4. Cholinergic Pharmacology Katzung’s Basic & Clinical Pharmacology,
Reading assignments:
Katzung’s Basic & Clinical Pharmacology,
13th Edi ,Ch-7 ,p ;
Dr.Sanjib Das

5. II. Cholinoceptor-Activating and Cholinesterase-Inhibiting Drugs
A. Spectrum of Action of Cholinomimetics Drugs
+ What are the major subtypes of cholinoceptors?
+ Know the differences between muscarinic and nicotinic receptors.
—Where are they located?
—With which signal transduction systems are they associated?
B. Mode of Action of Cholinomimetic Drugs
+ What are the major differences between "direct" and "indirect" cholinoceptor agonists?

6. C. Direct-Acting Cholinomimetics
1. Basic Pharmacology
+ How do choline esters differ from each other?
—How are they similar?
+ Which choline esters are potentiated by the presence of anticholinesterase agents?
+ What cellular events occur when cholinoceptors are activated?
+ What are the physiological responses produced by muscarinic and nicotinic agonists?
+What is EDRF?
2. Clinical Uses
+ GI and GU
+ Ophthalmology
3. Adverse Effects
+ salivation, sweating, colic, defecation, headache, loss of accommodation
4. Contraindications
+ peptic ulcer
+ asthma
+ coronary insufficiency
+hyperthyroidism

7. D. Indirect-acting Cholinomimetics
1. Basic Pharmacology + What are the major differences among the 3 groups of cholinesterase inhibitors? —How do these differences influence the pharmacokinetics of the drugs? —What is unique about parathion and malathion? + By what mechanisms can drugs inhibit acetylcholinesterase and/or butyrylcholinesterase? —Understand the importance of the mechanisms. + Understand differences between reversible and irreversible cholinesterase inhibitors. + What is "aging" as it relates to acetylcholinesterase inhibition? + Which organ systems are prominently affected by cholinesterase inhibitors? —What are the actions of acetylcholinesterase inhibitors on these systems? 2. Clinical Uses + GI and GU + Ophthalmology + Myasthenia gravis 3. Adverse Effects + Predictable based on excess acetylcholine and overstimulation of muscarinic and nicotinic receptors: miosis, salivation, sweating, bronchial constriction, vomiting and diarrhea, followed by peripheral nicotinic effects particularly manifest as neuromuscular blockade.

8. III. Cholinoceptor-Blocking Drugs
A. Muscarinic Receptor Antagonists 1. Basic Pharmacology + What is the original source of the prototypic antimuscarinic drugs? + What is the importance of their structures (tertiary vs. quaternary amines) as related to absorption and distribution? + What are the effects of antimuscarinic drugs on various organ systems? + Do all drugs affect each system similarly or is there some degree of organ selectivity? 2. Clinical Pharmacology + Gastric or intestinal hypersensitivity or secretion + Excessive salivation + To produce mydriasis and cycloplegia + Adjunct prior to general anesthesia + Asthma + Understand how antimuscarinics can be used to treat insecticide poisoning and exposure to nerve gas. + Understand the importance of "aging" as it relates to organophosphate poisoning and pralidoxime (2-PAM). 3. Adverse effects + Dry mouth (often seen at therapeutic doses with drugs used primarily for other properties) + Blurred vision + Others 4. Contraindications + Relative, not absolute

9. B. Ganglion Blocking Drugs
+ What is the selectivity of ganglion-blocking drugs for sympathetic vs. parasympathetic nervous systems?
+ For nicotinic vs. muscarinic receptors?
+ For autonomic ganglia vs. neuromuscular junction?
+ Even though ganglion blockers are very effective in lowering blood pressure in patients with malignant hypertension, why are they used rarely today?

10. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs
Drugs in this section mimic acetylcholine (cholinomimetic agents)
NBME

11. Cholinoceptor-Activating & Cholinesterase- Inhibiting Drugs
Drugs in this section mimic acetylcholine (cholinomimetic agents)
Agonists classified pharmacologically by receptor action
Muscarinic
Nicotinic
Further classified by their mechanism of action
Direct-acting cholinomimetic agents
Directly bind and activate muscarinic or nicotinic receptors
Indirect-acting agents inhibit acetylcholinesterase
Reduce hydrolysis of acetylcholine
Increase endogenous acetylcholine concentration in synaptic clefts
Excess acetylcholine stimulates cholinoceptors to evoke increased responses
Drugs act primarily where acetylcholine is physiologically released

12. Spectrum of Action of Cholinomimetic Drugs
Cholinoceptors are either:
G protein-linked (muscarinic)
Seven transmembrane domains
Third cytoplasmic loop is coupled to G proteins
Receptors are located
In CNS
In tissues targeted by PNS
In vascular endothelium (not innervated by PNS!)
Ion channel (nicotinic)
Five subunits form cation-selective ion channels
Located on:
All ANS ganglionic cells (“neuronal” type)
Adrenal gland (“neuronal” type)
Muscles innervated by somatic motor fibers (“NMJ” type)
Some CNS neurons (“neuronal” type)
An experimental animal was given a ganglionic stimulant .Which 2nd messenger system will be activated to release Epinephrine from adrenal medulla?
Ans: Lignand gated ion channel associated with Nn type of nicotinic receptor

13. C. Direct-Acting Cholinomimetics
1. Basic Pharmacology
+ How do choline esters differ from each other?
—How are they similar?
+ Which choline esters are potentiated by the presence of anticholinesterase agents?
+ What cellular events occur when cholinoceptors are activated?
+ What are the physiological responses produced by muscarinic and nicotinic agonists?
+What is EDRF?
2. Clinical Uses
+ GI and GU
+ Ophthalmology
3. Adverse Effects
+ salivation, sweating, colic, defecation, headache, loss of accommodation
4. Contraindications
+ peptic ulcer
+ asthma
+ coronary insufficiency
+hyperthyroidism

14. Basic Pharmacology of the Direct-Acting Cholinoceptor agonists
Classified as either:
Esters of choline (including acetylcholine)
Alkaloids (such as muscarine and nicotine)
Many have effects on both receptor types
Acetylcholine is both the prototypical drug agent and endogenous transmitter
Some drugs are selective for the muscarinic or nicotinic receptors
Choline esters
Quaternary ammonium group renders them relatively insoluble in lipids
Acetylcholine - acetic acid ester of choline
Methacholine - acetic acid ester of methylcholine
Carbachol and bethanechol are carbamic acid esters of the same alcohols
Choline esters are poorly absorbed and poorly distributed into CNS
Marked differences in susceptibility to hydrolysis by cholinesterases
Acetylcholine is very rapidly hydrolyzed
Methacholine is more resistant to hydrolysis
Carbachol and bethanechol are very resistant to hydrolysis
correspondingly longer durations of action
Methyl group (methacholine, bethanechol) reduces potency at nicotinic receptors
NBME
Do not cross BBB
NBME

15. Copyright ©2007 The McGraw-Hill Companies. All rights reserved
Copyright ©2007 The McGraw-Hill Companies.  All rights reserved. Privacy Notice. Any use is subject to the Terms of Use and Notice.  Additional Credits and Copyright Information.
Note: Large images and tables on this page may necessitate printing in landscape mode. Copyright ©2007 The McGraw-Hill Companies.  All rights reserved. Lange Pharmacology > Chapter 7. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs > Basic Pharmacology of the Direct-Acting Cholinoceptor Stimulants > Chemistry & Pharmacokinetics > Structure >
                             
Add to 'My Saved Images'    
Print   Close Window
From: McGraw Hill’s AccessMedicine; Katzung; Table 7-2
Note methyl group blocks nicotinic activity
Note carbamoyl group blocks hydrolysis

16. Tertiary natural cholinomimetic alkaloids
Pilocarpine
Nicotine
Lobeline is a plant derivative similar to nicotine in action
Muscarine - a quaternary amine
Source – Amantia muscaria Mushrooms
NBME
#Typical Vignette: Some body consumed wild mushroom and developed symptoms of excessive cholinergic manifestations .
Answer: imagine you are in ‘resting & digesting to figure out those .Remember you will not get CNS effects as these are quaternary amine.In contrast if the clinical condition says it’s a tertiary compound you will have CNS effects as well.

