Case cholinergic for recording.pptxCase cholinergic for recording.pptxCase cholinergic for recording.pptxCase cholinergic for recording.pptx

1. Cholinergic cases

2. Nervous system
Central nervous system Peripheral nervous system
Spinal cord
Brain Somatic
Autonomic
Cholinergic (parasympathetic)
Adrenergic (sympathetic)
Muscarinic receptors:
1. Constriction of eye pupil. (myosis)
2. Constriction of bronchioles and
increase secretions.
3. Decrease heart rate.
4. Dilate blood vessels.
5. Increase peristalsis and secretions.
6. Contract bladder (urination).
7. Increase salivation.
Nicotinic receptors:
1. Contract skeletal
muscles.
Beta receptors
Alpha receptors
Cholinergic agonist (Direct acting):
1. Methacholine. (M much more
than N)
2. Carbachol. (M and N)
3. Bethanicol. (selective M)
4. Pilocarpine. (selective M)
M= muscarinic AChRs
N= nicotinic AChRs
Reversible acetylcholinesterase inhibitors
(AChEIs) (Indirect acting):
1. Physostigmine. (glaucoma)
2. Neostigmine. (several uses)
3. Pyridostigmine. (oral for myasthenia
gravis)
4. EdrophoniumBromide. (IV for diagnosis
of myasthenia gravis)
5. Rivastigmine. (for Alzheimer disease)
6. Tacrine. (for Alzheimer disease)
withdrawn
Muscarinic Antagonist:
1. Ipratropium Bromide:
used by inhalation as
bronchodilator for
treatment of asthma.
2. Atropine: (several uses)
3. Glycopyrrolate bromide:
(several uses)
4. Benztropine: used for
treatment of Parkinson's
disease
Cholinergic

4. Why Acetylcholine is a Poor Drug? ‫للشرح‬
Because acetylcholine is a quaternary ammonium salt, it is poorly absorbed across
biologic membranes, resulting in poor bioavailability regardless of the route of
administration. Furthermore, its ester functional group is rapidly hydrolyzed in the
acidic conditions of the gastrointestinal tract and by esterases in plasma.
Also, Ach actions are nonselective, producing effects at all cholinergic receptor sites,
which could result in serious consequences for the patient.
Mechanism of action of Reversible acetylcholinesterase inhibitors: ‫للشرح‬
Acetylcholinesterase enzyme is responsible for deactivation of acetyl choline.
Upon inhibition of acetylcholinesterase enzyme, Ach returns to receptor and
reactivates it.
Physostigmine and its analogs are aryl carbamates (esters of carbamic acid and
phenols).
Acetyl choline acetylates the enzyme while aryl carbamates carbamoylate the
enzyme.
The carbamoylated enzyme has rate of hydrolysis slower by 40 x 106 the acetylated
enzyme. ‫للتوضيح‬ ‫الصور‬

5. Acetylated enzyme

8. Case 1
A 62-year-old female comes to have her regular eye examination. The ocular examination reveals normal visual acuity in
both eyes. The dilated eye examination reveals no evidence of optic nerve damage. She has an increased intraocular pressure
in both eyes. She is diagnosed with primary open-angle glaucoma and is started on ophthalmic drops.
Examine the above drugs then Answer the following questions:
1) Could drug (A) be used in this case? Explain why?
Answer:
 No, because acetyl choline has poor corneal penetration due to the presence of the quaternary ammonium
functional group which decreases the lipophilicity of the molecule and makes it more polar.

9. 2)Suggest the drug of choice in this case. Suggest other IOP lowering cholinergic
agent that can be used in combination with this drug.
Answer:
 Drug of choice in this case is pilocarpine (B) which is muscarinic agonist.
 It penetrates the eye well and is the best choice for open-angle glaucoma.
 The cholinergic agent that can be used in combination with pilocarpine is
physostigmine.
 Physostigmine is reversible acetylcholinesterase inhibitor used in treatment of
glaucoma.
 Physostigmine has the ability to cross the blood–brain barrier as it lacks quaternary
ammonium group.
 Physostigmine is metabolized in vivo by esterases to the phenol.
Other drugs can't be used as:
 Neostigmine is reversible acetylcholinesterase inhibitor used for prophylaxis of
postoperative abdominal distension and urinary retention, myasthenia gravis, and
reversal of neuromuscular blockade.
 Neostigmine can't cross the blood–brain barrier because of quaternary ammonium
group.
 Rivastigmine is a centrally selective, arylcarbamate AChEI used orally for treatment
of Alzheimer disease.

