PHARMACOLOGY - COMPLETE NOTES (2nd Yr MBBS)

SECTION 1: ANTIEPILEPTIC DRUGS

1A. CLASSIFICATION OF ANTIEPILEPTIC DRUGS

On the Basis of Clinical Utility

On the Basis of Mechanism of Action

1B. PHENYTOIN

Mechanism of Action

Uses

1. Focal (partial) seizures - simple and complex partial seizures (drug of choice along with CBZ)
2. Grand mal (GTCS) - generalized tonic-clonic seizures
3. Focal-to-bilateral tonic-clonic seizures
4. Status epilepticus - IV phenytoin/fosphenytoin (second-line after BZDs fail)
5. Cardiac arrhythmias - especially digoxin-induced ventricular arrhythmias (IV phenytoin)
6. Trigeminal neuralgia (less preferred than carbamazepine)
7. Neuropathic pain

Adverse Effects

• Nystagmus (earliest sign, at 20 µg/mL)
• Ataxia, diplopia, vertigo (at >30 µg/mL)
• Mental confusion, encephalopathy (at very high levels)
• CNS depression at toxic levels

• Gingival hyperplasia (20-30% of patients) - most characteristic; due to impaired collagen degradation
• Hirsutism (increased facial hair) - particularly distressing in young women
• Coarsening of facial features
• Folate deficiency - inhibits folate absorption → megaloblastic anaemia
• Osteomalacia - accelerated vitamin D metabolism by CYP induction
• Peripheral neuropathy
• Cognitive impairment

• Hypersensitivity rash (common)
• Stevens-Johnson syndrome (rare, severe)
• Hepatotoxicity (rare)
• Lymphadenopathy (pseudolymphoma)
• Teratogenicity - "Fetal Hydantoin Syndrome" - cleft palate, digit hypoplasia, facial dysmorphism

• Purple glove syndrome - purplish-black discoloration, edema, pain distal to injection site
• Cardiac arrhythmias and hypotension if given too rapidly (max rate: 50 mg/min)
• Fosphenytoin (water-soluble prodrug) is preferred for IV use

• Zero-order (saturation) kinetics at therapeutic doses - small dose increases cause disproportionately large increases in plasma levels
• Highly protein bound (~90% to albumin)
• Narrow therapeutic index (10-20 µg/mL)
• Strong CYP inducer - many drug interactions

1C. SODIUM VALPROATE

Mechanism of Action (Multiple)

1. Na+ channel block (use-dependent) - similar to phenytoin/CBZ
2. T-type Ca²+ channel block - explains efficacy in absence seizures
3. Increased GABA synthesis and release - activates glutamate decarboxylase (GAD)
4. Inhibition of GABA transaminase (GABA-T) - reduces GABA degradation → raises brain GABA levels
5. Inhibition of GABA reuptake
6. Indirect enhancement of K+ conductance

Therapeutic Uses

1. Sodium valproate is the drug of choice for all types of generalized epilepsy:
   • Generalized tonic-clonic (Grand mal)
   • Absence (Petit mal) seizures
   • Myoclonic epilepsy (juvenile myoclonic epilepsy - first choice)
   • Mixed seizure disorders (Lennox-Gastaut)
2. Focal (partial) seizures - second/third line
3. Status epilepticus - IV valproate (second-line, alternative to phenytoin)
4. Bipolar disorder (mania) - mood stabilizer
5. Migraine prophylaxis
6. Neuropathic pain (off-label)

Adverse Effects

• Nausea, vomiting, dyspepsia, diarrhea
• Reduced by enteric-coated formulations or taking with food

• Tremor (postural/action tremor, 10-15%) - dose-related
• Sedation, drowsiness (less than phenobarbital)
• Cognitive effects less than older agents

• Weight gain - significant, long-term concern
• Hyperammonemia - can cause encephalopathy even with normal liver function
• Polycystic ovary syndrome (PCOS) - hyperinsulinism, menstrual irregularities
• Alopecia (hair loss) - often regrows; curly regrowth is characteristic
• Pancreatitis (rare)

• Fatal hepatotoxicity - rare but most serious risk
• Greatest risk in children <2 years on polytherapy with metabolic disorders
• Idiosyncratic, not dose-related