17. Pharmacodynamics / Mechanism of Action
All muscarinic receptors are GPCR
Agonist binding:
Activates the IP3, DAG cascade (Gq)
Increases potassium flux (Gi)
In some tissues inhibits adenylyl cyclase activity (Gi)
Nicotinic receptor activation
Results in electrical and ionic changes
Depolarization of the nerve cell or neuromuscular end plate membrane
Prolonged agonist occupancy
Abolishes the effector response
“Depolarizing blockade"
Can produce muscle paralysis

18. Cholinergic Organ System Effects
NBME
Muscarinic cholinoceptor effects are predicted from:
Effects of parasympathetic nerve stimulation
Distribution of muscarinic receptors
Nicotinic agonist effects are similarly predictable from:
Physiology of the autonomic ganglia and skeletal muscle motor end plate
Eye:
Muscarinic agonists produce:
Contraction of the iris sphincter (miosis)
Contraction of ciliary muscle (accommodation)
Facilitates aqueous humor outflow
Useful in both open & closed angle glaucoma

19. Cholinergic Organ System Effects (continued)
NBME
Cholinergic Organ System Effects (continued)
Cardiovascular System:
Muscarinic agonists:
Reduce peripheral vascular resistance
Direct effect is to slow heart rate
Intravenous infusions of ACh cause vasodilation and reduces blood pressure
Acetylcholine-induced vasodilation requires intact endothelium
Releases nitric oxide (EDRF)
NO relaxes smooth muscle
Note that muscarinic vasodilation evokes:
SNS reflex
Increase in heart rate
Larger ACh doses mask this reflex (direct bradycardia)
Cardiovascular effects of all choline esters are similar to ACh

20. Cholinergic Organ System Effects (continued)
NBME
Respiratory System
Contracts the smooth muscle of the bronchial tree
Glands of mucosa are stimulated to secrete
Often exacerbates symptoms of asthma.
Gastrointestinal Tract
Increases secretions (salivary, gastric, pancreatic, intestinal)
Increases peristaltic activity
Contraction of longitudinal muscle
Relaxation of sphincters
Genitourinary Tract
Contracts detrusor muscle
Relaxes trigone and sphincter muscles
Promotes voiding (remember – micturition is it’s own reflex)
Secretory Glands
Stimulation of secretion by thermoregulatory sweat glands

21. Cholinergic Organ System Effects (continued)
NBME
Nicotinic agonists:
Autonomic ganglia are major site of action
Simultaneous SNS and PNS discharge
Predominant tone predicts activation of ganglia
SNS – vasculature
PNS – most other tissues
Nicotine has a somewhat greater affinity for neuronal than for skeletal muscle nicotinic receptors
Effects on Neuromuscular Junction
Produces muscle fasciculations
Subsequent development of depolarization blockade (flaccid paralysis)
Succinylcholine >> the depolarizing neuromuscular blocker is a nicotinic agonist

22. Clinical uses of choline esteres and alkaloid22
Clinical uses of choline esteres and alkaloid
NBME
Choline Ester
Clinical uses
Acetylcholine chloride.
Short t1/2, no clinical use
Methacholine chloride
Dx-bronchial hyperreactivity
Carbachol chloride
Bethanechol chloride
Rx-ileus (postop/neurogenic), urinary retention
Choline Alkaloid
Clinical uses
Muscarine
no clinical use, toxological importance
Nicotine
Lobeline
Pilocarpine
Rx-glaucoma (topical), xerostomia
New Drugs
Cevimeline is a synthetic direct-acting muscarinic receptor agonist that is administered orally to treat dry mouth and is undergoing investigation for the treatment of dry eyes.
The drug is used to treat these conditions in patients who have had radiation therapy for head and neck cancer and in those with Sjögren's syndrome (dry eyes, dry mouth, and arthritis).
Varenicline is a partial agonist at the nicotinic receptor subtype found in the brain that mediates the reinforcing effects of nicotine in smokers.
The drug is used as an aid to smoking cessation and has been found to reduce both the craving and withdrawal effects caused by the absence of nicotine 22

