---

Pharmacology Notes for 2nd Year MBBS

(Based on KD Tripathi - Essentials of Medical Pharmacology)

---

PART 1: ANTIDEPRESSANTS - Classification

Classification of Antidepressants (KD Tripathi)

• Imipramine, Amitriptyline, Clomipramine, Doxepin, Nortriptyline, Desipramine

• Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Citalopram, Escitalopram

• Venlafaxine, Duloxetine, Desvenlafaxine

• Irreversible: Phenelzine, Tranylcypromine, Isocarboxazid
• Reversible (RIMAs): Moclobemide

• Mirtazapine (NaSSA), Bupropion (NDRI), Trazodone, Agomelatine, Nefazodone

• Tianeptine

---

PART 2: SSRI - Mechanism, Therapeutic Uses, Adverse Effects

Mechanism of Action (MOA)

• SSRIs have minimal affinity for muscarinic, histaminergic (H1), and adrenergic (alpha-1) receptors - this explains their improved tolerability over TCAs
• There is no direct receptor agonist activity - they work purely by reuptake inhibition
• Full antidepressant effect takes 2-4 weeks because:
  • Initial serotonin excess activates autoreceptors (5-HT1A on soma, 5-HT1D on terminals) which provide negative feedback, temporarily limiting 5-HT release
  • Over weeks, these autoreceptors downregulate, allowing sustained increase in 5-HT output

Therapeutic Uses of SSRIs

Adverse Effects of SSRIs

• Nausea, vomiting, diarrhea, anorexia - due to stimulation of 5-HT3 and 5-HT4 receptors in the gut
• Usually subside after 1-2 weeks

• Headache, dizziness, insomnia or somnolence
• Agitation, restlessness, tremors
• Activation syndrome in young patients (especially important - increased risk of suicidality in <25 yrs; BLACK BOX WARNING)

• Decreased libido, anorgasmia, delayed ejaculation
• Incidence: 30-40% patients (often under-reported)
• Post-SSRI sexual dysfunction (PSSD) can persist even after discontinuation

• Triad: Mental status changes + Autonomic instability + Neuromuscular abnormalities
• Occurs especially when combined with MAOIs, triptans, linezolid, tramadol, St. John's Wort

• Occurs with abrupt stopping (especially Paroxetine - shortest half-life)
• Mnemonic: FINISH - Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances (electric shock), Hyperarousal/anxiety
• NOT seen with Fluoxetine (longest half-life ~6 days, self-tapers)

• SSRIs inhibit platelet serotonin uptake - impair platelet aggregation
• GI bleeding risk increases when combined with NSAIDs or aspirin

• Particularly in elderly patients
• Due to 5-HT-mediated inappropriate ADH release

• Short term: weight loss (anorexia); Long term: weight gain (especially Paroxetine)

• Citalopram and Escitalopram - dose-dependent QT prolongation

---

PART 3: ANTIANXIETY DRUGS

Classification

• Short-acting: Triazolam, Midazolam, Oxazepam, Lorazepam, Alprazolam
• Long-acting: Diazepam, Chlordiazepoxide, Clonazepam, Flurazepam

• Buspirone, Gepirone

• Propranolol

• Escitalopram, Paroxetine, Venlafaxine

• Hydroxyzine (for acute anxiety)

• Phenobarbitone

• Pregabalin (GAD), Meprobamate (obsolete)

---

Benzodiazepines - MOA, Adverse Effects, Therapeutic Uses

Mechanism of Action

Adverse Effects of Benzodiazepines

1. CNS Depression: Sedation, drowsiness, ataxia, impaired psychomotor performance, anterograde amnesia
2. Paradoxical excitation: In some patients (especially elderly, children), disinhibition occurs
3. Tolerance and Dependence: Physical and psychological dependence develops with long-term use
4. Withdrawal Syndrome: Rebound anxiety, insomnia, tremors, seizures (potentially life-threatening with long-acting BZDs)
5. Respiratory Depression: Minimal at therapeutic doses, but dangerous in combination with alcohol, opioids, or other CNS depressants
6. Amnesia: Anterograde amnesia (used therapeutically in pre-operative sedation)
7. Falls and fractures: In elderly patients due to muscle relaxation and sedation
8. Teratogenicity: Risk of cleft palate if used in first trimester (neonatal withdrawal syndrome)

