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Antimalarial Drugs — 2nd Year MBBS (KDT-style)

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I. Classification of Antimalarial Drugs

Based on Chemical Class

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Based on Stage of Action

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II. Chloroquine

Drug Profile

• Class: 4-Aminoquinoline; synthetic drug
• Active against: Erythrocytic asexual stages + some gametocytes (P. vivax, P. malariae, P. ovale); NOT against liver stages or hypnozoites

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Mechanism of Action

1. Chloroquine is a diprotic weak base — it crosses erythrocytic and plasmodial membranes and concentrates in the acidic food vacuole of the parasite (ion trapping)
2. The parasite digests host cell hemoglobin to obtain amino acids, releasing large amounts of free heme — which is toxic to the parasite
3. Normally the parasite polymerizes heme into non-toxic hemozoin (malaria pigment) and sequesters it
4. Chloroquine binds to free heme and inhibits its polymerization to hemozoin
5. → Accumulation of toxic heme causes oxidative damage to phospholipid membranes → lysis of both parasite and RBC

In short: Inhibits heme polymerization → toxic heme accumulation → parasite death

• Also raises intra-vacuolar pH (alkalinization), further disrupting parasite digestion of Hb
• Resistance: P. falciparum develops a PfCRT (chloroquine resistance transporter) mutation → pumps chloroquine out of the food vacuole

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Uses of Chloroquine

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Adverse Effects of Chloroquine

• Psoriasis (may precipitate acute attack)
• Porphyria (may precipitate acute attack)
• Severe hepatic/neurological disease — use cautiously
• Pregnancy: crosses placenta — generally avoided at high doses; low-dose prophylaxis considered acceptable

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III. Artemisinin-Based Combination Therapy (ACT)

Background

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Mechanism of Action of Artemisinin

1. Artemisinins contain a unique sesquiterpene lactone endoperoxide bridge
2. Inside the parasite's food vacuole, free heme (from Hb digestion) activates artemisinin by cleaving this endoperoxide bridge
3. This generates reactive free radicals (carbon-centered and oxygen-centered)
4. Free radicals promiscuously alkylate and oxidize multiple parasite proteins — including transport proteins, enzymes, and structural proteins
5. → Rapid parasite death (4-log₁₀ reduction in parasite burden per 48-hour erythrocytic cycle)
6. Also reduces gametocyte carriage — reduces onward transmission

In short: Heme-activated endoperoxide → free radicals → alkylation of parasite proteins → rapid parasite death

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Why Combination Therapy (ACT)?

• Artemisinins alone require >7 days of therapy to fully clear parasites (rapid but short half-life)
• Paired with a slower-acting, slower-eliminated partner drug with a different mechanism:
  • Rapid artemisinin component kills most parasites quickly
  • Partner drug clears the residual parasites and prevents recrudescence
  • 3-day ACT courses are effective vs. 7+ day monotherapy

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Major ACT Combinations (WHO Recommended)

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Uses of ACT

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Adverse Effects of Artemisinins

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Quick Exam Summary Table

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Sedative-Hypnotic Drugs — 2nd Year MBBS (KDT-style)

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I. Definition

• Sedative: A drug that reduces anxiety and produces calming without inducing sleep at therapeutic doses
• Hypnotic: A drug that produces drowsiness and facilitates the onset and maintenance of sleep
• The same drug can act as a sedative at low dose and a hypnotic at higher dose — hence the group is called sedative-hypnotics

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II. Classification of Sedative-Hypnotic Drugs

A. Benzodiazepines (BZDs)

• Diazepam, Chlordiazepoxide, Flurazepam, Clonazepam, Clorazepate

• Lorazepam, Alprazolam, Oxazepam, Temazepam, Nitrazepam

• Triazolam, Midazolam

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B. Barbiturates

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C. Non-Benzodiazepine Hypnotics ("Z-drugs") — GABA-A agonists

• Zolpidem, Zaleplon, Eszopiclone (selective α1-subunit agonists)

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D. Melatonin Receptor Agonists

• Ramelteon (MT1/MT2 agonist — for insomnia)

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E. Orexin Receptor Antagonists

• Suvorexant, Lemborexant

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F. Older/Miscellaneous

• Chloral hydrate, Paraldehyde, Meprobamate (largely obsolete)

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G. Antihistamines with sedative property

• Promethazine, Diphenhydramine

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III. Mechanism of Action of Benzodiazepines

The GABA-A Receptor Complex

• GABA binds at the α–β subunit interface
• Benzodiazepines bind at the α–γ subunit interface (a separate, distinct site)
• Barbiturates bind at yet another distinct site (within the channel pore region)

How BZDs Work — Step by Step

1. BZDs bind to the benzodiazepine binding site (BZ site) on the GABA-A receptor — allosteric site, separate from GABA binding site
2. This binding does NOT directly open the Cl⁻ channel — BZDs require GABA to be present
3. BZDs increase the affinity of the GABA receptor for GABA (allosteric potentiation)
4. This results in an increase in the FREQUENCY of Cl⁻ channel opening (without changing the duration or conductance)
5. ↑ Cl⁻ influx → hyperpolarization of the postsynaptic neuron → reduced neuronal excitability → CNS depression

Key point: BZDs are positive allosteric modulators of GABA-A. They cannot open Cl⁻ channels in the absence of GABA — this is why they have a ceiling effect and high safety.