• Neural tube defects (2-3%, e.g., spina bifida) - highest teratogenic risk among AEDs
• Fetal valproate syndrome - facial dysmorphism, cardiac defects, limb anomalies
• Cognitive impairment in children exposed in utero
• Absolutely avoid in women of childbearing age if possible; folic acid supplementation mandatory if used

• Inhibits platelet aggregation
• Thrombocytopenia (dose-related)

Important Drug Interactions

1. Valproate + Phenobarbital - inhibits phenobarbital metabolism → excessive sedation
2. Valproate + Phenytoin - displaces phenytoin from albumin binding + inhibits phenytoin metabolism → phenytoin toxicity
3. Valproate + Carbamazepine - increases carbamazepine epoxide metabolite (toxic) levels
4. Valproate + Lamotrigine - inhibits lamotrigine glucuronidation → lamotrigine toxicity (rash, Stevens-Johnson); lamotrigine dose must be halved
5. Valproate + Aspirin - aspirin displaces valproate from albumin → increased free valproate
6. Valproate + Clonazepam - absence status (petit mal status) can be precipitated
7. Enzyme inducers (CBZ, PHT, PHB) - increase valproate metabolism → reduced valproate levels

1D. CARBAMAZEPINE (CBZ)

Mechanism of Action

Therapeutic Uses

1. Focal (partial) seizures - drug of first choice for partial seizures (simple and complex)
2. Generalized tonic-clonic (Grand mal) seizures
3. Trigeminal neuralgia - drug of choice (most important non-epileptic use)
4. Glossopharyngeal neuralgia
5. Bipolar disorder (mania) - mood stabilizer, alternative to lithium
6. Diabetic neuropathy and other neuropathic pain
7. Alcohol withdrawal (alternative to BZDs)
8. NOT effective in absence, myoclonic, or atonic seizures (may worsen them)

Adverse Effects

• Diplopia (first to appear, may occur only for a short time of day)
• Ataxia, dizziness, vertigo
• Blurred vision
• Sedation (only at high doses - less sedating than phenobarbital)

• Nausea, vomiting, anorexia

• Benign leukopenia - in many patients; intervention needed only if neutrophils <1000/mm³
• Aplastic anemia - rare, idiosyncratic (monitor CBC)
• Agranulocytosis - rare but serious

• Rash - most common reason for discontinuation
• Stevens-Johnson syndrome - rare; risk markedly higher in HLA-B*1502 carriers (10× higher in Asians - genetic screening recommended before starting therapy in Asian patients)

• Hyponatremia (SIADH-like effect) - second most common reason for discontinuation

• Neural tube defects (spina bifida)
• Craniofacial abnormalities

• Autoinduction of CYP3A4 - CBZ accelerates its own metabolism; plasma levels fall in first few weeks of therapy → requires dose adjustment
• Induces many CYP enzymes → reduces levels of many drugs: OCP (oral contraceptive failure!), warfarin, other AEDs

1E. STATUS EPILEPTICUS - MANAGEMENT OUTLINE

Step 1: ABC + First line (0-5 min)

• Airway, Breathing, Circulation - stabilize patient
• Oxygen, IV access, blood glucose (treat hypoglycemia)
• Draw blood: glucose, electrolytes, AED levels, CBC, LFT, toxicology

Step 2: Benzodiazepines - First-line (5-20 min)

• IV Lorazepam 0.1 mg/kg (preferred - longer CNS duration) OR
• IV Diazepam 0.15-0.2 mg/kg (can repeat once) OR
• IM Midazolam (if no IV access - now preferred prehospital)
• Diazepam may be given rectally (rectal diazepam) in children in community

Step 3: Second-line agents (20-40 min) - if BZDs fail

• IV Fosphenytoin 20 mg PE/kg (at ≤150 mg PE/min) - preferred over phenytoin IV
• IV Phenytoin 20 mg/kg (at ≤50 mg/min, with cardiac monitoring)
• IV Sodium Valproate 25-40 mg/kg (faster, safer, fewer cardiac effects)
• IV Levetiracetam 60 mg/kg (increasingly used - safest profile)
• IV Phenobarbital 20 mg/kg (older option)

