1. CHOLINERGIC AGONISTS

2. WHAT ARE CHOLINERGIC AGONIST
Cholinergic agonists are drugs that mimic or potentiate the actions of acethycholine

3. WHAT ARE THE TWO MAJOR FAMILIES OF CHOLINERGIC RECEPTORS
1. Muscarinic- this receptor family earned its name because it was first identified using muscarine, an alkaloid found in certain poisonous mushroom.
2. Nicotine

4. The muscarinic receptors, namely, M1 to M5
The muscarinic receptors, namely, M1 to M5. They are found in ganglia, smooth muscle, myocardium, secretory glands and the CNS.
The nicotinic receptors.
1. Neuronal nicotinic (Nn) located in autonomic ganglia
2. Muscular nicotinic(NM), located in the neuromuscular junction

5. WHAT TYPES OF CHOLINERGIC AGONISTS ARE AVAILABLE FOR CLINICAL USE?
Cholinergic agonists can be divided into two major groups:
1. Direct-acting agonists chemically bind with and activate muscarinic and nicotinic receptors in the body.
2. Indirect-acting agonists inhibit the enzyme acethycholinesterase and therefore increase the concentration of acethylcholine within the synapse

6. DIRECT ACTING CHOLINERGIC AGONISTS
Acetyl choline
Bethanecol
Carbachol
methacholine
pilocarpine
Nicotine

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

8. INDIRECT ACTING (irreversible)
Ecothiophate
Isoflurophate
PARATHION
MALATHION

9. REACTIVATION OF ACETYLCHOLINEESTERASE
pralidoxime ( PAM )

10. 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.

11. 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.

13. 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.

14. 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.

15. Cholinergic agonists
Direct acting
Indirect acting

16. Direct acting Choline esters Acetylcholine Bethanechol Carbachol
Methacholine
Alkaloids
Muscarine
Pilocarpine

17. Acetyl choline —both muscarinic and nicotinic activities.
Actions---CVS: decrease in heart rate & cardiac output. Mimics effects of vagal stimulation.
Decrease in blood pressure—due to vasodilatation.---rise in intracellular calcium.
GIT: INCREASES MOTILITY OF THE GI AND BLADDER

18. PULMONARY SYSTEM: INCREASES SECRETION OF THE BRONCHIOLES
THE EYE- IT CAUSES CONSTICTION OF THE PUPILLARY SPHICTER MUSCLE, WHICH CAUSES MIOSIS AND ACCOMODATION.
PNS: contraction of skeletal muscle
CNS it affects neurotransmission
Endocrine: release epinephrine from the adrenal medulla and it stimulates sweat gland secretions

19. ACH – both muscarinic (M) and nicotinic (N) receptors
Bethanechol – strong M and low or no N
Carbachol – both (Strong N)
Pilocarpine – more M

20. What are the clinical indications
Acetylcholine is used to achieve miosis during ophthalmic surgery. In general, it is rarely used because it has widespread effects and is so rapidly hydrolyzed by acetylcholinesterase.

21. WHAT ARE THE ADVERSE REACTIONS
The adverse effects result from excessive generalized cholinergic stimulation. They include:
Diarrhea and decreased blood pressure
Urination
Miosis
Bronchoconstriction
Excitation of skeletal muscle
Lacrimation
Salivation and sweating
DUMBELS

22. THERAPEUTIC USES
Bethanechol increases intestinal motility, especially after surgery. Because this drug also stimulates the detrusor muscle of the bladder, it is also used to treat urinary retention.
BBB- Bethanechol stimulates the Bladder and Bowel.

23. Carbachol
This drug is rarely used in the clinics, but it can be used for GLAUCOMA and to stimulate miosis during ophthalmic surgery

24. Pilocarpine An alkaloid. Its physiologic actions
cause miosis and contraction of the ciliary muscle,
decreases heart rate,
causes bronchial smooth muscle contraction, increases secretions from salivary , lacrimal and sweat glands.

25. Clinical use
Pilocarpine is good miosis and opening the trabecular meshwork around the canal of schlemm.
Therefore is used treatment of glaucoma
Adverse effects? Pilocarpine is able to enter the brain and causes CNS disturbances such as hallucinations and convulsions, along with generalized cholinergic stimulation

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

27. 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.

28. 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.

29. Adverse Effects: Muscarinic Agonists   salivation  diaphoresis  colic  GI hyperactivity  headache  loss of accommodation

30. Indirect acting thru enzyme
Reversible inhibitors
Irreversible inhibitors
1. Isoflurophate
2. Echothiophate
3. Parathion
4. Edrophonium
5. Physostigmine
6. Neostigmine

31. How do they work?
By inhibiting the enzyme acetylcholinesterase which is responsible for the hydrolysis of acetylcholine.
Neuronal response to acetylcholine is therefore enhanced.

32. Which indirect- acting cholinergic agonists have the ability to irreversibly inhibit acetylcholinesterase?
Only the organophosphates
( isoflurophate, echothiophate and parathion) irreversibly inhibit acetylcholinesterase

33. Reversible" Anticholinesterases Used Clinically
Edrophonium
Diagnosis test for myasthenia gravis
Physostigmine - Used in treatment of glaucoma, antidote in atropine overdose
Neostigmine
Pyridostigmine: use for treatment of ileus, urinary retention, myastenia gravis
Demecarium
Ambenonium - Used in treatment of myasthenia gravis

34. Physostigmine Actions – muscarinic and nicotinic actions.
Miosis and spasm of accomodation.
Decreases intraocular pressure
High doses can cause convulsions

35. Neostigmine
Has a quarternary nitrogen. there fore it does not enter the CNS.
Use – antidote for tubocurarine & treatment of myasthenia gravis.

36. Acetylcholinesterase Inhibitors ("Irreversible") Soman Parathion Malathion Isoflurophate Echothiophate treatment of glaucoma. Note used as insecticides

37. Organo phosphate poisoning
Reactivation of acetylcholine esterase
Pralidoxime (PAM)
(Pyridine – 2 aldoxime chloride)

38. 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

40. 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

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

42. 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.