CHOLINERGIC DRUGS

For BNS 1st YearDr. Pravin Prasad

1st Year Resident, MD Clinical PharmacologyMaharajgunj Medical Campus

27th December, 2015 (Poush 12, 2072), Sunday

Nervous System: OverviewNervous System

(NS)

Central Nervous System(CNS)

Cerebrum, Cerebellum,

Brainstem, Spinal Cord

Peripheral Nervous System (PNS)

Somatic Nervous System

Autonomic Nervous System (ANS)

Sympathetic Nervous System

Parasympathetic Nervous System

Autonomic Nervous System: Organization

Sympathetic vs Parasympathetic NS

Sympathetic NS Parasympathetic NS

Thoracolumbar outflowMost ganglions are nearer to vertebral columnShorter preganlionic fibres

Craniosacral outflowGanglions are within or near to target organLonger preganglionic fibers

Preganglionic NT: Acetylcholine

Preganglionic NT: Acetylcholine

Postganlionic NT: Norepinephrine (Noradrenaline); Acetylcholine at some sites

Postganglionic NT: Acetylcholine; Nitric oxide at some sites

Cholinoceptors•Muscarinic (G Protein Coupled Receptor)

•Selective Agonist: Muscarine

•Antagonist: Atropine

•Five Subtypes: M1-M5

•M1, M3, M5: excitatory

•Nicotinic (Ligand gated cation channel)

•Selective Agonist: Nicotine

•Antagonist: d-tubocurarine

•Two subtypes: NN & NM

•Usually excitatory

Cholinergic TransmissionSite Type of

Receptor Selective Agonist Selective Antagonist

All postganglionic parasympathetic(parasym).Few postganglionic sympathetic (sym)1

Muscarinic Muscarine Atropine

Ganglia (sym. & parasym.)Adrenal Medulla

Nicotinic (NN) Dimethyl Phenyl Piperazinium (DMPP) Hexamethonium

Skeletal Muscles Nicotinic (NM) Phenyl Trimethyl Ammonium (PTMA) d-tubocurarine

CNS (cortex, basal ganglia, spinal cord, others)

Muscarinic Muscarine/ Oxotremorine Atropine

Nicotinic Carbachol d-tubocurarine

Cholinergic Transmission

• Synthesised from Acetyl CoA and Choline in presence of Choline Acetyl Transferase

• Stored in vesicles• Released when impulses

arrives by exocytosis• Degraded by

Acetylcholinesterase (AChE)

Muscarinic CholinoceptorsFeatures M1 M2 M3Location & Function

Autonomic ganglia: depolarization1

Gastric glands: increased secretionCNS (learning, memory, motor function)

Heart: Decrease rate, forceNerve endings: Decrease ACh releaseCNS: tremor, analgesiaVisceral smooth muscle: contraction

Visceral smooth muscle: contractionIris: constriction of pupilCiliary muscle: contraction2

Exocrine glands: secretionVascular endothelium: vasodilatation

Nature Gq protein coupled Gi/G0 protein coupled Gq protein coupledTransducer mechanism

IP3/DAG – increase Ca+

+

PLA2 increasd – PG synthesis

K+channel opening, decreased cAMP

IP3/DAG – increase Ca++

PLA2 increasd – PG synthesis

Agonists Oxotremorine, MCN 343A

Methacholine Bethanechol

Antagonists

Pirenzepine, Telenzepine

Methotramine, Triptiramine

Solifenacin, Darifenacin

Nicotinic CholinoceptorsFeatures NM NN

Location & Function

Neuromuscular junction: depolarization of muscle end plate – contraction of

skeletal muscle

Autonomic ganglia: depolarization –postganglionic

impulseAdrenal medulla: catecholamine

releaseCNS: site specific excitation or

inhibition

Nature

Intrinsic ion channel, pentamer of α2 β ε or γ

and δ, each with 4 transmembrane

segments

Intrinsic ion channel, pentamer of only α or α,β subunit, each with 4

transmembrane segments

Transducer mechanism

Opening of cation channels (Na+ K+)

Opening of cation (Na+ K+ Ca++) channels

Agonists PTMA, nicotine DMPP, nicotineAntagonists Tubocurarine, α-

Bungarotoxin Hexamethonium, Trimethaphan

Cholinergic (Cholinomimetic / Parasympathomimetic) Drugs

Cholinergic Agonists Anti-cholinesterasesCholine esters

Alkaloids Reversible Irreversible

Acetylcholine Pilocarpine Carbamates: Physostigmine, Neostigmine, Pyridostigmine, Edrophonium, Rivastigmine, Donepezil, Galantamine

