Cholinergic system and drugs

Dr. Karun Kumar

JR-II

Dept. of Pharmacology

Ach receptor agonists

1. Direct acting agonists Bind & activate Ach rec.

a) Choline esters Ach, Bethanechol, Carbachol

b) Plant alkaloids Muscarine, Nicotine,

Pilocarpine, Arecoline

c) Synthetic drugs Cevimeline, Varenicline,

Tremorine, Oxotremorine

2. Indirect acting agonists (Anti-chE)

i) Reversible anti-chE

a) Natural alkaloid Physostigmine

b) Others Edrophonium, Neostigmine,

Pyridostigmine, Donepezil, Galantamine,

Rivastigmine, Ambenonium, Demecarium

ii) Irreversible anti-chE OPs, Echothiophate,

Isoflurophate, Malathion,

Propoxur, Paraoxon, Carbaryl

Clinical uses

• Bethanechol

1. Urinary retention (Postoper. Or neurogenic bld.)

2. GIT atony (Expel gases, paralyitc ileus)

3. Xerostomia (Salivary gland malfunc., Sjogren’s)

• MethacholineMCT (bronchial asthma)

• CarbacholMiosis during ophthalmic surgery

• Pilocarpine

1. Ophthalmic Glaucoma, mydr., break adhesions

2. Sialagogue Xerostomia (laryng. surg., radioth.)

• Nicotine Smoking cessation programs

• Pilocarpine Xerostomia, Glaucoma

• Cevimeline Xerostomia

• Varenicline Smoking cessation

• Edrophonium Diff. b/w myasthenic & c. crisis

• Donepezil, Galantamine & Rivastigmine AD

• Pyridostigmine Myasthenia gravis

• Echothiophate Eye (glaucoma)

• Malathion Lice (Pediculosis)

• Neostigmine (NO CNS penetration – Quat. Amine)

Muscarinic

1. Postop. Paralytic ileus

2. Postop. urinary retention

Nicotinic

1. Myasthenia gravis (Oral 15-30 mg; 0.5-2.5 mg i.m/s.c)

2. Cobra bite

3. Curare poisoning

• Physostigmine (CNS penetr. – Tertiary amine)

1. Antidote in atropine poisoning (2 mg i.m./i.v.)

2. Ophthalmic (Glaucoma, mydr., adhesions break)

Poisoning• Organophosphates

1. Insecticides Malathion, Parathion, Dyflos

2. Nerve gases Soman, Sarin

3. Ophthalmic agents Echothiophate, Isoflurophate

• Carbamates

1. Reversible Physostigmine, Neostigmine, Pyridostigmine, Edrophonium,

Rivastigmine, Donepezil, Galantamine

2. Irreversible Carbaryl, Propoxur

Anti-chE poisoning

M Miosis

U Urination

S Sec. ↑ (Salivation, lacrimation & sweating)

C Cardiac contraction & conduction slows

A Abdominal cramps

R Redn. In i.o.t. (esp. in glaucoma)

I Inc. (↑) GI motility

N NO dependent vasodilatation

I Inc. sec. from GIT & tracheobronchial tract

C Constriction of tracheobronchial tract

Treatment

1. Termination of further exposure to the poison

2. Maintain patent airway PPV

3. Supportive measures

4. Specific antidotes

a) Atropine Counteracts muscarinic symptoms

Dose 2 mg i.v. every 10 mins. Till atr. Signs

b) ChE reactivator Pralidoxime, Diacetylmonoxime

Dose 1-2 gms slow i.v. infusion

Review Questions

1. A woman with facial muscle spasms is treated with an agent that inhibits the release of acetylcholine. Which side effect is most likely to occur in this patient?

(A) bradycardia

(B) urinary incontinence

(C) dry mouth

(D) diarrhea

(E) constriction of the pupils

2. A man receives an injection of epinephrine to treat

an allergic reaction to a bee sting. Which effect

would result from this treatment?

(A) increased glucose absorption from the gut

(B) increased hepatic output of glucose

(C) increased uptake of glucose by skeletal muscle

(D) increased formation of glycogen

(E) increased conversion of glucose to fat

3. A man complains of dry mouth after radiation

therapy for throat cancer, and he is treated with

cevimeline. Which mechanism produces the

therapeutic effect of this drug?

(A) activation of muscarinic M2 receptors

(B) increased formation of IP3

(C) increased cAMP levels

(D) increased cGMP levels

(E) increased potassium efflux

4. A woman in a smoking cessation program receives

a drug that reduces craving and withdrawal effects.

