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Anticholinergic Drugs (Antimuscarinic Agents)

As per KDT Pharmacology - MBBS 2nd Year

Note: KDT (KD Tripathi's Essentials of Medical Pharmacology) is not directly available in this library, but the content below is compiled from equivalent standard references - Lippincott Illustrated Reviews: Pharmacology, Katzung's Basic and Clinical Pharmacology, and Goodman & Gilman - which fully align with KDT's coverage for this topic.

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Definition

• Lippincott Pharmacology, Ch. 5

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Classification

1. Natural Alkaloids (Belladonna Alkaloids)

2. Synthetic/Semisynthetic Compounds

• Ipratropium (ATROVENT) - bronchodilator
• Tiotropium (SPIRIVA) - long-acting bronchodilator
• Glycopyrrolate - preanaesthetic, antisialagogue
• Propantheline - peptic ulcer
• Aclidinium, Umeclidinium - COPD

• Dicyclomine - IBS/gut spasm
• Oxybutynin (DITROPAN) - overactive bladder
• Tolterodine (DETROL) - overactive bladder
• Solifenacin, Darifenacin, Fesoterodine - uroselective agents
• Benztropine (COGENTIN), Trihexyphenidyl - Parkinsonism
• Tropicamide, Cyclopentolate - ophthalmic use

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Mechanism of Action

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PROTOTYPE DRUG: ATROPINE

Pharmacological Actions (Dose-Dependent)

Eye (M3 blockade)

• Mydriasis - pupil dilation (radial muscle activation unopposed)
• Cycloplegia - loss of accommodation (ciliary muscle paralysis)
• Unresponsiveness to light
• Raised intraocular pressure in angle-closure glaucoma (danger!)

Gastrointestinal Tract

• Reduces GI motility and peristalsis (antispasmodic)
• Does NOT significantly reduce HCl secretion - hence NOT useful for peptic ulcer
• Reduces saliva production (antisialagogue) - xerostomia (dry mouth)
• Salivary glands are the most sensitive to atropine

Exocrine Glands (M3 blockade)

• Reduces salivary, sweat, lacrimal, and bronchial secretions
• Anhidrosis - can cause hyperthermia, especially dangerous in children

Cardiovascular (Dose-dependent - classic for MCQs!)

Respiratory

• Bronchodilation (M3 blockade)
• Decreases bronchial secretions - useful in anaesthesia as premedication

Urinary Tract (M3 blockade)

• Relaxes detrusor muscle - causes urinary retention
• Contracts trigone and sphincter
• Dangerous in elderly men with BPH

CNS (Tertiary amines only)

• Low doses: mild sedation, reduced motion sickness
• Toxic doses: excitement, hallucinations, delirium, coma
• At therapeutic doses: atropine has minimal CNS effects (unlike scopolamine)

Pharmacokinetics

• Well absorbed orally and from mucous membranes
• Tertiary amine - crosses BBB
• Duration: ~4 hours systemically; several days if applied topically to eye
• Excreted mainly in urine

Therapeutic Uses of Atropine

1. Preanaesthetic medication - reduces secretions, prevents vagal bradycardia
2. Organophosphate poisoning - antidote (large doses)
3. Bradycardia (sinus bradycardia, AV block) - IV atropine
4. Ophthalmology - mydriasis and cycloplegia for fundus examination and refraction
5. Antispasmodic - intestinal, ureteric, biliary colic
6. Reversal of neuromuscular block - given with neostigmine to prevent bradycardia
7. Peptic ulcer - largely replaced by better drugs

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SCOPOLAMINE (Hyoscine)

Actions of Scopolamine

• Motion sickness - most effective drug available; blocks muscarinic receptors in vestibular system
• PONV (Post-operative nausea and vomiting) - prevention
• Sedation (unlike atropine)
• Blocks short-term memory formation
• Can produce euphoria - abuse potential

Therapeutic Uses

1. Motion sickness - transdermal patch (Transderm Scop) - effective up to 72 hours
2. PONV prevention - patch applied behind ear the evening before surgery
3. Preanaesthetic medication - for sedation and antisialagogue effect
4. Obstetrics (historically) - amnesia during labour ("twilight sleep")

Administration

• Transdermal patch behind the ear (most common for motion sickness)
• Must be applied 4 hours before anticipated trigger

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OTHER IMPORTANT AGENTS

Glycopyrrolate

• Quaternary amine - does NOT cross BBB (no CNS effects)
• Used as preanaesthetic to reduce secretions
• Given with neostigmine during reversal of NMB to prevent bradycardia
• No CNS side effects - preferred over atropine in some settings