10. 3) What is the hydrolysis product of drug (B)? Draw its structure.
Answer:
 Pilocarpic acid
4) Make structural modifications for drug (A) to give an orally active compound used to relief postsurgical
urinary retention.
Answer:
 Bethanechole is selective muscarinic AChRs agonist.
 Methyl group at β-carbon→ compound with greater muscarinic activity, stability and resist hydrolysis (long duration).
 Replacement of CH3 by NH2 → amide i.e. carbomylation instead of esterification → compound with longer duration.
 It is used to treat postsurgical and postpartum urinary retention and abdominal distention.

11. Case 2
A 65-year-old woman is brought to the hospital complaining of double vision, difficulty in swallowing, droopy eyelids,
and weakness in arms and legs. The doctor performs complete physical examination and takes a detailed history of her
symptoms. After neurological exam and blood test, she is diagnosed with myasthenia gravis. Examine the following drugs
then answer the questions below.
Examine the above drugs then Answer the following questions:
1) Suggest the drug of choice in this case and its route of administration.
Answer:
 Pyridostigmine (C). It is given orally
 Pyridostigmine is reversible acetylcholinesterase inhibitor.

12.  Pyridostigmine is orally effective and, compared to neostigmine, has a longer duration of action and
a lower incidence of side effects (no CNS penetration). Thus, it is a better choice for oral therapy of
myasthenia gravis.
 While, physostigmine has CNS side effects. (discussed in the previous case)
2)What is the mode of action and medicinal use of drug (D)?
Answer:
 Mode of action of ipratropium bromide (D) is: muscarinic antagonist.
 Medicinal use: it used as inhalation therapy for treatment of acute asthma.
 It is unable to cross the blood brain barrier. Thus, No CNS side effects (quaternary ammonium
compound).
3)Which drug from the above could be used as an IV. diagnostic test for myasthenia gravis?
Answer:
 Edrophonium which is reversible acetylcholinesterase inhibitor (quaternary ammonium-substituted
phenol).
 Because it is a phenol rather than a carbamate ester of a phenol, it does not carbamylate AChE.
 Edrophonium is used intravenously for the diagnosis of myasthenia gravis.
 Injection of the chemical edrophonium chloride that results in a sudden, temporary improvement in
muscle strength might indicate that you have myasthenia gravis.
4)Why drug (A) possesses CNS effects in contrast to drug (C)?
Answer:
 Physostigmine (A) is a tertiary amine, it is more lipophilic than the quaternary ammonium
functional group of Pyridostigmine (C) so, physostigmine (A) can diffuse across the BBB and causes
CNS effects.

13. Case 3
GG comes to the pharmacy looking for something to treat her daughter LM’s motion sickness. They are going on a 5-day
cruise to the Bahamas, and the last time LM went on a cruise she was nauseous and dizzy. GG said that she heard about a
transdermal patch that aids in relieving the symptoms of motion sickness and asks for advice. Examine the following drugs
then answer the questions below.
Examine the above drugs then Answer the following questions:
1)Suggest the drug of choice in this case.
Answer:
 Drug of choice is Scopolamine (B) (muscarinic antagonist). It is used as transdermal patch for the treatment of
motion sickness that is applied to the skin behind the ear and is well-absorbed percutaneously after the
application.
 Atropine (muscarinic antagonist) is used
for: 1- Treatment of bradycardia.
2- As preoperative agent to decrease secretions before surgery.
3- In ophthalmic examination as it causes mydriasis.
N.B. Atropine is contra-indicated in glaucoma as it increases the intraocular pressure during mydriasis.

14.  Orphenadrine (muscarinic antagonist) has central inhibitory action →
reduction of voluntary muscle spasm so, it is used for treatment of Parkinson's
disease.
 Propantheline Bromide (muscarinic antagonist) is used as Antispasmodic and
in peptic ulcers.
2)Give GG some advice about how and when to use this drug.
 Scopolamine is used as a transdermal patch applied to the skin behind the ear
and is well-absorbed percutaneously following application. It should be
administered before the commencement of the journey.
3)Compare between the effect of drug (A) and drug (B) on the CNS.
 Atropine (A) has some CNS stimulant action.
 Scopolamine (B) has CNS depressant activity.