23. Some Terminology (Jargon)
NBME
“Low” Dose Acetylcholine
Generally, only activates vascular muscarinic receptors (endothelium)
Evokes synthesis and release of NO
Produces vasodilation (decrease in BP)
Produces reflex tachycardia
Effects that are blocked by atropine (muscarinic antagonist).
In the presence of ganglionic blockade or other elimination of baroreceptor-mediated reflexes, a “low” dose ACh will now decrease both blood pressure and heart rate.
Remember: Only direct effects on heart are observed when reflex is blocked by ganglionic blockade!!
“High” Dose Acetylcholine plus atropine
Death occurs if muscarinic receptors are not blocked
Now, nicotinic receptors in both SNS & PSNS are activated but output from PSNS is blocked by atropine
Thus, only SNS effects are observed
See illustrations of this phenomena later in slide presentation

24. D. Indirect-acting Cholinomimetics
1. Basic Pharmacology + What are the major differences among the 3 groups of cholinesterase inhibitors? —How do these differences influence the pharmacokinetics of the drugs? —What is unique about parathion and malathion? + By what mechanisms can drugs inhibit acetylcholinesterase and/or butyrylcholinesterase? —Understand the importance of the mechanisms. + Understand differences between reversible and irreversible cholinesterase inhibitors. + What is "aging" as it relates to acetylcholinesterase inhibition? + Which organ systems are prominently affected by cholinesterase inhibitors? —What are the actions of acetylcholinesterase inhibitors on these systems? 2. Clinical Uses + GI and GU + Ophthalmology + Myasthenia gravis 3. Adverse Effects + Predictable based on excess acetylcholine and overstimulation of muscarinic and nicotinic receptors: miosis, salivation, sweating, bronchial constriction, vomiting and diarrhea, followed by peripheral nicotinic effects particularly manifest as neuromuscular blockade.

25. Indirect-Acting Cholinomimetics: Basic Pharmacology
NBME
ACh effects terminated by Acetylcholinesterase
Indirect-acting cholinomimetics inhibit this enzyme
Cholinesterase inhibitors fall into three chemical groups:
(1) Simple alcohols bearing a quaternary ammonium group (doesn’t enter CNS); compete for ACh at the enzyme
Edrophonium
(2) Carbamic acid esters of alcohols bearing quaternary (doesn’t enter CNS); or tertiary ammonium (enter CNS); groups (carbamates); carbamoylate the active site
Neostigmine – quaternary
Physostigmine – tertiary (crosses BBB)
Carbaryl – high lipid solubility (rapid CNS effects); insecticide
(3) Organic derivatives of phosphoric acid (organophosphates); phosporylate the active site
Echothiophate; used for glaucoma
Soman; nerve agent
Sarin; nerve agent
Malathion, parathion
Bioactivated to give active phosphorylating agent
used as insecticides.

26. Indirect-Acting Cholinomimetics: Basic Pharmacology (Structures)

27. Cholinesterase Inhibitors: Absorption, Distribution, and Metabolism
Absorption of quaternary carbamates is predictably poor
Permanent charge renders them relatively insoluble in lipids
The tertiary amine carbamates (physostigmine; carbaryl) are well absorbed
Distribute into the CNS (crossess BBB)
Duration of their effect is determined by stability of inhibitor-enzyme complex
Organophosphates (except for echothiophate)
Are well absorbed both topically and orally
Are distributed to all parts of the body, including the CNS

28. Cholinesterase Inhibitors: Pharmacodynamics
NBME
Acetylcholinesterase is primary target
Butyrylcholinesterase is also inhibited
Quaternary alcohols (edrophonium) reversibly bind to the active site
Inhibition is short-lived (on the order of 2–10 minutes)
Carbamate esters undergo a two-step hydrolysis
Covalent bond of the carbamoylated enzyme is slowly hydrolyzed
(reactivated)
Inhibition is longer (on the order of 30 minutes to 6 hours)
Organophosphates
Results in a phosphorylated AChE active site
Covalent phosphorus-enzyme bond is extremely stable
Inhibition lasts hundreds of hours
Lifetime of enzyme protein
“Aging” strengthens phosphorus-enzyme bond
Before aging, pralidoxime (2-PAM) can restore enzyme function
(Reactivation)