Therapeutic Uses of Benzodiazepines

1. Anxiety disorders: GAD, panic disorder, social anxiety (short-term only)
2. Insomnia: Temazepam, triazolam (short-acting preferred)
3. Epilepsy: Diazepam (status epilepticus IV/PR), Clonazepam (myoclonic, absence seizures)
4. Muscle relaxation: Diazepam (spasticity, tetanus, back spasms)
5. Alcohol withdrawal: Diazepam, Chlordiazepoxide (first-line)
6. Pre-operative sedation / Conscious sedation: Midazolam (IV), Lorazepam
7. Panic disorder: Alprazolam, Clonazepam
8. Procedural amnesia: Midazolam before endoscopy/cardioversion

---

Buspirone - MOA, Uses, Adverse Effects

• No sedation, no dependence, no withdrawal, no abuse potential
• Onset: 2-4 weeks (not effective for acute anxiety)

---

PART 4: OPIUM ALKALOIDS - ENUMERATE

• Morphine (10% of opium - the prototype)
• Codeine (0.5%)
• Thebaine (0.2% - toxic, precursor for synthetic opioids)

• Papaverine (smooth muscle relaxant, used in vasospasm)
• Noscapine (narcotine - antitussive)

---

PART 5: MORPHINE AND OTHER OPIOIDS

Mechanism of Action of Morphine

1. Presynaptic: Activation of opioid receptors inhibits adenylyl cyclase (lowering cAMP), decreases Ca2+ influx via voltage-gated Ca2+ channels - this reduces release of pain neurotransmitters (Substance P, Glutamate, CGRP)
2. Postsynaptic: Opens K+ channels - causes hyperpolarization - inhibits neuronal firing

• Supraspinal: PAG (periaqueductal gray), rostral ventromedial medulla (RVM)
• Spinal: Substantia gelatinosa (Rexed lamina II) of dorsal horn
• Peripheral: On nociceptors (more active during inflammation)

Clinical Uses of Morphine

1. Pain relief:
   • Moderate to severe acute pain (post-operative, trauma, MI pain)
   • Cancer pain (WHO analgesic ladder - Step III)
   • Renal/biliary colic (with an antispasmodic)
2. Acute Left Ventricular Failure (Acute Pulmonary Edema): Morphine is part of the classic LMNOP regimen. It causes venodilatation, reduces anxiety, decreases preload and myocardial oxygen demand.
3. Myocardial Infarction (STEMI): IV morphine for pain and anxiety relief
4. Pre-anesthetic medication: To reduce anxiety, enhance anesthetic effect, provide analgesia
5. Antitussive: Codeine (methyl morphine) preferred; morphine suppresses cough at medullary level
6. Diarrhea: Morphine reduces GI motility; codeine, loperamide used clinically
7. Dyspnea in terminal illness: Morphine is highly effective for relieving dyspnea (air hunger)

Adverse Effects of Morphine

• Euphoria (wanted), sedation, drowsiness
• Miosis (pin-point pupils) - pathognomonic sign, persists even with tolerance (due to parasympathomimetic effect on Edinger-Westphal nucleus via μ and κ receptors)
• Nausea and vomiting (via CTZ stimulation - chemoreceptor trigger zone)
• Respiratory Depression - most dangerous; depression of respiratory center in medulla; decreases sensitivity to CO2

• Hypotension (vasodilation via histamine release and direct effect)
• Bradycardia (vagal stimulation)

• Constipation - decreased peristalsis, increased tone of sphincters; does NOT develop tolerance (most persistent side effect)
• Nausea and vomiting

• Urinary retention - increased tone of detrusor muscle and vesical sphincter
• Urinary hesitancy

• Flushing, sweating, pruritus (especially after IV use - histamine release)

• Miosis (pin-point pupils) - diagnostic sign in overdose

• Decreased GnRH, LH, FSH, testosterone - hypogonadism with chronic use
• Increased ADH - may cause urinary retention

• Tolerance develops to most effects EXCEPT miosis and constipation
• Physical dependence: withdrawal syndrome on abrupt stopping
• Psychological dependence (addiction): strong craving

• Increased intracranial pressure (ICP) - due to CO2 retention causing cerebral vasodilation

---

WHY IS MORPHINE CONTRAINDICATED IN HEAD INJURY?