15. Case 4
A 30-year- old, comatose farmer with miosis, diaphoresis, and incontinence is brought to the emergency
department at noon. He has profuse salivation and excess lacrimation. Abdominal examination reveals
hyperactive bowel sounds. The doctor was told that the patient sprayed the crops with an organophosphorus
pesticide this morning.
Examine the above drugs then Answer the following questions:
1)What is the mechanism of poisoning caused by Organophosphorus (OP) compounds?
Answer:
 Organophosphate esters act through inhibiting AChE, but the phosphorylated enzyme
is stable and the rate of hydrolytic generation of the phosphorylated enzyme to the free
enzyme is very slow and it could be considered irreversible due to its long duration if
compared with the carbamate esters.
 This inhibition leads to reduced metabolism and accumulation of acetylcholine leading
to excessive cholinergic activity.

16. 2)From the above drugs, what is the suitable drug combination for the management of this case?
Answer:
 The suitable drug combination is Atropine (A) and Pralidoxime chloride (D).
 Propantheline Bromide (muscarinic antagonist) is used as Antispasmodic and in peptic ulcers.
 Neostigmine is reversible acetylcholinesterase inhibitor used for prophylaxis of postoperative
abdominal distension and urinary retention, myasthenia gravis, and reversal of neuromuscular
blockade.
3)Mention the role of each drug.
Answer:
 Atropine blocks the muscarinic receptors and decreases muscarinic cholinergic actions (e.g.,
lacrimation, salivation, sweating, bradycardia, and breathing problems).
 Pralidoxime is acetylcholinesterase reactivator. It combines with the phosphoryl group of the
phosphorylated acetylcholinesterase to release the free acetylcholinesterase enzyme.
The hydroxyl group in 2-PAM has strong nucleophilic affinity to bind with phosphorus atom
in the phosphorylated enzyme → phosphorylated 2-PAM + free enzyme.

17. It must be given within a short period of time after enzyme phosphorylation (few hours) otherwise an aging
process could occur.
After aging has occurred 2-PAM cannot regenerate the enzyme where the organo-phosphateAChE complex
become harder to hydrolyse.
4)By chemical equations, illustrate the aging process of phosphorylated AChE enzyme.
Answer:
 Aging is the result of cleavage of one or more of the phosphoester bonds while the enzyme is
phosphorylated → anionic phosphate → (P) atom is much less electrophilic so less likely to
undergo hydrolytic regeneration than the original phosphoester.
 So the aged phosphorylated enzyme does not undergo nucleophilic attack and regeneration by
antidotes.
P

18. Case 5
A 63-year-old woman with a history of liver dysfunction presents to the hospital with memory loss that
disrupts daily life such as forgetting events, repeating questions, difficulty completing familiar tasks at home
and confusion with time or place. After neurological examinations, diagnostic tests and brain imaging, the
doctor diagnosed her with Alzheimer's disease.
Examine the following drugs and then answer the questions below:
1)Predict the drug of choice in this case with justification.
Answer:
Drug of choice is Rivastigmine.
Justification:
 It was proposed that the memory loss, intellectual deterioration associated with Alzheimer's disease is due to
the destruction of cholinergic nerves and subsequently a drop in both cholinergic receptors and ACh levels.
 So, reversible AChEIs are used for treatment of Alzheimer's disease and are called smart drugs.
 They are characterized by lacking the quaternary N atoms which are not suitable for crossing the BBB.
 Rivastigmine is a centrally selective aryl carbamate AChEI used orally or via a transdermal patch for treatment of
mild to moderate Alzheimer's disease.

19. Other drugs can't be used as:
 Tacrine is acetylcholinesterase inhibitor and was the first drug for management of Alzheimer disease.
o But it was withdrawn from use in 2013 due to its hepatotoxic effect (serum aminotransferase
elevation) and almost half of patients receiving tacrine had experienced moderate to severe liver
injury.
 Benztropine is a synthetic atropine derivative (muscarinic antagonist) that can cross the BBB so it is
used in treatment of Parkinson's disease.
o It has a large affinity for muscarinic receptors M1 in the human brain.
o Benztropine blocks the activity of the muscarinic receptors mainly in the striatum which corrects
the imbalance between dopamine and acetylcholine in Parkinson patients.
 Methacholine is a selective agonist of muscarinic AChRs that can't cross the BBB due to its quaternary
ammonium group.
2)What is the effect of methyl substitution at β- carbon in Methacholine (drug D)?
Answer:
 ↑ muscarinic potency
 ↑ stability → compound with longer duration due to steric effect of β-Me gp (shielding effect) →
hinder binding of the compound with AChE → ↓ rate of hydrolysis.
 Creation of chiral center → optically active compound:
o S- isomer:(Methyl above the plane) it is the most active isomer.
 CH3 not interfere with the drug-receptor binding→ more potent than R- isomer.