29. Cholinesterase Inhibitors: Organ System Effects
Most prominent effects are on:
Cardiovascular and gastrointestinal systems
Eye and skeletal muscle
Actions amplify the actions of endogenous acetylcholine
Effects are similar to direct-acting cholinomimetics
Little effect on vascular smooth muscle and on blood pressure
Remember PNS does not innervate peripheral vasculature!)
At NMJ:
Low (therapeutic) concentrations increase force of contraction
Higher doses produce depolarizing neuromuscular blockade
NBME

30. Cholinesterase Inhibitors: Clinical Uses
Eye
Glaucoma (closed & open angle)-(Physiostigmine,Ecothiophate)
Reduce intraocular pressure
Contraction of the ciliary body
Facilitates outflow of aqueous humor
Gastrointestinal and Urinary Tracts (Neostigmine,pyridostigmine)
Clinical disorders related to inactivity of smooth muscle activity
Postoperative ileus
Congenital megacolon
Urinary retention
Neurogenic bladder
Reflux esophagitis
Insufficient salivary secretion
Reversal of Non-depolarizing Neuromuscilar blockers (Neostigmine ,pyridostigmine)
NBME
NBME
NBME

31. Cholinesterase Inhibitors: Clinical Uses (cont’d)
Neuromuscular Junction (Dx-Edrophonium ); T/t: Neostigmine, pyridostigmine)
Myasthenia gravis
Autoimmune disease affecting NMJ
Cholinesterase inhibitors are valuable therapy
Edrophonium (Tensilon test) – i.diagnostic test for MG (improvement in muscle strength after inj.) ii.differential diagnosis bet. MG & Cholinergic crisis.
NBME
Q. Pt.with MG. on Neostigmine therapy for couple of years presently complaints progressive muscle weakness.What will you do as a physician?
Answer:Tensilon (Edrophonium) test 1.if symptoms worsen (more weakness of muscles) –patient is having too much Neostigmine in the system (Cholinergic crisis)----reduce Neostigmine dose 2.If symptoms improves—too little neostigmine in the system---increase the dose of Neostigmine.

32. Cholinesterase Inhibitors: Clinical Uses (cont’d)
Atropine intoxication (physostigmine)
Reversal of competitive blockade by cholinomimetics
Physostigmine has tertiary structure so reverses both CNS and peripheral effects
Central Nervous System (Tacrine & donepezil )
Alzheimer’s disease
Tacrine & donepezil have anticholinesterase and cholinomimetic actions
Used in therapy for mild to moderate Alzheimer's disease
NBME
Q.A child ate some berries from bush & developed all anticholinergic sysmptoms.How will you treat him?\
Answer:Tertiary CHEI compounds as they counteract both central & peripheral symptoms
Q.A geriatric patient with signs & symptoms suggesting Alzheimer’s disease should be treated with which drug? (terciary) /or mech.of benefit (potentiating Ach in the brain will reduce symptoms including memory loss )/or what are the potential adverse effects (figure out excessive cholinergic manifestations by putting yourself in ‘resting & digesting ‘state)
NBME

