CHOLINERGIC AGONISTS

DIRECT ACTING

Acetyl choline

Bethanecol

Carbachol

cevimeline

pilocarpine

INDIRECT ACTING ( reversible)AmbenomiumDonepezilEdrophoniumGalantamineNeostigminePhysostigminePyridostigmineRivastigminetacrine

INDIRECT ACTING (irreversible)

Ecothiophate

isoflurophate

REACTIVATION OF ACETYLCHOLINEESTERASE

pralidoxime ( PAM )

CHOLINERGIC AGONISTS

Neurotransmission at cholinergic neuronsSynthesis, storage, release, and binding of acetyl choline.Synthesis—choline cotransport system involving sodium.Storage in vesicles.—contains ach & ATP.Release—opening of ca channels. Binding—ach binds to either of two receptors muscarinic or nicotinic.

Degradation-acetylcholine esterace cleaves acetyl choline to choline and acetate in synaptic cleft.

Recycling- choline recaptured by sodium and gets transported back to the neuron.

Muscarinic receptors – decreased HR, increased glandular secretory activity, stimulation of smooth muscle contractions.M1,M2,M3,M4 & M5

Nicotinic receptors – increased B.P (peripheral vasoconstriction), contraction of skeletal muscle. NM, NN.

Location of muscarinic receptors

Ganglia of pns

Autonomic effector organs—heart, smooth muscle, brain and exocrine glands.

Location of nicotinic receptors

Cns, adrenal medulla, neuro muscular junction.

Cholinergic agonists

Direct acting

Indirect acting

Direct acting

Choline esters

Acetylcholine

Bethanechol

Carbachol

Methacholine

Alkaloids

Muscarine

Pilocarpine

Acetyl choline —both muscarinic and nicotinic activities.

Actions---decrease in heart rate & cardiac output. Mimics effects of vagal stimulation.

Decrease in blood pressure—due to vasodilatation.---rise in intracellular calcium.

Increases salivary, intestinal, bronchial secretion.

ACH – both muscarinic (M) and nicotinic (N) receptors

Bethanechol – strong M and low or no N

Carbachol – both (Strong N)

Pilocarpine – more M

Gastrointestinal & Genitourinary

Bethanechol  

GI smooth muscle stimulant >> postoperative abdominal distention >> paralytic ileus >>esophageal reflux; (promotes increased

esophageal motility)  

Urinary bladder stimulant post-operative; post-partum urinary retention

Carbachol not used due to more prominent nicotinic receptor activation

Methacholine used for diagnostic purposes. testing for bronchial hyper reactivity and asthma

Opthalmological Uses  Acetylcholine and Carbachol may be used for intraocular use as a miotic in surgery  Carbachol may be used also in treatment of glaucoma.

 Pilocarpine is used in management of glaucoma and has become the standard initial drug for treating the closed-angle form. effective even in open angle type.Opens the trab mesh work around schlemm canal.  Sequential administration of atropine (mydriatic) and Pilocarpine (miotic) is used to break iris-lens adhesions

Major contraindication to the use of muscarinic agonists

Asthma  Choline esters (muscarinic agonists) can produce bronchoconstriction. In the

predisposed patient, an asthmatic attack may be induced.

Hyperthyroidism  Choline esters (muscarinic agonists) can induce atrial fibrillation in

hyperthyroid patients.

Peptic ulcer Choline esters (muscarinic agonists), by increasing gastric acid secretion,

may exacerbate ulcer symptoms.

Coronary vascular disease  Choline esters (muscarinic agonists), as a result of their hypotensive effects,

can further compromise coronary blood flow.

Adverse Effects:

Muscarinic Agonists 

 salivation  diaphoresis

 colic  GI hyperactivity

 headache  loss of accommodation

Indirect actingthru enzyme

Reversible inhibitors

Irreversible inhibitors

Reversible" Anticholinesterases Used Clinically

Edrophonium

Pyridostigmine - Used in treatment of myasthenia gravis

Neostigmine

Physostigmine

Demecarium

Ambenonium - Used in treatment of myasthenia gravis

Physostigmine

Actions – muscarinic and nicotinic actions.

Miosis and spasm of accomodation.

Decreases iop.

High doses can cause convulsions

Neostigmine

Has a quarternary nitrogen. there fore it does not enter the cns.

Use – antidote for tubocurarine & treatment of myasthenia gravis.

Acetylcholinesterase Inhibitors ("Irreversible")

Soman Parathion Malathion

Isoflurophate Echothiophate

Organo phosphate poisoning

Reactivation of acetylcholine esterase

Pralidoxime (PAM)

(Pyridine – 2 aldoxime chloride)

Drugs affecting the release:

· Drugs which increase Ach release (mainly venom toxins)

· b bungarotoxin

· Banded krait venom

· Black widow spider venom

· These toxins cause a massive release of Ach which results in fasciculations of muscle

followed by paralysis as all of the Ach is drained from the nerve terminal

Drugs which decrease Ach release

· Botulinum toxin· Produced by the Clostridium botulinum· This bacterium lives in unsterilised canned foods.

Drug that interfere with the synthesisCholine uptake inhibition· Hemicholinium

Glaucoma a disease of the eye marked by increased

pressure within the eyeball that can result in damage to the optic disk and gradual loss of vision.

Myasthenia gravis a disease characterized by progressive weakness

and exhaustibility of voluntary muscles without atrophy or sensory disturbance and caused by an autoimmune attack on acetylcholine receptors at neuromuscular junctions.