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Here are your crisp, exam-oriented notes from Shanbhag Pharmacology covering Antiepileptic Drugs and Opioid Analgesics:

📚 ANTIEPILEPTIC DRUGS — Exam Notes

1. CLASSIFICATION OF SEIZURES

Type	Features
GTCS (Grand mal)	Aura → epileptic cry → LOC → tonic → clonic → postictal confusion
Absence (Petit mal)	Sudden staring + brief LOC, no convulsion
Myoclonic	Brief shock-like muscle jerks
Simple partial (SPS)	Focal motor/sensory, NO LOC
Complex partial (CPS)	Aura + amnesia + automatism, WITH impaired consciousness

2. CHEMICAL CLASSIFICATION (Quick List)

Hydantoins: Phenytoin, Fosphenytoin
Barbiturates: Phenobarbitone
Iminostilbenes: Carbamazepine, Oxcarbazepine
Carboxylic acid: Sodium valproate, Divalproex
Succinimide: Ethosuximide
BZDs: Lorazepam, Diazepam, Clonazepam, Clobazam
Newer: Lamotrigine, Topiramate, Gabapentin, Pregabalin, Tiagabine, Vigabatrin, Zonisamide, Levetiracetam, Lacosamide

3. CLINICAL CLASSIFICATION (Drug of Choice Table)

Seizure	Preferred Drug	Alternatives
GTCS	Na Valproate, Lamotrigine, Carbamazepine	Oxcarbazepine, Levetiracetam, Phenytoin, Clobazam, Topirate, Phenobarbitone
SPS/CPS	Carbamazepine, Lamotrigine, Na Valproate	Levetiracetam, Gabapentin, Phenytoin, Topiramate, Tiagabine, Zonisamide
Absence	Na Valproate, Ethosuximide	Clonazepam, Lamotrigine, Clobazam
Myoclonic	Na Valproate	Clonazepam, Clobazam, Levetiracetam
Status epilepticus	Lorazepam/Diazepam → Fosphenytoin/Phenytoin → Phenobarbitone	Midazolam, Propofol (GA)

4. MECHANISM OF ACTION

Na⁺ Channel Blockers (Prolong inactivated state)

Phenytoin, Fosphenytoin, Carbamazepine, Oxcarbazepine, Na Valproate, Lamotrigine, Topiramate, Zonisamide, Lacosamide

GABA Enhancers

Drug	Mechanism
Benzodiazepines	Facilitate GABA activity
Phenobarbitone	Facilitate GABA + GABA mimetic
Na Valproate	↑ GABA synthesis (↑GAD), ↓ GABA breakdown (↓GABA-T)
Vigabatrin	Inhibits GABA transaminase (↓ GABA breakdown)
Gabapentin, Pregabalin	Release GABA
Tiagabine	Blocks uptake of GABA into neurons

Other Mechanisms

Ethosuximide + Na Valproate: Block T-type Ca²⁺ channels in thalamus (absence seizures)

5. INDIVIDUAL DRUG PROFILES

PHENYTOIN ⭐

MOA: Prolongs Na⁺ channel inactivation → ↓ high-frequency firing
Kinetics: Dose-dependent (zero-order at high dose); t½ = 10-60 hrs; 90% protein bound; enzyme inducer; therapeutic monitoring essential
Uses: GTCS, partial seizures, trigeminal neuralgia, status epilepticus (IV in normal saline - NOT glucose)
ADRs - The H's mnemonic:
1. Hypertrophy/Hyperplasia of gums
2. Hypersensitivity (skin rash, neutropenia, hepatic necrosis)
3. Hirsutism
4. Hyperglycaemia
5. Megaloblastic anaemia (↓folate)
6. Osteomalacia (↑Vit D metabolism)
7. Hypocalcaemia
8. Fetal Hydantoin syndrome (cleft lip, cleft palate, digital hypoplasia)
High conc. toxicity: Vestibulocerebellar (vertigo, ataxia, nystagmus), CVS (hypotension, arrhythmia), GIT

