunctional receptor proliferation releases K⁺)
• Malignant hyperthermia - with halothane (life-threatening)
• Bradycardia (especially in children)
• Increased intraocular and intragastric pressure
• Muscle pains (post-operative myalgia from fasciculations)
• Prolonged apnea in pseudocholinesterase deficiency (dibucaine number)

III. Spasmolytics (Antispastic Drugs)

1. Baclofen

• Structural analogue of GABA
• Acts at GABA-B receptors in the spinal cord
• Inhibits both monosynaptic and polysynaptic reflex transmission
• Dose: 40-80 mg/day orally; intrathecal pump for severe spasticity
• ADRs: Sedation, drowsiness, dizziness, muscle weakness, nausea
• Overdose: Seizures, flaccid paralysis, respiratory depression, coma - managed with ICU care, physostigmine for CNS reversal

2. Diazepam (Benzodiazepine)

• Enhances GABA-A receptor activity - increases Cl⁻ conductance → neuronal inhibition
• Acts at supraspinal and spinal levels
• Effective but causes significant sedation and dependence
• Also used for acute muscle spasm and as adjunct in tetanus

3. Tizanidine

• Alpha-2 adrenergic agonist (similar to clonidine)
• Acts in spinal cord to reduce excitatory interneuron activity
• Causes less weakness than baclofen
• ADRs: Sedation, dry mouth, hypotension, hepatotoxicity

4. Dantrolene (Peripheral Spasmolytic)

• Unique - acts directly on skeletal muscle, not the CNS
• Inhibits Ca²⁺ release from sarcoplasmic reticulum (blocks ryanodine receptor)
• Used for spasticity AND malignant hyperthermia (drug of choice)
• ADRs: Hepatotoxicity (monitoring required), muscle weakness, sedation

IV. Antispasmodics (for Peripheral Muscle Spasm)

V. Clinical Applications Summary

Pharmacovigilance

Definition

"The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems."

• Identifying new information about hazards associated with medicines
• Preventing harm to patients

Adverse Drug Reaction (ADR) - Key Definition

Objectives / Aims of Pharmacovigilance

1. Early detection of previously unknown (hitherto unknown) adverse reactions and drug interactions
2. Detection of increases in frequency of known adverse reactions
3. Identification of risk factors and possible mechanisms underlying adverse reactions
4. Estimation of benefit-risk analysis quantitatively
5. Dissemination of information needed to improve drug prescribing and regulation
6. Identify new signals - unexpected patterns of harm
7. Prevent harm to patients - ensure drug safety throughout the product life cycle

Classification of ADRs

By Type (Rawlins and Thompson Classification):

By Severity:

• Mild - no antidote needed, resolves spontaneously (e.g., nausea)
• Moderate - may require treatment or hospitalization (e.g., drug-induced rash)
• Severe / Serious - life-threatening, causes hospitalization, disability, or death
  • SUSAR = Suspected Unexpected Serious Adverse Reaction (important in clinical trials)

By Expectedness:

• Expected (Labeled) - already documented in product information
• Unexpected (Unlabeled) - not previously documented; requires special reporting

Methods of Pharmacovigilance

1. Spontaneous Reporting (Yellow Card / Voluntary Reporting)

• The backbone of PV systems worldwide
• Healthcare professionals and patients report ADRs voluntarily to national centers
• Detects signals of rare, new, or serious ADRs
• Limitation: Underreporting is a major problem (iceberg phenomenon - only 10% of ADRs are reported)

2. Cohort Event Monitoring (CEM)

• Prospective, observational study of events in patients using a specific medicine
• Patients monitored from start of treatment for a defined period
• Useful for newly approved drugs

3. Case-Control Studies

• Compare patients with ADR (cases) vs. those without (controls)
• Identifies risk factors for ADRs

4. Prescription Event Monitoring (PEM)

• Large-scale observational study linking prescriptions to subsequent events
• Used in the UK's Drug Safety Research Unit

5. Record Linkage Studies

• Links prescription databases with hospital records to find associations

6. Intensive Medicines Monitoring Programs

• Intensive surveillance of selected drugs in specific settings

Causality Assessment (WHO-UMC Scale)

Pharmacovigilance Programme of India (PvPI)

• Established in 2010 by the Ministry of Health and Family Welfare
• National Coordination Centre (NCC): Indian Pharmacopoeia Commission (IPC), Ghaziabad
• India is a full member of the WHO Programme for International Drug Monitoring (PIDM), based at Uppsala Monitoring Centre (UMC), Sweden
• Reports are submitted to UMC via VigiFlow (web-based tool)
• ADR reports submitted as Individual Case Safety Reports (ICSRs)

1. Create a nationwide system for patient safety by ensuring drug safety
2. Identify and analyze new signals from reported cases
3. Collaborate with WHO and global databases
4. Provide regulatory recommendations to CDSCO (Central Drugs Standard Control Organisation)

• Healthcare professionals report to nearest AMC (ADR Monitoring Centre)
• Over 250+ AMCs established across India
• Online portal: www.pvpi.gov.in
• Toll-free helpline: 1800-180-3024

Signal Detection

Information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association between an intervention and an event, or a new aspect of a known association, that is judged to be of sufficient likelihood to justify verification.

• Signals are detected from spontaneous reports, literature, clinical trials, epidemiological studies
• Once a signal is validated, it leads to a regulatory action (e.g., label change, restriction, withdrawal)

Benefit-Risk Analysis

• Benefits: Proven therapeutic good; patient's subjective assessment of effects
• Risks: Probability of harm; severity; reversibility
• Drugs are approved when benefits outweigh risks for the indicated population
• Post-marketing PV continuously re-evaluates this balance

Importance / Why Pharmacovigilance Matters

Summary Diagram

Drug Approved (Marketing Authorization)
        ↓
Post-Marketing Surveillance
        ↓
ADR Reported (Spontaneous / Active Monitoring)
        ↓
Signal Detection
        ↓
Causality Assessment (WHO-UMC Scale)
        ↓
Benefit-Risk Analysis
        ↓
Regulatory Action
(Label update / Restriction / Withdrawal)