Cholinergic Pharmacology

Synthesis, Release and Degradation of Acetylcholine (ACh)

• Acetyl CoA + Choline --(Choline acetyltransferase (CHAT))--> Acetylcholine

• Vesicular Acetylcholine Transporter (VACHT) transports Acetylcholine into vesicles

• Botulinum Toxin inhibits Acetylcholine release

• Acetylcholine --(Choline esterase)--> Choline + Acetate

• Choline is taken up again

Types of Cholinesterase (CHE) enzyme

• True ChE:

  • Present in synapse

  • Specific only for Ach

  • Essential for life

  • Slow regeneration (2-3 months)

• Pseudo (Butyryl ) ChE:

  • Synthesized in the liver, present in plasma

  • Non-specific (acts on any esters in the blood)

  • Not essential for life

  • May be deficient Genetically

  • Rapid regeneration (2-3 Weeks)

Cholinergic Receptors

• Muscarinic

• Nicotinic:

  • Neuronal (Nn): CNS, Autonomic ganglia, Adrenal medulla → catecholamines release.

  • Muscle (Nm) →skeletal muscle depolarization → contraction

CHOLINERGIC RECEPTORS & ACH ACTIONS

• M1 Receptors:

  • CNS→ excitatory

    • Arousal, Learning & Short-term memory (\downarrow Ach → Alzheimer).

    • In basal ganglia, balance between ACH & DA controls movement: \downarrow DA & \uparrow ACH (Action) → Parkinson Disease

    • In Vestibular Pathway → Control Posture Balance &Vomiting

  • Gastric cells → Histamine release → \uparrowHCL

• M2 Receptors

  • CNS

  • Presynaptic neurons → inhibit ACh release.

  • Heart:

    • SAN → slowing of heart rate

    • AVN:\downarrow conduction \uparrow Refractory Period (RP).

    • Atria → \downarrow Action potential duration \downarrow Refractory period \downarrow Contractility

• M3 receptors:

  • Smooth muscles Contraction

    • Bronchospasm

    • GIT, Urinary Bladder: → Evacuation Contraction of wall & Relaxation of sphincters.

  • Eye

    • constrictor pupillae: → miosis → \uparrow aqueous drainage → \downarrow I.O.P.

    • ciliary muscle: → Accommodation for near vision

  • Exocrine glands→ \uparrow All secretions (except milk).

  • B.V. endothelium (Non innervated): No role in physiologic control of B.P. If stimulated by agonist→ NO release → VD → \downarrow BP.

Classification of Cholinomimetics

• Direct

  • Natural Alkaloids

  • 4ry Amines

• Indirect

  • Reversible

  • Irreversible

Directly Acting (on cholinergic receptors)

• Choline Esters:

  • 4ry drugs → low lipid solubility poorly absorbed & poor CNS and membrane crossing.

  • Bethanechol → marked muscarinic effects on GIT & bladder→ Prokinetic used in megacolon & urinary retention.

• Natural Alkaloids:

  • Pilocarpine:

    • 3ry drug; selective M3 agonist on:

      • Eye: Miotic used for: Glaucoma

      • Exocrine glands: \uparrow secretion → Used in dryness of eye & mouth (Sjogren Syndrome)

      • Scalp blood vessels: VD→ used as hair tonic.

  • Cevemiline

    • Selective M3 agonist → used in dryness of eye & mouth.

Choline Esterase Inhibitors Mechanism of Action

• Ultra Short Acting: Edrophonium (4ry)

• Intermediate Acting: Reversible

• Irreversible:

  • Very Long Acting

  • Organophosphate

  • Aging of enzyme may occur if bind for Long time

Carbamates

• Neostigmine

  • Synthetic

  • 4ry → poorly absorbed, not cross BBB or conjunctiva.

  • Muscarinic effects: on bladder & GIT.

  • Nicotinic effects: \uparrow skeletal muscle power.

• Physostigmine

  • Natural

  • 3ry → well absorbed, crosses BBB & conjunctiva.