Step 4: Refractory Status Epilepticus (>40 min) - ICU management

• Intubation + mechanical ventilation required
• IV Anesthetic agents (continuous EEG monitoring mandatory):
  • Midazolam infusion (first choice)
  • Propofol infusion
  • Thiopental/Pentobarbital (barbiturate coma)
  • Ketamine (emerging evidence)

Step 5: Identify and treat underlying cause

• Metabolic causes, CNS infection, stroke, drug toxicity, withdrawal

1F. PRINCIPLES OF TREATMENT OF EPILEPSY

1. Correct diagnosis is essential - identify seizure type and epilepsy syndrome before starting treatment; wrong drug can worsen certain seizure types (e.g., CBZ worsens absence seizures)
2. Start with monotherapy - use one drug at a time; ~50-60% of patients can be controlled on a single drug
3. Start with the drug of first choice for that seizure type/syndrome
4. Start at a low dose and titrate up gradually - minimizes adverse effects and allows tolerance to develop to some side effects
5. Increase dose to maximum tolerated before declaring failure - adequacy of trial must be established
6. Assess efficacy by seizure frequency and tolerability - keep a seizure diary
7. Add a second drug only if first fails (polytherapy when monotherapy fails); combination should ideally have different mechanisms of action
8. Therapeutic drug monitoring (TDM) - especially for phenytoin (zero-order kinetics), carbamazepine, phenobarbital
9. Patient education and compliance is critical - abrupt withdrawal can precipitate status epilepticus
10. Withdrawal of AEDs should be gradual (over 6 months), considered only after 2-3 years seizure-free; risks must be weighed
11. Teratogenicity considerations - especially in women of childbearing age (use safer alternatives, supplement folic acid)
12. Lifestyle modifications - avoid seizure triggers (sleep deprivation, alcohol, flickering lights, stress)
13. Surgical treatment may be considered for drug-resistant focal epilepsy

1G. GRAND MAL (GTCS) - DRUGS USED

• Sodium Valproate (drug of choice for idiopathic/genetic generalized epilepsy)
• Carbamazepine (preferred when focal onset; also effective for secondarily generalized GTCS)
• Phenytoin
• Lamotrigine
• Levetiracetam
• Topiramate

• Phenobarbital
• Primidone (metabolized to phenobarbital)
• Oxcarbazepine
• Zonisamide
• Perampanel

SECTION 2: PARKINSONISM

2A. DRUGS USED IN PARKINSONISM - CLASSIFICATION

2B. LEVODOPA + CARBIDOPA COMBINATION

Rationale of Use (Why the Combination?)

• Dopamine cannot cross the blood-brain barrier (BBB)
• Levodopa crosses the BBB via the L-amino acid transporter (LAT) and is converted to dopamine in the brain
• However, when given orally alone, only 1-3% of levodopa actually reaches the brain - the remaining 97-99% is decarboxylated to dopamine in the peripheral tissues (gut wall, liver, blood vessels) by aromatic amino acid decarboxylase (AAAD/dopa-decarboxylase)

• Carbidopa is a peripheral dopa-decarboxylase inhibitor that does NOT cross the BBB
• It inhibits peripheral decarboxylation of levodopa → more levodopa is available to cross the BBB
• Result: ~10× more levodopa reaches the brain, so the dose of levodopa can be reduced 4-5 fold

Four Advantages of the Levodopa + Carbidopa Combination

1. Reduced dose of levodopa needed - 4 to 5 fold reduction in levodopa dose (same central efficacy achieved with much less drug)
2. Reduced peripheral dopaminergic side effects:
   • Less nausea and vomiting (peripheral dopamine stimulates CTZ chemoreceptors)
   • Less orthostatic hypotension
   • Less cardiac arrhythmias
   • This is because peripheral dopamine formation is inhibited
3. Faster onset of therapeutic effect - more levodopa available for CNS uptake immediately; less time needed to build up central dopamine levels
4. Better bioavailability and more predictable plasma levels - less variability in response; "on-off" fluctuations may be reduced initially; allows more precise dose titration