FOSPHENYTOIN

Prodrug → converted to phenytoin by phosphatases
Can be given in saline OR glucose; less vein irritation
Preferred in status epilepticus; dose expressed as phenytoin equivalents (PE)

CARBAMAZEPINE ⭐

Related to TCAs chemically
MOA: Slows Na⁺ channel recovery from inactivation
Kinetics: Autoinduction (induces its own metabolism); induces OC pills, valproate, phenytoin, lamotrigine, topiramate
DOC for: Trigeminal neuralgia, also used in bipolar disorder, mania
Uses: GTCS, partial seizures
ADRs: Sedation, diplopia, ataxia, nausea, water retention (SIADH/ADH release), aplastic anaemia/agranulocytosis, skin rash

OXCARBAZEPINE

Analogue of carbamazepine; prodrug
Less enzyme induction, fewer drug interactions
Less potent, less hepatotoxic than carbamazepine

PHENOBARBITONE

Potentiates GABA activity
Cheapest antiepileptic; used in GTCS, partial seizures, febrile convulsions prophylaxis
IV in status epilepticus (when diazepam + phenytoin fail)
ADR: Sedation (tolerance develops), megaloblastic anaemia, skin rashes, behavioral changes in children

ETHOSUXIMIDE

DOC for absence seizures (with Na valproate)
MOA: Inhibits T-type Ca²⁺ current in thalamic neurons
ADR: GI disturbances, hiccough, eosinophilia, bone marrow depression

SODIUM VALPROATE ⭐ (Broad spectrum)

MOA: Na⁺ channel + T-Ca²⁺ channel + ↑GABA (↑GAD, ↓GABA-T)
Uses: Absence, myoclonic, partial, GTCS, mania, bipolar, migraine prophylaxis
ADR Mnemonic - VALPROATE:
- Vomiting, Anorexia (GI)
- Liver (fulminant hepatitis - avoid <3 yrs)
- Pancreatitis (acute, rare)
- Rashes, Obesity (weight gain)
- Alopecia, Tremor
- Elevation of liver enzymes
Teratogenic: Neural tube defects (spina bifida) - avoid in pregnancy
Inhibits metabolism of phenytoin, ethosuximide, phenobarbitone

BENZODIAZEPINES

Drug	Key Use
Lorazepam	1st choice in status epilepticus (rapid onset + long action)
Diazepam	Status epilepticus (IV); rectal in children; short duration
Clonazepam	Absence + myoclonic seizures (long-acting BZD)

6. NEWER ANTIEPILEPTICS (Table Summary)

Drug	MOA	Key Use	Key ADR
Lamotrigine	Na⁺ channel	GTCS, absence, myoclonic, partial	Skin rash; valproate ↑ its levels; carbamazepine ↓ its levels
Topiramate	Na⁺ + ↑GABA + ↓glutamate	GTCS, partial, migraine, alcoholism	Weight loss, confusion; ↓ OCP efficacy
Zonisamide	Na⁺ channel	Add-on in partial seizures	Ataxia, headache; related to sulphonamides
Lacosamide	Na⁺ channel	Refractory partial seizures	Dizziness, diplopia, cardiac arrhythmias
Gabapentin	Releases GABA	Partial, neuropathy, migraine, bipolar	Sedation, fatigue; rare drug interactions
Pregabalin	Releases GABA	Partial seizures, neuropathic pain	Skin rash, sedation
Tiagabine	Blocks GABA reuptake	Add-on in partial seizures	Sedation, dizziness
Vigabatrin	Inhibits GABA-T	Adjunct in partial seizures	Visual disturbances, psychosis
Levetiracetam	Binds synaptic vesicle protein (SV2A)	Adjunct in GTCS, partial, myoclonic	Sedation, dizziness, fatigue

7. STATUS EPILEPTICUS - Treatment Algorithm

Tonic-clonic seizures without regaining consciousness >30 min = emergency!