33. Cholinesterase Inhibitors: Acute Toxicity
NBME
“SLUDGE” DUMBBELSS
Salivation  Diarrhea
Lacrimation  Urination
Urinary incontinence  Miosis
Diarrhea  Bronchoconstriction
Gastrointestinal cramps  Bradycardia
Emesis  Excitation; Emesis
 Lacrimation
 Salivation
 Sweating
Can be reversed by atropine (muscarinic antagonist)
Cholinesterase inhibitor poisoning also treated by:
Maintenance of vital signs (respiration)
Decontamination to prevent further absorption
Atropine parenterally in large doses
Therapy may also include treatment with pralidoxime to “rescue” un-aged inhibited enzyme; but pralidoxime contraindicated for carbamate intoxication
Q.What are the manifestations of CHEI poisioning?
Answer:Same as Directly acting drugs (figure out by putting yourself in rest & digest mode)EXCEPT Vascular effects (as cholinergic receptors on blood vessels are not innervated)
Q.Typical Vignette:A farmer or gardener or somebody who works in pesticide or organophosphorus or insecticide of warfare industies got acutely or chronically exposed to any of those CHEI agents and developed symptoms mimicing excessive cholinergic activities.What is the life saving drug (Atropine),which one works specifically in organophosphorus poisioning but contraindicated in carbamate poisioning (Pralidoxime)?

34. Irreversibly acting Cholinomimetics
NBME
Irreversibly acting Cholinomimetics
These compounds phosphrylate the esteric site of AchE,at serine hydroxyl groups.
1.Phosphorylation-reversible by pralidoxime (2PAM)
2.Removal of part of organophosphate molecule (aging). Complex no longer reversible by 2PAM.
R-leaving group
P-organophosphate

35. Nicotinic Toxicity: Usually produced by nicotine
Fatal dose is approximately 40 mg
Amount in two regular cigarettes
Most is destroyed by burning
Ingestion is usually followed by vomiting
Limits absorbed dose
Readily absorbed from the skin
Toxic effects include:
CNS stimulation – convulsions, coma, respiratory arrest
Skeletal muscle end plate depolarization - respiratory paralysis
Hypertension and cardiac arrhythmias
Treatment is symptom-directed (Muscarinic antagonists and mechanical respiration)
Most significant toxicity is due to chronic use (smoking)
NBME
NBME

36. Cholinergic agents: Direct muscarinic agonists:
Choline esters:
Acetylcholine
Bethanechol
Carbachol
Alkaloids:
Muscarine
Pilocarpine
Direct nicotinic agonists:
Nicotine
Lobeline

37. Cholinesterase Inhibitors Indirect Parasympathomimetics
Reversible inhibitors:
Simple Alcohol ester:
Edrophonium
Alzheimer drugs:
Donepezil
Tacrine
Rivastigmine
Carbamates: (pseudo-reversible):
Neostigmine
Physostigmine
Pyridostigmine
Ambenonium
Demecarium
Carbaryl
Irreversible inhibitors:
Organophosphates:
Echothiophate
Soman
Sarin
Parathion
Malathion
Isoflurophate

38. Parasympathomimetics Resting Vegetative Eye GI GU
SLUDGE
DUMBBELSS
Physostigmine crosses BBB

39. The administration of pralidoxime would be most useful in treating a 29-year-old man 2 hours after an excessive exposure to which to the following cholinergic poisons?
Carbaryl
Donepezil
Parathion
Pilocarpine
Sarin
Answer: C
Only for organophosphates;
Sarin ages to rapidly

40. III. Cholinoceptor-Blocking Drugs
A. Muscarinic Receptor Antagonists 1. Basic Pharmacology + What is the original source of the prototypic antimuscarinic drugs? + What is the importance of their structures (tertiary vs. quaternary amines) as related to absorption and distribution? + What are the effects of antimuscarinic drugs on various organ systems? + Do all drugs affect each system similarly or is there some degree of organ selectivity? 2. Clinical Pharmacology + Gastric or intestinal hypersensitivity or secretion + Excessive salivation + To produce mydriasis and cycloplegia + Adjunct prior to general anesthesia + Asthma + Understand how antimuscarinics can be used to treat insecticide poisoning and exposure to nerve gas. + Understand the importance of "aging" as it relates to organophosphate poisoning and pralidoxime (2-PAM). 3. Adverse effects + Dry mouth (often seen at therapeutic doses with drugs used primarily for other properties) + Blurred vision + Others 4. Contraindications + Relative, not absolute