Which effect results from receptor activation by this

drug?

(A) sodium influx

(B) potassium efflux

(C) increased cAMP

(D) increased cGMP

(E) IP3 formation

5. A man receives a drug that increases cGMP levels.

Which adverse effect is most likely to result from this

medication?

(A) constipation

(B) cough

(C) dry mouth

(D) sedation

(E) headache

6. An agricultural worker is brought to the

emergency department after abrupt onset of bowel

and bladder incontinence and muscle weakness. He

is given oxygen and antidotal drug treatments. Which

drug mechanism would increase muscle strength in

this patient?

(A) blockade of muscarinic receptors

(B) activation of nicotinic receptors

(C) increased neurotransmitter degradation

(D) induction of drug-metabolizing enzymes

7. A 30-year-old woman undergoes abdominal surgery. In spite of minimal tissue damage, complete ileus (absence of bowel motility) follows, and she complains of severe bloating. She also finds it difficult to urinate. Mild cholinomimetic stimulation with bethanechol or neostigmine is often effective in relieving these complications of surgery. Neostigmine and bethanechol in moderate doses have significantly different effects on which one of the following?

(A) Gastric secretion

(B) Neuromuscular end plate

(C) Salivary glands

(D) Sweat glands

(E) Ureteral tone

8. Parathion has which one of the following

characteristics?

(A) It is inactivated by conversion to paraoxon

(B) It is less toxic to humans than malathion

(C) It is more persistent in the environment than DDT

(D) It is poorly absorbed through skin and lungs

(E) If treated early, its toxicity may be partly reversed

by pralidoxime

9. Ms Brown has been treated for myasthenia gravis for several years. She reports to the emergency department complaining of recent onset of weakness of her hands, diplopia, and difficulty swallowing. She may be suffering from a change in response to her myasthenia therapy, that is, a cholinergic or a myasthenic crisis. Which of the following is the best drug for distinguishing between myasthenic crisis (insufficient therapy) and cholinergic crisis (excessive therapy)?

(A) Atropine

(B) Edrophonium

(C) Physostigmine

(D) Pralidoxime

(E) Pyridostigmine

10. A crop duster pilot has been accidentally exposed

to a high concentration of a highly toxic agricultural

organophosphate insecticide. If untreated, the cause

of death from such exposure would probably be

(A) Cardiac arrhythmia

(B) Gastrointestinal bleeding

(C) Heart failure

(D) Hypotension

(E) Respiratory failure

11. Mr Green has just been diagnosed with

dysautonomia (chronic idiopathic autonomic

insufficiency). You are considering different therapies

for his disease. Pyridostigmine and neostigmine may

cause which one of the following?

(A) Bronchodilation

(B) Cycloplegia

(C) Diarrhea

(D) Irreversible inhibition of acetylcholinesterase

(E) Reduced gastric acid secretion

12. Parasympathetic nerve stimulation and a slow

infusion of bethanechol will each:

(A) Cause ganglion cell depolarization

(B) Cause skeletal muscle end plate depolarization

(C) Cause vasodilation

(D) Increase bladder tone

(E) Increase heart rate

13. Actions and clinical uses of muscarinic

cholinoceptor agonists include which one of the

following?

(A) Bronchodilation (asthma)

(B) Improved aqueous humor drainage (glaucoma)

(C) Decreased gastrointestinal motility (diarrhea)

(D) Decreased neuromuscular transmission and

relaxation of skeletal muscle (during surgical

anesthesia)

(E) Increased sweating (fever)

14. Which of the following is a direct-acting

cholinomimetic that is lipid-soluble and is used to

facilitate smoking cessation?

(A) Acetylcholine

(B) Bethanechol

(C) Neostigmine

(D) Physostigmine

(E) Varenicline

15. A 3-year-old child is admitted after taking a drug

from her parents’ medicine cabinet. The signs

suggest that the drug is an indirect-acting

cholinomimetic with little or no CNS effect and a

duration of action of about 2–4 h. Which of the

following is the most likely cause of these effects?

(A) Acetylcholine

(B) Bethanechol

(C) Neostigmine

(D) Physostigmine

16. Which of the following is the primary second-

messenger process in the contraction of the ciliary

muscle when focusing on near objects?

(A) cAMP (cyclic adenosine monophosphate)

(B) DAG (diacylglycerol)

(C) Depolarizing influx of sodium ions via a channel

(D) IP3 (inositol 1,4,5-trisphosphate)

(E) NO (nitric oxide)