Step 1: Lorazepam 0.1 mg/kg IV  OR  Diazepam 10 mg IV (repeat x1 after 10 min)
            ↓ (if seizure continues)
        Fosphenytoin 20 mg/kg IV  OR  Phenytoin 20 mg/kg IV (50 mg/min in NS)
            ↓ (if seizure continues)
Step 2: Phenobarbitone 10-15 mg/kg IV (100 mg/min)
            ↓ (if seizure continues)
Step 3: General anaesthesia — IV Midazolam or Propofol

8. IMPORTANT DRUG INTERACTIONS

Drug	Interaction
Phenytoin	Induces OCP, steroids, Vit D, theophylline; mutual induction with CBZ; chloramphenicol/INH/warfarin INCREASE phenytoin levels
Carbamazepine	Induces OCP, phenytoin, valproate; INH/erythromycin INCREASE CBZ levels
Valproate	Inhibits metabolism of phenytoin, ethosuximide, phenobarbitone; +CBZ = ↑ teratogenicity

💊 OPIOID ANALGESICS — Exam Notes

1. CLASSIFICATION

Opioid Agonists:

Natural: Morphine, Codeine, Thebaine*, Papaverine* (*no analgesia)
Semisynthetic: Heroin, Hydromorphone, Oxymorphone, Pholcodine
Synthetic: Pethidine, Tramadol, Methadone, Fentanyl, Tapentadol, Remifentanil

Agonist-Antagonists: Pentazocine, Butorphanol, Nalorphine, Nalbuphine

Partial μ-agonist + κ-antagonist: Buprenorphine

Pure Antagonists: Naloxone, Naltrexone, Nalmefene

2. OPIOID RECEPTORS

Receptor	Effects
μ (mu)	Analgesia (spinal + supraspinal), respiratory depression, dependence, sedation, euphoria, miosis, ↓GI motility
κ (kappa)	Analgesia (spinal + supraspinal), respiratory depression, dysphoria, psychotomimetic effect
δ (delta)	Analgesia (spinal + supraspinal), respiratory depression, proconvulsant

3. MORPHINE - PHARMACOLOGICAL ACTIONS

Mnemonic: MARPHINE CVS

Miosis
Analgesia
Respiratory depression
Physical and psychological dependence
Histamine release, Hypotension, Hypothermia
Itching
Nausea and vomiting
Euphoria
Cough suppression, Constipation
Vagal stimulation (bradycardia)
Sedation and hypnosis

CNS Effects of Morphine

Effect	Detail
Analgesia	Via μ-receptors; ↓ excitatory NT release in dorsal horn
Euphoria	Relieves anxiety, fear, apprehension = relieves "total pain"
Respiratory depression	↓ sensitivity of resp. centre to CO₂; commonest cause of death in acute poisoning
Miosis	Stimulates III CN nucleus; pinpoint pupils = acute poisoning sign
Cough suppression	Direct action on cough centre in medulla
Nausea/vomiting	CTZ stimulation (5-HT₃ antagonists/H₁ blockers for control)

Peripheral Effects

CVS: Vasodilation → ↓BP (depression of VMC + histamine release)
GIT: Constipation (↓GI motility, ↑sphincter tone) - direct GIT + CNS action
Urinary bladder: Urinary retention (↑urethral sphincter tone)
Biliary tract: ↑intrabiliary pressure (↑Oddi sphincter tone)
Histamine release: Itching, urticaria, bronchospasm

4. MORPHINE - PHARMACOKINETICS

Oral bioavailability poor (extensive first-pass)
Routes: oral, IV, IM, SC, epidural, intrathecal
Metabolized by liver (glucuronide conjugation)
Morphine-6-glucuronide = more potent analgesic, excreted in urine

5. ADVERSE EFFECTS OF MORPHINE

Nausea, vomiting, constipation
Respiratory depression
Hypotension
Drowsiness, mental clouding
Itching, skin rashes
Difficulty in micturition
Neonatal respiratory depression (if given to mother in labour)
Drug tolerance (except miosis)
Drug dependence (physical + psychological) - major drawback