Four Disadvantages of the Combination

1. Central dopaminergic side effects are unmasked/enhanced:
   • Dyskinesias (involuntary movements) - peak-dose chorea, dystonia - occur earlier and more prominently
   • Hallucinations, psychosis, confusion (central dopamine excess)
   • Wearing-off phenomenon and on-off fluctuations still occur
2. Carbidopa does not prevent central adverse effects - nausea mediated centrally via area postrema (outside BBB) may still occur
3. No neuroprotective benefit - symptomatic only; does not slow disease progression; neuronal degeneration continues; long-term efficacy wanes as more neurons die
4. Motor complications develop over time:
   • Wearing-off (end-of-dose deterioration): Duration of effect of each dose shortens
   • On-off fluctuations: Sudden, unpredictable swings between mobile (on) and immobile (off) states
   • Peak-dose dyskinesias: Involuntary choreiform movements at maximum drug concentration

2C. ANTIPARKINSONIAN DRUGS - MOA, THERAPEUTIC USES, ADVERSE EFFECTS

1. Levodopa / Carbidopa (Sinemet)

• MOA: Precursor of dopamine; crosses BBB; decarboxylated in residual nigrostriatal neurons to dopamine → restores dopaminergic neurotransmission in striatum. Carbidopa inhibits peripheral AAAD
• Therapeutic uses: Mainstay of PD treatment; most effective for bradykinesia; reduces rigidity and tremor
• Adverse effects: Nausea/vomiting, orthostatic hypotension, cardiac arrhythmias (peripheral); dyskinesias, on-off fluctuations, hallucinations, psychosis, confusion (central); wearing-off phenomenon; impulse control disorders

2. Dopamine Agonists (Bromocriptine, Pramipexole, Ropinirole)

• MOA: Directly stimulate D2 (and D3) dopamine receptors in striatum; do not require conversion; longer half-life than levodopa
• Therapeutic uses:
  • Early PD monotherapy - delay need for levodopa, reducing early exposure and motor complications
  • Adjunct to levodopa in advanced PD with motor fluctuations
  • Pramipexole - also used in restless leg syndrome and depression (off-label)
• Adverse effects: Nausea, vomiting, orthostatic hypotension, somnolence ("sleep attacks"), hallucinations (more than levodopa), confusion, impulse control disorders (gambling, hypersexuality, binge eating), peripheral edema, erythromelalgia (ergot derivatives); bromocriptine (ergot) - also pulmonary and retroperitoneal fibrosis

3. MAO-B Inhibitors (Selegiline, Rasagiline)

• MOA: Selectively inhibit MAO-B → reduce catabolism of dopamine in the striatum → increased dopamine availability. At normal doses, MAO-A (which metabolizes tyramine) is not inhibited, so tyramine (cheese) interaction does not occur
• Therapeutic uses:
  • Early PD - monotherapy or adjunct to delay levodopa start
  • Adjunct to levodopa - reduces wearing-off, extends duration of levodopa effect
  • Possible neuroprotective effect (still debated)
• Adverse effects: Insomnia (metabolized to amphetamine-like compounds - selegiline), nausea, dry mouth, orthostatic hypotension; may enhance dyskinesias when combined with levodopa; risk of serotonin syndrome with SSRIs/TCAs/meperidine

4. COMT Inhibitors (Entacapone, Tolcapone)

• MOA: Inhibit catechol-O-methyltransferase (COMT), which metabolizes levodopa (peripherally) and dopamine (centrally). Result: prolonged half-life of levodopa and dopamine → smoother, longer "on" time
• Therapeutic uses: Adjunct to levodopa/carbidopa to reduce "wearing-off"; extend on-time in PD with motor fluctuations
• Adverse effects: Diarrhea, urine discoloration (orange-brown), augmented levodopa side effects (dyskinesias, nausea); tolcapone - fulminant hepatic necrosis (requires liver monitoring; largely replaced by entacapone)