  • Muscarinic effects:

    • Miotic: used in glaucoma.

    • Antagonize central and peripheral effects of atropine.

• Pyridostigmine: neostigmine analogue

  • \uparrowduration, fewer visceral side effects

  • \uparrow selectivity on skeletal muscles compared to neostigmine).

Irreversible: Organo-phosphates compounds

• Highly lipid soluble, absorbed from all sites of body even skin

• Symptoms of Accidental toxicity:

  • Malathion (Insecticides).

  • Sarin: (Nerve gas)

Therapeutic Uses of Cholinomimetics

• 3ry Amines:

  • Hair Tonic: Pilocarpine [Direct]

  • Alzheimer: donepezil and Rivastigmine (Indirect)

  • Atropine Toxicity: Physostigmine (Indirect)

  • Dry Eye &Mouth: Pilocarpine & Cevemiline

  • Miotics in Glaucoma: Pilocarpine, Physostigmine

• 4ry Amines: For Muscarinic Effects

  • Post-Operative: Paralytic Ileus/ Urinary retention WITHOUT OBSTRUCTION: Neostigmine & Bethanechol

  • Megacolon: Bethanechol

• FOR NICOTINIC EFFECTS (Nm) :

  • Myasthenia Gravis: Pyridostigmine (Long Acting): atropine can be used before it

  • Antidote for Competitive NMBs: Neostigmine PRECEDED WITH ATROPINE: to block undesirable Muscarinic Effects

  • Diagnosis of Myasthenia gravis: Edrophonium (Ultra short acting)

Adverse Effects and Contraindications

• CNS: Irritability Convulsions (Lipophilic Agents)

• Eye: (with eye drops):

  • Miosis: disturbance in dark vision

  • Lid twitches, brow ache, frontal headache (Muscle contraction)

• Exocrine: Lacrimation -salivation, \uparrowHCl → CI peptic ulcer

• CVS:

  • Bradycardia and hypotension

  • Cardiac arrest (→ never given IV)

  • CI: Infarction

• Bronchospasm and\uparrow secretion CI Asthma

• \uparrow Urination- diarrhea colic , Nausea and Vomiting CI: urinary or intestinal obstruction (→ rupture)

• Muscle Fasciculations and paralysis in toxic dose.

Organophosphate Poisoning: \uparrowAch

• Muscarinic DUMBLES

  • Diarrhea

  • Urination

  • Miosis

  • Bronchospasm & Bradycardia

  • Lacrimation

  • Emesis

  • Salivation

• Nicotinic MATCH

  • Muscle twitches

  • Adrenal gland activation

  • Tachycardia, Tremors

  • Cramping of muscles

  • HTN

• Causes of death (Important):

  • Respiratory symptoms, muscle paralysis and failure and excess secretion

  • CNS: convulsion and coma

Treatment of Toxicity

• Decontamination

• Anticonvulsant (Diazepam) for convulsion

• Artificial respiration and blood transfusion

• Toxin Specific Measures:

  • Atropine: M antagonist in very large dose till dryness of respiratory secretion

  • ChE enzyme reactivator (Pralidoxime): for reduction of effect of Ach on N receptors (Given as soon as possible before aging of enzymes)

Antimuscarinic Drugs: Atropine

• 3ry Amine

• Competitive Antagonist of Ach at M receptors

• CNS

  • Respiratory center stimulation

  • Antiemetic: block M receptor in vomiting center.

  • Antiparkinsonian.

• Eye (effects persist for > 72 hrs)

  • Passive Mydriasis: (paralysis of constrictor).

  • Cycloplegia (loss of accommodation).

  • \downarrow Aqueous out flow →\uparrowIOP → Acute glaucoma in narrow chamber

• CVS

  • Tachycardia & \uparrowAVN conduction

  • No effect on blood pressure: M3 has no role in regulating blood pressure

  • Vasodilation (histamine release in toxic dose).

• Secretions

  • \downarrow Salivation (→ dry mouth)

  • \downarrow lacrimation (→ dry sandy eyes)

  • \downarrow Sweating (→\uparrow body temperature)

  • \downarrow Bronchial secretions.