Carbamates: Carbaryl, Propoxur

Methacholine Arecoline Organophosphates: Dyflos, Echothiophate, Malathion, Diazinon, Tabun, Sarin, Soman

Carbachol Muscarine

Bethanechol Acridine: Tacrine

Muscarinic Actions of Cholinergic Agonists (ACh)Organ Recept

or Involved

Mechanism Effect

Heart M2 Hyperpolarization of SA Node

Bradycardia, cardiac arrest

M2 Increased Refractory Period at AV node and His-Purkinje Fibres

Delayed conduction, Prolonged P-R interval, Heart Block

Blood Vessels

PLc – IP3/DAG mediated EDRF (NO release): Vasodilation

Fall in BP, flushing

M3 VasoconstrictionRelease of NO – dilatation of cavernous sinus

Erection of penis

Muscarinic Actions of Cholinergic Agonists (ACh)Organ Recepto

r Involved

Mechanism Effects

Smooth Muscle

M3 + M2 Increased tone and peristalsis of GIT, sphincters relaxed

Abdominal cramps, evacuation of bowels

M3 Increased peristalsis in ureters, detrusor contracts, trigone & sphincter relaxes

Voiding of bladder

M3 Constriction of bronchial muscles

Bronchospams, dyspnoea, asthamatic attack

Muscarinic Actions of Cholinergic Agonists (ACh)Organ Receptor

Involved Mechanism Effects

Glands M3 + M2 Increased secretion Salivation, sweating, lacrimation, increased tracheobronchial and gastric secretions

Eyes M3

Contraction of circular muscle of iris

Miosis

Contraction of ciliary muscle

Blurring of near vision, increased aqueous outflow, decreased intra ocular pressure in glaucomatous eye

Nicotinic Actions of Cholinergic Drugs (ACh)

Organ Receptor Involved Mechanism & Effects

Autonomic Ganglia NN

• Stimulation of sym. & parasym. ganglia (higher doses)

Skeletal Muscles NM

• Iontophoreic application of ACh to muscle end plate: contraction of fibres

• Intra-arterial injection: twitching and fasciculations

CNS Action of ACh• Intravenous injection: No central effects• Direct injection into brain: arousal response followed by depression• Complex neurological and behavioural effects

Drug interactionsSynergism AntagonismAnticholinesterases: potentiation

Atropine, Atropine like substances

Methacholine: potentiation (lesser extent)

Adrenaline

Carbachol, bethanechol: additive

Choline esters: Uses and Side Effects•Uses:

•Rarely used (evanescent and non selective action)

•Bethanechol: non-obstructive urinary retention, neurogenic bladder

•Side effects:•Belching, colic•Involuntary urination/defecation

•Flushing, sweating•Fall in BP•Bronchospasm

Cholinomimetic AlkaloidsPilocarpine•Source: Pilocarpus microphyllus

•Prominent muscarinic actions; ganglionic action via M1 receptors

•CVS Effects:•Small dose – fall in BP (muscarinic, ?M2)

•Higher dose – rise in BP and tachycardia (ganglion mediated; M1)

•Eyes:•Local application – penetrates cornea, miosis, ciliary muscle contraction, fall in intraocular tension (M3)

•Use: As Miotics (counteract mydriatics used for refraction, along with mydriatics to prevent/break adhesions), In open angle glaucoma,

•S/E: marked sweating, salivation, increased secretions

Arecholine•Source: betel nut Areca catechu•Muscarinic as well as Nicotinic actions•No therapeutic use

Cholinomimetic Alkaloids

Muscarine•Source: mushrooms Amanita muscaria, Inocybe sps.

•Only muscarinic actions•Not used therapeutically, has toxicological importance

Cholinomimetic Alkaloids

Mushroom PoisoningEarly type (Muscarinic)

Hallucinogenic Type

Late type (Phalloidin)

Toxic principle

Inocybe and related sps.