Ipratropium (Atrovent)

• Quaternary amine - inhaled, acts locally in airways
• Bronchodilator - used in COPD and asthma
• Minimal systemic absorption - minimal side effects
• Does not affect mucociliary clearance

Tiotropium (Spiriva)

• Long-acting (24h) inhaled anticholinergic
• First-line in COPD
• Kinetic selectivity for M3 over M2

Oxybutynin / Tolterodine / Solifenacin / Darifenacin

• Selective for bladder (M3)
• Used in overactive bladder / urge incontinence
• Darifenacin and solifenacin have M3 selectivity - fewer side effects

Benztropine / Trihexyphenidyl (Artane)

• Tertiary amines that cross BBB
• Used in Parkinson's disease - reduce tremor and rigidity
• Block cholinergic excess after dopamine depletion in striatum

Tropicamide / Cyclopentolate

• Ophthalmic use - mydriasis and cycloplegia
• Shorter duration than atropine - preferred for eye examination

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ADVERSE EFFECTS (Side Effects)

"Can't see, can't spit, can't pee, can't shit, red as a beet, hot as a hare, dry as a bone, mad as a hatter"

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CONTRAINDICATIONS

1. Glaucoma (angle-closure) - raises intraocular pressure
2. BPH (Benign Prostatic Hyperplasia) - precipitates urinary retention
3. Myasthenia Gravis - worsens weakness
4. Tachyarrhythmias - atropine worsens
5. Ulcerative colitis / paralytic ileus - reduce motility further
6. Pyloric stenosis

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TOXICITY / POISONING

• Can occur from belladonna plants (e.g., Datura stramonium / "devil's trumpet")

• Red as a beet (flushed skin)
• Hot as a hare (hyperthermia - anhidrosis)
• Dry as a bone (dry skin, dry mouth)
• Blind as a bat (blurred vision, mydriasis)
• Mad as a hatter (delirium, confusion)
• Sinus tachycardia
• Urinary retention
• Dilated pupils

• A reversible cholinesterase inhibitor (tertiary - crosses BBB)
• Given IV 0.5-1 mg slowly with monitoring
• Caution: can cause bradycardia and seizures if given too rapidly
• Do NOT give physostigmine if TCA overdose suspected - can worsen cardiotoxicity (heart block, asystole)

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ORGANOPHOSPHATE POISONING - ATROPINE AS ANTIDOTE

• OPs cause cholinergic excess by inhibiting acetylcholinesterase
• Atropine blocks muscarinic manifestations: SLUDGE (Salivation, Lacrimation, Urination, Defecation, GI upset, Emesis) + bradycardia, bronchospasm
• Given IV in large doses (2-4 mg initially, repeated every 5-10 min until secretions dry)
• Does NOT reverse nicotinic effects (muscle weakness, fasciculations) - pralidoxime (2-PAM) is used for that

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DRUG INTERACTIONS

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QUICK SUMMARY TABLE (MCQ-Friendly)

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• Lippincott Illustrated Reviews: Pharmacology, Chapter 5 - Cholinergic Antagonists
• Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 8 & 58
• Goodman & Gilman's The Pharmacological Basis of Therapeutics

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Antimalarial Drugs - Complete Notes

As per KDT Pharmacology - MBBS 2nd Year

Sources: Katzung's Basic & Clinical Pharmacology (16th ed.), Goodman & Gilman's Pharmacological Basis of Therapeutics, Lippincott Illustrated Reviews: Pharmacology - all equivalent to KDT coverage.

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Life Cycle Relevance - Why It Matters for Drug Action

Key: P. falciparum and P. malariae have NO hypnozoites - no relapses. P. vivax and P. ovale DO have hypnozoites - relapses possible. Only primaquine/tafenoquine eradicate hypnozoites ("radical cure").

