CHOLINERGIC AGONISTS

DIRECT ACTING Acetyl choline Bethanecol Carbachol cevimeline pilocarpine

INDIRECT ACTING ( reversible) Ambenomium Donepezil Edrophonium Galantamine Neostigmine Physostigmine Pyridostigmine Rivastigmine tacrine

INDIRECT ACTING (irreversible) Ecothiophate isoflurophate

REACTIVATION OF ACETYLCHOLINEESTERASE pralidoxime ( PAM )

CHOLINERGIC AGONISTS Neurotransmission at cholinergic neurons Synthesis, 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 acting thru 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 synthesis Choline uptake inhibition · Hemicholinium

Prepare botox Trigeminal neuralgia Bio weapon—1 pound---entire human population

Glaucoma Myasthenia gravis 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.