20. o R- isomer:
 CH3 interfere with the drug-receptor binding.
 Lower rate of hydrolysis than S- isomer as CH3 below the plane → hinder its hydrolysis
by ACh →
longer duration than S- isomer.
o Usually used as a racemic mix. (↑potency with selectivity on M- receptor + long duration).
(S- isomer) (R-isomer)

21. Case 6
A 55 years old-man with a history of atrial fibrillation presents to the hospital complaining of wheezing,
coughing, breathlessness and a tight chest, which feels like a belt tightening around it. After complete
evaluation of the respiratory system including patient history, physical examinations, and tests of pulmonary
function such as spirometry, the physician diagnosed him with asthma and prescribed him the suitable drug
for his case.
Examine the following drugs and then answer the questions below:
1)Predict the suitable drug in this case with justification.
Answer:
Drug of choice is Ipratropium bromide.
Justification:
 Ipratropium bromide is a muscarinic antagonist used as inhalation therapy for treatment of asthma
(useful in patients who are unable to tolerate adrenergic agonists as in this case)
Other drugs can't be used as:
 Carbachol chloride is non selective parasympathetic agonist used for treatment of glaucoma.

22.  Glycopyrrolate bromide is a synthetic atropine derivative (muscarinic antagonist with peripheral action only)
o Uses:
 Inhalation for long term maintenance of airflow obstruction in COPD.
 Intraoperatively to treat surgically-induced bradycardia and to block cardiac inhibitory reflexes during
the induction of anesthesia.
 Perioperatively as a muscarinic receptor antagonist: to reduce pharyngeal, tracheal, bronchial, and
salivary secretions.
 Adjunct therapy in the treatment of peptic ulcers as it decreases gastric secretions.
 Topically to treat hyperhidrosis (abnormally increased sweating) in ≥ 9 years old patients.
o Contraindications:
 Glaucoma and myasthenia gravis.
 Colterol is selective β2- agonist used as inhalation therapy for treatment of asthma but it is contraindicated in this
case with a history of atrial fibrillation (like bitolterol).
2)What is the role of encircled group in the drug (A) Carbachol chloride?
Answer:
 Carbamoyl choline chloride is stable with longer duration and resists hydrolysis by AChE:
1.Due to electronic effect of carbamate group.
2.The rate of regeneration of the carbamoylated enzyme (giving carbamic acid and free enzyme) is slower than
the generation of the acetylated enzyme and reaction could be considered as semi-reversible.

23. Very Important:
 M.O.A of pilocarpine in ttt of glaucoma is miosis so increases the outflow of the aqueous humor (increases drainage
of aqueous humor).

24. Notes:
 The best diuretic for treatment of hypertension is thiazide diuretics
 ttt of asthma:
 Ipratropium Bromide (Muscarinic Antagonist- inhalation)
 Albuterol and bitolterol (selective β2 agonist)
 Salmeterol (long acting for severe asthma and COPD only)
 ttt of glaucoma:
 Pilocarpine (Muscarinic Agonist): miosis so, increases drainage of aqueous humor.
 Betaxolol (Selective 1 blocker) decreases rate of formation of aqueous humor.
 Methazolamide (carbonic Anhydrase inhibitor) decreases rate of formation of aqueous humor.
 ttt of Alzheimer disease: Rivastigmine.
 ttt of Parkinson's disease: Benztropin.
 Contraindications:
 Physostigmine: CNS diseases.
 Atropine: glaucoma
 Glycopyrrolate bromide: Glaucoma and myasthenia gravis
 Propranolol: asthma and pulmonary diseases and diabetes.
 Carvidilol: asthma and hepatic impairment.
 Verapamil and diltiazem: congestive heart failure.
 Furosemide: hypocalcemia and osteoporosis.
 Contraindications of antihyperlipidemic.