Muscimol; isoxazole (A. muscaria)

Peptide toxin of A. phalloides, Galerina

Mechanism Blocks M receptors in CNS

Inhibit RNA and protein synthesis

Features Muscarinic Hallucinogenic, central manifestations

Damage to GIT, liver, kidney

Presentation

Within an hour of eating

After hours of ingestion

Treatment Atropine Nonspecific, Atropine contraindicated

Supportive

Anti-cholinesterases (AChE)•Inhibits Cholinesterases (ChE) protects ACh from hydrolysis cholinergic effects

•Some have additional direct action on Nicotinic receptors

AChE: Mechanism of Action•Normally, after showing its activity, ACh is degraded by hydrolysis by Cholinesterase(ChE) into choline and acetic acid

•Hydrolysis of AChEs is either slow (carbamates, about 30 mins) or extremely slow (organophosphates, days), hence the enzyme ChE is rendered inactive normal ACh at the junction cannot be hydrolysed prolonged action of ACh (cholinomimetic action)

•Hydrolysis after ageing not possible, new ChE needs to be formed

AChE: Pharmacological Actions•Due to amplification of endogenous Ach•Intensity of action on muscarinic, nicotinic and CNS varies among different agents

Characteristics Example Muscari

nic

NicotinicCNSGangl

iaSkeleta

l Muscle

Lipid soluble

Physostigmine, organophosphates

+++ + Less prominent

+++

Lipid insolube

Neostigmine Less prominent

+ +++ none

AChE: Pharmacological Actions•Ganglia: stimulation at low dose, blockade at high dose

• Stimulation via M1 receptors• High dose: persistent depolarization depletion of ACh blockade of transmission

•CVS: complex, unpredictable effects• Muscarinic: bradycardia, hypotension; Ganglionic: tachycarida, hypertension• Action on medullary centres(stimulation then depression), ganglion blockade at high

doses•Skeletal Muscles: twitching and fasciculations at low dose, weakness and paralysis at high dose• Prolonged action of ACh on motor end plates and prejunctional fibres twitching and

fasciculations• High dose: persistent depolarization neuromuscular transmission blockade

weakness and paralysis•CNS: general arousal at low dose, excitement, confusion at high dose

• Lipophilic agent: generalised alerting response, improved cognition in Alzheimer’s Disease

• Higher doses: excitement, mental confusion, disorientation, tremors, convulsions, coma

AChE: Pharmacokinetics•Physostigmine:

•Rapid absorption (oral, parenteral, topical in eye)

•Crosses BBB, central effects

•Metabolism by hydrolysis

•Neostigmine:•Poor oral absorption (20-30 times parenteral

dose)•Does not cross BBB, cornea

•Partially hydrolysed and partially excreted unchanged in urine

•Organophosphates:•Absorbed from all sites•Hydrolysed and oxidised and then excreted

AChE:UsesAs Miotic•Glaucoma:

• Increases tone of ciliary muscle and sphincter pupillae opening of trabeculae intra ocular tension (iot) falls in open angle glaucoma

•Pilocarpine – rapid and short lasting (4-6hrs), 6-8hrly instillation required; fluctuation of iot in between seen, S/E: diminution of vision especially in dim light, spasm of accommodation, brow pain; nausea, diarrhoea, sweating, bronchospasm with higher concentration; also used in combination for angle closure glaucoma

•Physostigmine 0.1% - supplement pilocarpine•Reversal of mydriasis after refraction•Prevent/break adhesions (iris-lens, iris-cornea): in conjunction with mydriatics

AChE:Uses•Myasthenia gravis(MG):• Treatment

•Neostigmine 15 mg orally 6 hrly, adjusted according to response, dose requirement fluctuates in accordance to remission and exacerbation

•Pyridostigmine•Atropine if muscarinic side effects seen, cholinergic weakness/crisis if dose adjustment not adequate

•Diagnostic Tests•Ameliorative Test: Inj Edrophonium 2mg i.v. (test dose) followed by 8 mg i.v. after 30-60 sec. reversal of weakness and short lasting improvement of strength: +ve for MG

•Provocative Test: hazardous – not performed

•Demonstration of anti-NR antibodies in plasma or muscle biopsy specimen

AChE:Uses•Post-operative paralytic ileus/urinary retention: Inj. Neostigmine 0.5-1 mg s.c.

•Post-operative decurarization: Neostigmine 0.5-2 mg i.v. preceeded by atropine to block muscarinic effects rapidly reversal of muscle paralysis induced by competitive neuromuscular blockers

•Cobra bite: Neostigmine + Atropine to prevent respiratory paralysis can be used

•Belladona poisoning/Dhatura poisoning: Physostigmine 0.5-2 mg i.v. repeat as required (S/E – hypotension, arrhythmia, undesireable central effects: last resort), Neostigmine safer

•Drug Overdose: TCA, phenothiazines, antihistaminics – Physostigmine (rare)

•Alzheimer’s Disease: cerebroselective AChE (rivastigmine, donepezil, galantamine)

Phew!!!!•That will be all for today

•Please revise the topic….

•Next class: Thursday 31st December, 2015; Topic: Anticholinergics Drugs

Thank you