5. Anticholinergics (Trihexyphenidyl/Benzhexol, Benztropine)

• MOA: Block muscarinic receptors in the striatum → restore acetylcholine/dopamine balance (in PD, dopamine is reduced → relative cholinergic excess)
• Therapeutic uses:
  • Tremor-predominant PD (especially in younger patients)
  • Drug-induced parkinsonism (neuroleptic-induced)
  • Adjunct in early PD
• Adverse effects: Peripheral: dry mouth, constipation, urinary retention, blurred vision (cycloplegia), tachycardia; Central: confusion, hallucinations, cognitive impairment, memory loss (especially in elderly - use with caution)

6. Amantadine

• MOA: Multiple mechanisms - releases dopamine from presynaptic terminals; NMDA receptor antagonist (reduces glutamate-mediated excitotoxicity); mild anticholinergic activity
• Therapeutic uses:
  • Early mild PD
  • Levodopa-induced dyskinesias - treatment (NMDA antagonism)
  • Adjunct in advanced PD
• Adverse effects: Livedo reticularis (mottled skin discoloration), ankle edema, confusion, hallucinations, nervousness, insomnia

SECTION 3: ATYPICAL ANTIPSYCHOTICS

3A. CLASSIFICATION

First Generation / Typical / "Conventional" Antipsychotics (for comparison):

• Phenothiazines: Chlorpromazine, Trifluoperazine, Thioridazine, Fluphenazine, Perphenazine
• Butyrophenones: Haloperidol, Droperidol
• Thioxanthenes: Flupenthixol, Zuclopenthixol

Second Generation / Atypical Antipsychotics:

3B. MECHANISM OF ACTION

What defines an "atypical" antipsychotic:

Key Mechanisms:

• All antipsychotics block dopamine D2 receptors in the mesolimbic pathway (therapeutic - reduces positive symptoms)
• Typical antipsychotics block D2 equally in all pathways → EPS (nigrostriatal), hyperprolactinemia (tuberoinfundibular), cognitive effects (mesocortical)

• Atypical antipsychotics are combined D2 + serotonin 5-HT2A receptor antagonists
• 5-HT2A blockade in the nigrostriatal pathway releases dopamine → offsets D2 blockade there → reduced EPS
• 5-HT2A blockade in the mesocortical pathway → increases dopamine release → improves negative symptoms and cognition
• This "serotonin-dopamine antagonism" model explains much of the atypical profile
• Atypicals typically have higher 5-HT2A/D2 affinity ratio compared to typicals

• Clozapine: Also blocks D1, D4, muscarinic M1-M4, H1, α1 receptors - broadest receptor profile
• Quetiapine: H1 (sedation), α1 (hypotension) blockade prominent
• Risperidone: Potent 5-HT2A + D2 + α1 + H1 antagonist; at higher doses can cause EPS
• Aripiprazole: Partial D2 agonist + partial 5-HT1A agonist + 5-HT2A antagonist - "dopamine system stabilizer" - activates D2 when dopamine is low (prevents EPS, improves negative symptoms), blocks D2 when dopamine is high (prevents psychosis)
• Olanzapine: Strong muscarinic antagonism → fewer EPS; significant H1 → weight gain

• Low affinity and fast dissociation from D2 receptors (compared to haloperidol) - may explain why it causes fewer EPS
• D4 receptor affinity (4× > D2) - D4 is enriched in frontal cortex
• Effective in treatment-resistant schizophrenia by mechanisms not fully understood

3C. THERAPEUTIC USES

1. Schizophrenia - both positive symptoms (hallucinations, delusions) and negative symptoms (social withdrawal, flat affect, alogia) - negative symptoms respond better to atypicals than to typicals
2. Bipolar disorder - acute mania (quetiapine, olanzapine, risperidone, aripiprazole); bipolar depression (quetiapine, lurasidone); maintenance
3. Treatment-resistant schizophrenia - Clozapine (40-60% response rate where others fail)
4. Major depressive disorder (adjunct) - aripiprazole, quetiapine, brexpiprazole as augmentation
5. Psychosis in dementia (though caution - increased mortality risk; black box warning)
6. Tourette's syndrome - risperidone, aripiprazole
7. Irritability in autism - aripiprazole, risperidone (FDA approved)
8. Agitation - acute management
9. Nausea/vomiting (quetiapine, olanzapine low-dose, off-label)
10. Suicidality in schizophrenia - Clozapine is the only drug with proven anti-suicidal effect