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Classification of Antimalarial Drugs

Group 1: Quinolines

Group 2: Artemisinins (Sesquiterpene Lactones)

• Artemisinin, Artesunate, Artemether, Dihydroartemisinin

Group 3: Antifolates

• Type 1 (DHPS inhibitors): Sulfadoxine, Dapsone
• Type 2 (DHFR inhibitors): Pyrimethamine, Proguanil (cycloguanil)
• Combination: Sulfadoxine-Pyrimethamine (Fansidar), Atovaquone-Proguanil (Malarone)

Group 4: Antibiotics

• Doxycycline, Tetracycline, Clindamycin

Group 5: Miscellaneous

• Atovaquone (hydroxynaphthoquinone)
• Lumefantrine (used in ACT with artemether)
• Halofantrine

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DRUG 1: CHLOROQUINE

Mechanism of Action

Pharmacokinetics

• Well absorbed orally (GI tract); also IM/SC routes
• Very large volume of distribution (100-1000 L/kg) - concentrated in liver, spleen, kidney, lung
• 60% protein bound
• Metabolized by CYP to desethylchloroquine (active)
• Long half-life: Initial 3-5 days; terminal 1-2 months (traces in urine for years)
• Excreted mainly in urine; renal excretion increased by urine acidification

Activity

• Blood schizonticide (erythrocytic stages)
• Active against: P. vivax, P. ovale, P. malariae, P. knowlesi, and chloroquine-SENSITIVE P. falciparum
• NOT active against: liver stages, hypnozoites, gametocytes

Therapeutic Uses

1. Treatment of uncomplicated malaria (sensitive strains) - fever clears in 24-48 h, parasitemia in 48-72 h
2. Chemoprophylaxis - in areas without chloroquine-resistant P. falciparum
3. Amebic liver abscess - backup after metronidazole failure (concentrates in liver)
4. Rheumatoid arthritis, SLE - anti-inflammatory use
5. Drug of choice for: P. ovale, P. malariae

For P. vivax/ovale: always add primaquine for radical cure (to kill hypnozoites)

Adverse Effects

• Usually well tolerated even with prolonged use
• Pruritus (common in Africans)
• Nausea, vomiting, headache, abdominal pain
• Retinopathy / Macular damage - with long-term high-dose use (bull's-eye maculopathy) - irreversible
• Cinchonism (less than quinine)
• Hypotension, ECG changes (QT prolongation) with rapid IV injection
• Bleaching of hair
• Haematological: Hemolysis in G6PD deficiency

Resistance

• Now widespread in P. falciparum - due to mutations in PfCRT gene (P. falciparum chloroquine resistance transporter) - transporter pumps chloroquine out of the food vacuole
• Also pfmdr1 (P-glycoprotein) plays a role
• Uncommon but increasing in P. vivax
• Resistance reversal by verapamil, desipramine (no clinical use established)

Contraindications

• Retinal or visual field abnormalities
• G6PD deficiency (caution)
• Porphyria
• Psoriasis (may exacerbate)

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DRUG 2: QUININE

Mechanism of Action

Pharmacokinetics

• Orally well absorbed; IV for severe malaria
• 80% protein-bound
• Metabolized in liver (CYP3A4) to 3-hydroxyquinine
• Half-life: 8-12 hours
• Excreted in urine

Activity

• Blood schizonticide (erythrocytic stages)
• Active against all 4 species
• Effective against chloroquine-resistant P. falciparum
• Weak gametocidal activity

Therapeutic Uses

1. Severe/complicated falciparum malaria - IV quinine (or IV artesunate preferred)
2. Oral treatment of resistant falciparum - combined with doxycycline/tetracycline (7 days)
3. Nocturnal leg cramps (limited use)

Adverse Effects - "CINCHONISM"

Cinchonism: Tinnitus, headache, nausea, vomiting, dizziness, visual disturbances, flushing, abdominal pain

• Cardiotoxicity: QT prolongation, ventricular arrhythmias, hypotension (rapid IV)
• Hypoglycemia - stimulates insulin release from pancreas (important in pregnancy!)
• Blackwater fever - intravascular hemolysis → hemoglobinuria → renal failure (rare)
• Hemolysis in G6PD deficiency
• Thrombocytopenia

Contraindications

• Underlying visual/auditory problems
• Cardiac abnormalities
• Do NOT give with mefloquine (additive cardiac toxicity)
• Renal insufficiency (reduce dose)
• Can elevate plasma warfarin and digoxin levels

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DRUG 3: PRIMAQUINE

Mechanism of Action

Activity

• Tissue schizonticide - kills liver stages (hypnozoites and primary exoerythrocytic forms)
• Gametocidal - kills P. falciparum gametocytes (reduces transmission)
• Weak blood schizonticidal activity
• NOT effective as a single agent for acute malarial attacks

Therapeutic Uses

1. Radical cure of P. vivax and P. ovale - to prevent relapses (only drug that kills hypnozoites)
2. Terminal prophylaxis - after leaving endemic area, to eliminate residual hepatic parasites
3. Chemoprophylaxis - 30 mg/day (alternative regimen per CDC)
4. Gametocidal - single low dose with treatment to reduce transmission
5. Pneumocystis jirovecii pneumonia - with clindamycin (alternative regimen)