6. ACUTE MORPHINE POISONING

Triad: Respiratory depression + Pinpoint pupils + Coma

Treatment:

Hospitalize; maintain airway
Ventilatory support
Gastric lavage with KMnO₄
Naloxone 0.4-0.8 mg IV (repeat till respiration normal; short acting → repeat doses needed)

7. MORPHINE DEPENDENCE - Treatment

Gradual withdrawal of morphine
Methadone substitution: 1 mg methadone = 4 mg morphine; oral, long-acting, mild withdrawal
Buprenorphine: Sublingual; substitution therapy
Naltrexone: Pure antagonist - opioid blockade to prevent relapse (oral, long-acting)
Psychotherapy, rehabilitation

8. CONTRAINDICATIONS OF MORPHINE

Head injury - miosis masks pupillary signs; respiratory depression → CO₂ retention → ↑↑ICP
Bronchial asthma - histamine-induced bronchospasm
COPD/emphysema - low respiratory reserve
Hypotensive states
Hypothyroidism/hypopituitarism (exaggerated response)
Infants/elderly
Undiagnosed acute abdomen (masks diagnosis)

9. MORPHINE vs PETHIDINE (Comparison Table)

Feature	Morphine	Pethidine
Source	Natural opium alkaloid	Synthetic
Analgesic dose	10 mg IM/IV	100 mg IM/IV
Potency	10x more potent	Less potent
Duration	6-8 hours	3-4 hours
Constipation	++	Less prominent
Miosis	++	Less prominent
Antitussive	Yes	No
Histamine	Releases more	Less
Anticholinergic	No	Yes (dry mouth, tachycardia)
Neonatal resp. depression	Severe	Less
Special toxicity	-	Tremors, convulsions (norpethidine metabolite)

10. OTHER OPIOIDS - Special 'S' Features

Drug	Special Feature
Codeine	Selective cough suppressant; low addiction
Pethidine	Spasmodic effect less than morphine; Seizures (norpethidine)
Methadone	Substitution therapy in opioid dependence
Tramadol	Seizures can occur; Serotonin syndrome with SSRIs; also inhibits NA/5-HT reuptake
Tapentadol	Serotonin syndrome risk; inhibits NE > 5-HT reuptake
Buprenorphine	Sublingual; Substitution therapy; NOT fully reversed by naloxone
Pentazocine	Sympathetic stimulation (↑HR, ↑BP)
Fentanyl	Short acting; 100x more potent than morphine
Heroin	Severe addiction liability

11. NALOXONE (Pure Opioid Antagonist)

Competitive antagonist at all opioid receptors
IV: Immediately reverses all opioid actions (especially respiratory depression)
Short acting → repeated doses needed
Not orally effective (high first-pass)
Uses:
1. Acute morphine/opioid poisoning
2. Opioid overdose
3. Neonatal asphyxia due to maternal opioids
Note: Does NOT completely reverse buprenorphine-induced respiratory depression

Naltrexone: Oral, longer acting; used for opioid blockade therapy + alcoholism treatment

Nalmefene: IV, longer than naloxone; opioid overdose

12. THERAPEUTIC USES OF OPIOIDS

Analgesia - moderate to severe pain (MI, burns, cancer, trauma); WHO analgesic ladder
Preanaesthetic medication - ↓ anaesthetic dose required
Acute pulmonary oedema (cardiac asthma) - IV morphine: ↓preload, ↓anxiety, shifts blood from pulmonary to systemic
Postanaesthetic shivering - Pethidine
Cough suppression - Codeine, Dextromethorphan
Diarrhoea - Loperamide, Diphenoxylate (synthetic opioids)

WHO Analgesic Ladder (Remember this!):

Start: NSAID/Paracetamol (mild pain)

Weak opioid (codeine) ± NSAID ± adjuvant (moderate pain)

Strong opioid (morphine/methadone) ± NSAID ± adjuvant (severe pain)

Adjuvants: antidepressants, antiepileptics, anxiolytics, steroids

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