• Morphine depresses the medullary respiratory center
• This leads to decreased respiratory rate and tidal volume
• Result: accumulation of CO2 in blood (hypercapnia)
• CO2 is a potent cerebral vasodilator - causes cerebral vasodilation
• This increases cerebral blood volume and ICP (intracranial pressure)
• In a head injury patient, ICP is already elevated due to edema/hematoma
• Further rise in ICP can cause cerebral herniation and death

• Morphine causes pin-point pupils (miosis)
• Pupillary response is a critical neurological monitoring sign in head injury
• Miosis from morphine masks changes in pupillary size that indicate herniation (uncal herniation causes ipsilateral mydriasis)
• This prevents accurate clinical monitoring

• Morphine causes sedation and CNS depression
• This interferes with GCS (Glasgow Coma Scale) assessment - a vital tool for monitoring neurological deterioration in head injury
• Cannot distinguish drug-induced drowsiness from worsening of brain injury

• Morphine causes vasodilation and hypotension
• Head injury patients already have compromised cerebral perfusion
• Hypotension further reduces Cerebral Perfusion Pressure (CPP)
• CPP = MAP - ICP. If MAP falls and ICP rises, CPP becomes critically low leading to cerebral ischemia

• Morphine stimulates the CTZ causing nausea and vomiting
• A head-injured patient with reduced GCS cannot protect the airway
• Risk of aspiration pneumonia

• Respiratory depression (CO2 retention, raised ICP)
• Sedation (masks clinical signs, interferes with neurological assessment)
• Vomiting (aspiration risk)
• Pupil constriction (miosis masks neurological monitoring signs)

---

PART 6: PETHIDINE (MEPERIDINE) OVER MORPHINE - ADVANTAGES

• Toxic metabolite Normeperidine accumulates with repeated doses - causes CNS excitation, myoclonus, tremors, and seizures (not reversed by naloxone)
• Shorter duration of action (2-3 hours vs morphine's 4-6 hours)
• Should NOT be used in patients on MAOIs (severe serotonin syndrome risk)
• Not suitable for chronic pain management

---

PART 7: ACUTE MORPHINE POISONING - TREATMENT IN DETAIL

Diagnosis - Classic Triad (Opioid Toxidrome)

1. Coma (CNS depression)
2. Respiratory Depression (slow, shallow breathing, RR <12/min)
3. Pin-point pupils (Miosis) - bilateral, symmetric - pathognomonic

Treatment in Detail

1. Secure airway - position patient, suction secretions
2. Supplemental oxygen - high flow O2 via mask
3. Bag-mask ventilation / Intubation if respiratory rate <8/min or SpO2 dropping; mechanical ventilation if required
4. DO NOT give oxygen alone in the hope that this will reverse respiratory depression - specific antidote is required

• Dose: 0.4-2 mg IV initially (adults); may repeat every 2-3 minutes up to 10 mg
• Pediatric dose: 0.01 mg/kg IV
• Onset: Within 1-2 minutes IV; 2-5 min intramuscular
• Duration of action of naloxone: 30-90 minutes (SHORTER than most opioids)
• Therefore: Repeated doses or infusion may be needed because the opioid's duration exceeds naloxone's
• Naloxone infusion: 2/3 of the initial effective bolus dose given per hour as continuous infusion

• IV (preferred), IM, intranasal (Narcan nasal spray), subcutaneous, endotracheal

1. IV fluids - for hypotension (IV crystalloids as bolus)
2. Vasopressors (dopamine, norepinephrine) if hypotension persists despite fluids
3. Cardiac monitoring - continuous ECG, pulse oximetry, capnography
4. Warming measures for hypothermia
5. Foley catheter - monitor urine output

• Activated charcoal (1 g/kg) if within 1-2 hours of ingestion
• Gastric lavage only if massive ingestion and within 1 hour
• DO NOT induce emesis (risk of aspiration, rapid CNS depression)