Pharmacokinetics

• Well absorbed orally
• Rapidly metabolized; short half-life (~6 hours)
• Metabolites accumulate in tissues

Adverse Effects

• Usually well tolerated
• Nausea, epigastric pain, abdominal cramps, headache (especially on empty stomach)
• HEMOLYTIC ANEMIA - most important - in G6PD-deficient patients (due to oxidative stress)
• Methemoglobinemia (cyanosis) - in NADH methemoglobin reductase deficiency
• Leukopenia, agranulocytosis (rare)
• Cardiac arrhythmias (rare)

Contraindications

• G6PD deficiency - must TEST BEFORE prescribing - causes life-threatening hemolysis
• Pregnancy - fetus is relatively G6PD deficient
• Granulocytopenia / methemoglobinemia
• Mediterranean and Asian G6PD variants - most severe hemolysis
• Myelosuppressive drugs concurrently

MCQ Key: Primaquine is the ONLY drug that prevents relapses (P. vivax/ovale). Always test for G6PD before use.

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DRUG 4: ARTEMISININS

Examples

• Artemisinin (parent compound)
• Artesunate (water-soluble - IV/oral; preferred)
• Artemether (oil-soluble - IM; in Coartem with lumefantrine)
• Dihydroartemisinin (DHA) - most active metabolite

Mechanism of Action

• Artemisinins contain an endoperoxide bridge (trioxane ring)
• In the parasite food vacuole, iron from heme cleaves the endoperoxide bridge → generates free radicals (reactive oxygen species)
• Free radicals alkylate and damage parasite proteins and membranes → parasite death
• Most rapidly acting antimalarials - kill ring forms (early trophozoites)

Activity

• Most potent and fastest-acting blood schizonticides
• Active against all erythrocytic stages including rings (which other drugs miss)
• Active against ALL Plasmodium species
• Gametocidal against P. falciparum (reduce transmission)
• NOT active against liver stages

Artemisinin-Based Combination Therapies (ACTs) - WHO First-Line Treatment

Therapeutic Uses

1. First-line for uncomplicated P. falciparum (as ACT)
2. Severe/complicated malaria - IV Artesunate is now preferred over IV quinine (more effective, safer)
3. Multidrug-resistant falciparum malaria

Pharmacokinetics

• Short half-life (~1-2 hours for artesunate/artemether)
• Artesunate → rapidly converted to DHA (active)
• Oral, IV, IM, rectal routes available
• This short half-life is why they are ALWAYS used with longer-acting partner drugs

Adverse Effects

• Generally very well tolerated - best safety profile of all antimalarials
• Nausea, dizziness, headache (mild)
• Possible neurotoxicity in animal studies (high doses); not clearly established in humans at therapeutic doses
• Embryotoxic in animals - use with caution in first trimester (IV artesunate used for severe malaria in pregnancy)
• QT prolongation (with lumefantrine combination)

Resistance

• Partial artemisinin resistance (ART-R) - emerging in Southeast Asia (Myanmar, Thailand) and now Africa
• Associated with Kelch13 (K13) gene mutations in P. falciparum
• Manifests as delayed clearance of parasitemia (not complete treatment failure yet)

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DRUG 5: MEFLOQUINE

Mechanism of Action

Pharmacokinetics

• Oral only (causes severe local irritation parenterally)
• Peak plasma in ~18 hours; long half-life (~20 days) - allows weekly dosing
• Highly protein-bound, extensively distributed in tissues
• Slowly excreted in feces

Activity

• Strong blood schizonticide against P. falciparum and P. vivax
• NOT active against hepatic stages or gametocytes

Therapeutic Uses

1. Chemoprophylaxis - weekly dosing for chloroquine-resistant areas
2. Treatment of uncomplicated falciparum malaria (not severe malaria)
3. Used in ACT: Artesunate + Mefloquine

Adverse Effects

• Nausea, vomiting, dizziness, diarrhea
• Neuropsychiatric effects (most important): Anxiety, depression, hallucinations, psychosis, nightmares, insomnia, seizures
• Cardiotoxicity: QT prolongation
• NOT for use in patients with psychiatric illness or seizure disorder

Contraindications

• Psychiatric illness or history of seizures
• Do NOT use concurrently with quinine (additive cardiac toxicity)
• Cardiac conduction abnormalities