BZDs vs Barbiturates at GABA-A Receptor

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IV. Advantages of Benzodiazepines Over Barbiturates

1. Wide Therapeutic Index / High Safety Margin

• BZDs cannot directly activate Cl⁻ channels — require endogenous GABA → ceiling effect on CNS depression
• Fatal overdose with BZDs alone is extremely rare
• Barbiturates have a narrow therapeutic index — overdose easily causes respiratory depression and death

2. Specific Antidote Available

• Flumazenil (a competitive BZ antagonist at the BZ site) reverses BZD effects
• No antidote available for barbiturate overdose

3. Less Respiratory Depression

• BZDs cause significantly less respiratory depression at therapeutic doses compared to barbiturates

4. Less Cardiovascular Depression

• BZDs have minimal cardiovascular effects at therapeutic doses

5. No Enzyme Induction

• Barbiturates are potent inducers of hepatic CYP450 enzymes → reduce efficacy of many co-administered drugs (warfarin, OCP, phenytoin, corticosteroids, etc.)
• BZDs do not induce hepatic enzymes → far fewer drug interactions

6. Less Physical Dependence and Tolerance

• Though BZDs do cause dependence, it is significantly less severe and develops more slowly than with barbiturates
• Barbiturates have high abuse and addiction potential with rapid tolerance development

7. No Suppression of REM Sleep (or minimal)

• Barbiturates markedly suppress REM sleep → REM rebound insomnia on discontinuation
• BZDs (especially short-acting) have lesser REM suppression

8. Less Rebound Insomnia

• Abrupt withdrawal from barbiturates causes severe rebound insomnia and potentially life-threatening withdrawal seizures
• BZD withdrawal, while significant, is generally less severe

9. No Cross-Reactions with Excitatory Neurotransmitters

• Barbiturates also inhibit glutamate (AMPA) receptors and affect Na⁺/K⁺ channels — producing non-specific CNS depression
• BZDs act selectively on GABA-A → more predictable, targeted effect

10. No Porphyria Precipitation

• Barbiturates precipitate acute porphyria attacks (enzyme induction)
• BZDs are safe in porphyria

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V. Therapeutic Uses of Benzodiazepines

1. Anxiety Disorders (Anxiolytic)

• Short-term management of Generalized Anxiety Disorder (GAD), panic attacks, phobias, acute situational anxiety
• Drugs: Diazepam, Lorazepam, Alprazolam, Clonazepam
• Note: SSRIs/SNRIs are preferred for long-term anxiety; BZDs used for acute/bridging therapy

2. Insomnia (Hypnotic)

• Reduce sleep latency, decrease nocturnal awakenings
• Drugs: Nitrazepam, Flurazepam (long-acting); Temazepam, Lorazepam (intermediate); Triazolam (short-acting)
• Used for short-term insomnia only (tolerance develops within 2–4 weeks)

3. Epilepsy / Seizures (Anticonvulsant)

• Status epilepticus: IV Lorazepam (first choice) or IV Diazepam (first-line emergency treatment)
• Absence seizures / Myoclonic seizures: Clonazepam
• Febrile seizures: IV/rectal Diazepam
• Alcohol withdrawal seizures: Diazepam, Lorazepam, Chlordiazepoxide

4. Alcohol Withdrawal Syndrome

• Chlordiazepoxide and Diazepam — prevent delirium tremens, withdrawal seizures, and manage autonomic symptoms
• Long-acting BZDs preferred (self-tapering due to long t½)

5. Preoperative Medication (Premedication)

• Midazolam IV/IM — short-acting, produces sedation, anxiolysis, and anterograde amnesia
• Diazepam orally before procedures

6. IV Conscious Sedation / Procedural Sedation

• Midazolam — for endoscopy, minor surgical procedures, ICU sedation

7. Muscle Relaxant (Central)

• Diazepam — useful in muscle spasm, spasticity (multiple sclerosis, cerebral palsy), tetanus
• Mechanism: Enhancement of GABA inhibition at spinal cord level (interneurons) and supraspinal centers

8. Induction of Anesthesia

• Midazolam (IV) — produces rapid unconsciousness with amnesia; used for induction in balanced anesthesia

9. Bipolar Disorder / Acute Mania (Adjunct)

• Lorazepam, Clonazepam — used as adjunctive agents for acute agitation in manic episodes

10. Panic Disorder

• Alprazolam, Clonazepam — high potency BZDs; effective for acute panic attacks

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VI. Quick Comparison Table — Classification by Duration

Lorazepam, Oxazepam, Temazepam undergo direct glucuronide conjugation (no active metabolites) — safe in elderly, liver disease (mnemonic: LOT)

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VII. Adverse Effects of Benzodiazepines

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