• Oxygen (positive pressure if needed)
• Furosemide IV
• Positive pressure ventilation (CPAP/BiPAP)
• Morphine-induced pulmonary edema also responds to naloxone

• ICU monitoring for at least 24 hours after long-acting opioid poisoning (e.g., methadone, sustained-release morphine)
• Watch for re-narcotization (return of symptoms as naloxone wears off)

---

PART 8: OPIOIDS vs NSAIDs - MAJOR DIFFERENCES

---

PART 9: OPIOID ANTAGONISTS

Classification

• Naloxone (short-acting, IV) - drug of choice for acute opioid overdose
• Naltrexone (long-acting, oral) - for opioid and alcohol dependence
• Nalmefene (long-acting, IV/IM) - similar to naloxone, longer duration

• Buprenorphine (partial μ agonist, κ antagonist) - opioid dependence treatment
• Nalorphine (historical - μ antagonist, κ agonist - causes dysphoria)

• Methylnaltrexone (Relistor) - does not cross BBB
• Naloxegol - for opioid-induced constipation
• Alvimopan - post-operative ileus

• Pentazocine, Butorphanol, Nalbuphine, Dezocine

---

Naloxone - MOA, Uses, Adverse Effects

1. Acute opioid overdose - drug of choice; reverses coma, respiratory depression, miosis within 1-2 minutes
2. Neonatal opioid depression - when mother received opioids during labor
3. Post-anesthetic respiratory depression - reversal of opioid anesthesia
4. Diagnosis of opioid dependence (Naloxone challenge test)
5. Combined with oral opioids - Naloxone added to oral oxycodone (Targiniq) to prevent IV abuse (naloxone not absorbed orally)

• In non-dependent patients: Nausea, vomiting, tachycardia, hypertension (rapid reversal of opioid analgesia)
• In opioid-dependent patients: Precipitates acute withdrawal syndrome (agitation, sweating, tachycardia, hypertension, gooseflesh, abdominal cramps, diarrhea)
• High doses may cause pulmonary edema, ventricular arrhythmias
• No respiratory depression even in high doses (pure antagonist)
• Short duration (30-90 min) - re-narcotization possible

---

Naltrexone - Uses and Key Points

• Oral, long-acting (half-life 4-10 hours; active metabolite 6-beta-naltrexol: 13 hours)
• Opioid dependence - blocks euphoria from opioids, reduces craving; must be opioid-free for 7-10 days before starting (to avoid precipitating withdrawal)
• Alcohol dependence - reduces craving and reward from alcohol (via endorphin system)
• Depot formulation (Vivitrol) - monthly injection for compliance
• Adverse effects: Hepatotoxicity (at high doses), nausea, insomnia

---

QUICK SUMMARY TABLE - Opioid Receptors

---

IMPORTANT EXAM MNEMONICS

• Miosis
• Opioid dependence
• Respiratory depression
• Pain relief (analgesia)
• Hypotension
• Increased ICP (via CO2)
• Nausea/vomiting (CTZ)
• Euphoria

• Respiratory depression (head injury - raised ICP)
• Sedation (masks neurological signs)
• Vomiting (aspiration risk)
• Pupil constriction (miosis - masks herniation signs)

• Frequency of Cl- channel opening increases
• Receptor is GABA-A
• Omega site (allosteric, between alpha and gamma subunits)
• GABA required (facilitators, not direct agonists)

---

---

What's Covered Above (Index)

---

1. SSRIs - "Frequency" of Cl- channel opening for BZDs; SSRIs work by SERT inhibition; full effect in 2-4 weeks due to autoreceptor downregulation
2. Morphine in head injury - 4 reasons: CO2 retention → cerebral vasodilation → raised ICP; miosis masks herniation signs; sedation masks GCS; hypotension reduces CPP
3. Naloxone - pure antagonist, IV, onset 1-2 min, duration 30-90 min (SHORTER than opioids - repeat doses needed)
4. Opioids vs NSAIDs - Opioids: no anti-inflammatory, ceiling absent, dependence yes; NSAIDs: anti-inflammatory, ceiling present, no dependence
5. Normeperidine (toxic metabolite of pethidine) - causes seizures NOT reversed by naloxone