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DRUG 6: PROGUANIL (Chloroguanide)

Mechanism of Action

• Also has a direct causal prophylactic effect on liver stages (independent of cycloguanil conversion)

Uses

1. Causal prophylaxis - prevents development of liver stages
2. Atovaquone-Proguanil (Malarone) - treatment and prophylaxis of P. falciparum
3. Safe in pregnancy (one of few antimalarials)

Adverse Effects

• Very safe; minimal toxicity
• Occasional nausea, diarrhea at high doses
• Mouth ulcers

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DRUG 7: SULFADOXINE-PYRIMETHAMINE (Fansidar / SP)

Mechanism

• Sulfadoxine inhibits dihydropteroate synthase (DHPS) - competes with PABA
• Pyrimethamine inhibits dihydrofolate reductase (DHFR)
• Sequential blockade of folate synthesis → synergistic action

Uses

1. Treatment of chloroquine-resistant P. falciparum (now limited by resistance)
2. Intermittent Preventive Treatment in Pregnancy (IPTp) - given 2nd/3rd trimester in Africa
3. Combined with artesunate in ACT

Resistance

• Widespread due to point mutations in DHPS gene (sulfadoxine resistance) and DHFR gene (pyrimethamine resistance)
• Now unsuitable for treating acute malaria in most regions

Adverse Effects

• Sulfonamide reactions: rash, Stevens-Johnson syndrome
• Hemolysis in G6PD deficiency
• Avoid in last trimester of pregnancy (kernicterus risk)

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DRUG 8: ATOVAQUONE-PROGUANIL (Malarone)

Mechanism

• Atovaquone inhibits the mitochondrial electron transport chain (Complex III - cytochrome bc1 complex) → disrupts mitochondrial membrane potential → inhibits pyrimidine synthesis
• Proguanil acts synergistically (direct effect on mitochondria; and via cycloguanil → DHFR inhibition)

Uses

1. Treatment of P. falciparum malaria (including chloroquine-resistant strains)
2. Chemoprophylaxis - daily dosing; started 1-2 days before travel (vs. 1-2 weeks for mefloquine/chloroquine)
3. Alternative for areas with multidrug resistance

Adverse Effects

• Generally well tolerated
• Nausea, vomiting, headache, abdominal pain
• Rash

Contraindications

• Severe renal impairment (atovaquone not well absorbed if vomiting)

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DRUG 9: DOXYCYCLINE

Mechanism

• Inhibits protein translation in the parasite apicoplast (organelle derived from plant chloroplasts) → delayed death mechanism (kills progeny of treated parasites)
• Slow-acting blood schizonticide

Uses

1. Chemoprophylaxis (daily) - for chloroquine and mefloquine-resistant areas (e.g., Thai-Myanmar border)
2. Treatment of falciparum malaria - combined with quinine (7-day course)
3. Alone unsuitable for treatment (too slow)

Adverse Effects

• Photosensitivity (common)
• GI upset, esophageal ulceration (take with plenty of water)
• Vaginal candidiasis

Contraindications

• Pregnancy (effects on fetal bones and teeth)
• Children < 8 years (deposits in growing bones/teeth → discoloration, stunted growth)

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MNEMONIC SUMMARY OF MECHANISMS

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DRUG OF CHOICE - QUICK TABLE (MCQ Goldmine)

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IMPORTANT ADVERSE EFFECTS - EXAM TABLE

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RESISTANCE MECHANISMS - MCQ KEY FACTS

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MALARIA IN SPECIAL SITUATIONS

Pregnancy

• Chloroquine: Safe in all trimesters (sensitive strains)
• Proguanil: Safe (give with folate supplementation)
• Quinine: Use for 1st trimester severe malaria; causes hypoglycemia
• Artemisinins: Preferred for 2nd/3rd trimester severe malaria (IV artesunate)
• Primaquine: CONTRAINDICATED (fetus is G6PD deficient → hemolysis)
• Doxycycline: CONTRAINDICATED (fetal bone/teeth effects)
• SP (Fansidar): Used for IPTp in Africa (not for treatment)
• Mefloquine: Avoid (teratogenic concerns in 1st trimester)

G6PD Deficiency

• Avoid: Primaquine, Tafenoquine, Dapsone, Quinine (oxidative hemolysis risk)

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• Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 52
• Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapter 66
• Lippincott Illustrated Reviews: Pharmacology - These are the authoritative standard references equivalent to KDT for MBBS 2nd year antimalarial pharmacology.