3D. ADVERSE EFFECTS

3E. ADVANTAGES OF ATYPICAL ANTIPSYCHOTICS OVER TYPICAL (OLDER) NEUROLEPTICS

1. Lower risk of extrapyramidal side effects (EPS): Substantially reduced incidence of drug-induced parkinsonism, acute dystonia, and akathisia due to the serotonin-dopamine balance mechanism (5-HT2A blockade releasing dopamine in nigrostriatal pathway)
2. Lower risk of tardive dyskinesia (TD): Chronic use risk is ~7% with atypicals vs ~20-30% with typicals; this is the most clinically significant advantage given that TD is often irreversible
3. Improved efficacy against negative symptoms: Typicals are largely ineffective for negative symptoms (blunted affect, alogia, avolition, social withdrawal). Atypicals - via 5-HT2A blockade and indirect mesocortical dopamine enhancement - show greater improvement in negative symptoms
4. Improved cognitive function: Typicals worsen cognition; atypicals improve or preserve cognitive function - clinically meaningful for quality of life and functioning in schizophrenia
5. No significant hyperprolactinemia (for most): Typicals cause prolactin elevation (gynecomastia, galactorrhea, sexual dysfunction, amenorrhea, osteoporosis) via tuberoinfundibular pathway D2 blockade. Most atypicals (except risperidone) spare this pathway
6. Efficacy in treatment-resistant schizophrenia: Clozapine - effective in 40-60% of patients who fail 2 or more prior antipsychotics; typicals essentially have no role here
7. Better patient compliance: Fewer EPS (less subjective distress from akathisia, stiffness) leads to better adherence; improved negative symptoms and cognition further improve quality of life and self-care
8. Reduced need for anticholinergic co-prescription: Typicals often require anticholinergic drugs (e.g., trihexyphenidyl) to manage EPS - these add their own anticholinergic adverse effects; atypicals generally do not need this
9. Available in long-acting injectable (LAI) forms: Risperidone, paliperidone, olanzapine, aripiprazole LAI - improve adherence in non-compliant patients (though this is not exclusive to atypicals)

QUICK REVISION TABLE

What's covered in this answer:

Antiepileptic Drugs

• Classification - by clinical utility (seizure type) AND by mechanism of action (9 MOA groups)
• Phenytoin - MOA (use-dependent Na+ block), uses (7), adverse effects (dose-related, chronic, idiosyncratic including purple glove syndrome and fetal hydantoin syndrome), zero-order kinetics
• Sodium Valproate - MOA (5 mechanisms), therapeutic uses (all generalized epilepsies + bipolar + migraine), adverse effects (GI, CNS, metabolic, hepatotoxicity, teratogenicity - neural tube defects), drug interactions (with phenytoin, phenobarbital, CBZ, lamotrigine)
• Carbamazepine - MOA (Na+ channel block + autoinduction), therapeutic uses (focal seizures, trigeminal neuralgia, bipolar), adverse effects (HLA-B*1502 SJS, hyponatremia, aplastic anemia)
• Status Epilepticus - full stepwise management (BZDs → fosphenytoin/valproate/levetiracetam → anaesthetic agents)
• Principles of Epilepsy Treatment - 13 principles
• GTCS drugs - first-line and second-line with notes

Parkinsonism

• Full drug classification (8 classes, 20+ drugs)
• Levodopa + Carbidopa - MOA, 4 advantages, 4 disadvantages, rationale
• All classes: MOA, therapeutic uses, adverse effects (dopamine agonists, MAO-B inhibitors, COMT inhibitors, anticholinergics, amantadine)

Atypical Antipsychotics

• Classification by chemical class (9 subgroups with examples)
• MOA - D2 + 5-HT2A blockade model; clozapine's unique properties; aripiprazole as partial agonist
• Therapeutic uses (10 clinical uses)
• Adverse effects - full table including agranulocytosis (clozapine), metabolic syndrome, QTc prolongation
• 9 advantages over typical neuroleptics (EPS, TD, negative symptoms, cognition, prolactin, treatment-resistance, compliance)