  • Gastric secretion is least affected

• Smooth Muscle

  • Bronchodilation.

  • GIT Retention

  • Urinary Retention

Adverse effects and Contraindications

• Confusion, restlessness, hallucinations, delirium & mania.

• Blurred vision and photophobia.

• Acute glaucoma in patients with narrow anterior chamber (CI: glaucoma).

• Dry mouth and skin

• Hyperthermia (complete skin dryness).

• Vasodilation & flushing. (Histamine release)

• Tachycardia.

• Urine retention in old patients with enlarged prostate (CI: enlarged prostate).

• Constipation.

Atropine Toxicity

• Anticholinergic Toxidrome

  • Mad as a Hen: Altered mental status

  • Blind as a bat: Mydriasis

  • Red as a beet: Flushed skin

  • Hot as a hare: Dry skin (anhydrosis)

  • Dry as a bone: Dry mucous membranes

• Treatment:

  • Physostigmine

  • Diazepam

  • Cooling blankets

Clinical Uses of Atropine & atropine Substitutes

• Pre-anesthetic Medication:

  • \downarrowsalivary and bronchial secretion

  • Anti-emetic (\downarrowAspiration Pneumonia)

  • Bronchodilation: ≠ some anesthetics

  • Stimulate R.C. ≠ Anesthetics

  • \downarrowSevere vagal Bradycardia in Anesthesia.

  • Drug Used: Glycopyrrolate Hyoscine [Scopolamine]

Advantages of Hyoscine (Scopolamine):

• Mydriatic (briefer than atropine).

• More Safe in thyrotoxicosis & cardiac patients: (Less risk of arrhythmia)

• More CNS depressant action→ drowsiness & amnesia.

• More effective in motion sickness

• Disadvantage: May induce CNS excitement & hallucination when used in females→ vivid dreams.

• Anti-Parkinson (PD): Drug Used: Benztropine- Benzhexol

  • Used for tremors or Drug induced PD

• Vomiting of Motion Sickness & Minieres Disease Drug Used: Hyoscine (More Effective than atropine)

Mydriatic Cycloplegics

• Drug Used: cyclopentolate -tropicamide – homatropine):

• Advantages: shorter acting and easier to reverse (except in children).

• Uses:

  • Iridocyclitis

  • Measuring refractive errors

  • Fundus Examination

Bronchial Atropine Substitutes

• Advantages: 4ry amines given by inhalation with No systemic Effect and Not dry Secretion Used in asthma & COPD: delayed onset.

• Drug Used: Ipratropium (M2 / M3 blocker): (Disadvantage: Tolerance)

• Tiotropium (selective M3 blocker)

  • Longer acting with No Tolerance.

Antisecretory antispasmodics:

• 4ry drugs→ less absorption → less CVS & CNS effects

• Drug Used:

  • Glycopyrrolate

  • Hyoscine butylbromide: Used in renal, biliary & intestinal colic & in irritable bowel syndrome.

  • 3ry drugs: Dicyclomine; selective M1 blocker (in Myenteric plexus) → antispasmodic

  • Before neostigmine during reversal of action of Competitive Muscle blockers: to ↓its M side effects (Bradycardia, Bronchospasm)

• Drug Used: Glycopyrrolate

• Urinary atropine substitutes:

  • Oxybutynin: Darifenacin, solifenacin, tolterodine, Trospium, Emepronium

  • Used in nocturnal enuresis & in urge incontinence and overactive bladder.

Atropine Still Used In:

• CVS:

  • Hyperactive carotid sinus

  • Heart block (AV block)

  • Bradycardia (in infarction or digoxin toxicity).

• Organophosphate poisoning - mushroom poisoning (Amanita muscaria).

• Fundus examination in children

Drugs with Atropine-Like Action: additive atropine effects

• Antiarrhythmics: quinidine - procainamide – disopyramide.

• Antihistamines (1st generation).

• Tricyclic antidepressants – antipsychotics– pethidine.