41. Cholinoceptor-Blocking Drugs
Divided into muscarinic and nicotinic subgroups
Muscarinic antagonists
Nicotinic antagonists:
Ganglion-blockers
Neuromuscular junction blockers (paralytics)
Not discussed in this block
Antimuscarinic drugs:
Tertiary compounds used for their effects in eye or CNS
Quaternary amines selectively produce peripheral effects
Prototypic drug is Atropine
Causes reversible (competitive) blockade
Not selective between M1, M2, and M3 subtypes
NBME

42. Cholinoceptor-Blocking Drugs: Organ System Effects
Central Nervous System
Minimal stimulant effects on CNS
Toxic doses can cause agitation, hallucinations, and coma
Often used with dopamine precursor in Parkinson’s disease
Eye
Muscarinic cholinoceptor activation constricts pupil
Blockade by topical atropine results in mydriasis
Belladonna ("beautiful lady")
Paralysis of the ciliary muscle, or cycloplegia (ophthalmic exam)
Cause acute glaucoma in patients with narrow anterior chamber angle
Cardiovascular System
SA node under PNS tone - sensitive to muscarinic blockade
Atropine produces tachycardia
Few hemodynamic effects
Antimuscarinics can cause cutaneous vasodilation
Mechanism is unknown (atropine flush)

43. Cholinoceptor-Blocking Drugs: Organ System Effects (cont’d)
Respiratory System
Bronchodilation and reduction of secretion
Antimuscarinic drugs are not as useful as beta-adrenoceptor stimulants in the treatment of asthma
Gastrointestinal Tract
Reduces motility and secretion in GI tract
Can be useful as preoperative adjuvant before abdominal surgery
Genitourinary Tract
Can produce urinary retention, especially with BPH
Oxybutynin and tolterodine are used to treat overactive bladder
Sweat Glands
Suppresses thermoregulatory sweating (Sympathetic!)
Body temperature can be elevated ("atropine fever")

44. Figure out Receptor subtypes for each indication
Cholinoceptor-Blocking Drugs (anti muscarinics): Therapeutic Applications
Figure out Receptor subtypes for each indication
Parkinson's Disease (benztropine, trihexphenidyl)
Motion Sickness (scopolamine)
Preoperative medication – prevents laryngospasm (glycopyrrolate); some are also amnestic (scopalamine)
Relieves bronchodilation – asthma and COPD (ipratropium, tiotropium)
Relief of vagal syncope
Traveler's diarrhea, mild GI hypermotility
Combined with an opioid antidiarrheal (abuse deterrent)
NBME
Patch behind the ear
NBME
NBME
Scopolamine is available in patch form to be placed behind the ear prior to travel.
1.Anticholinergics are useful in the treatment of both idiopathic & drug induced parkinsonism
2.VIII Nerve contains Ach.A/E with scopalamine is sedation & anterograde amnesia
3.Ipratropium doesnot dry up secretion But reduce volume of secretion in pts with COPD

45. Cholinoceptor-Blocking Drugs: Therapeutic Applications
Urinary urgency, frequency, incontinence (Oxybutynin;
Tolterodine – M3 selective)
Reversal of cholinergic poisoning
Requires a tertiary (not quaternary) drug
Large doses of atropine may be needed
Drug may have to be repeated
Ophthalmology (homatropine, cyclopentolate, tropcainamide, scoplolamine, atropine)
Retinal examination
Prevention of synechiae after surgery
Hyperhidrosis
Relief is incomplete at best
Understand ecccrine (cholinergic) vs. apocrine (adrenergic) glands
NBME
Oxybutynin available as a patch
NBME
Q. Typical vignette of Urinary incontinence would be somebody with cerebrovascular accidents or head trauma or spinal cord injury or lesion or upper motor neuron lesion .
NBME

46. Use of Atropine to Stimulate the Heart
For the treatment of sinus bradycardia as with a vasovagal response
For use in cardiopulmonary resuscitation (CPR) in accordance with the ACLS algorithm for cardiac arrest associated with ventricular asystole or slow pulseless electrical activity
For pre-operative use to decrease secretions (i.e., aspiration prophylaxis) and block cardiovagal reflexes and/or succinylcholine-induced arrhythmias during surgery

47. Non-anticholinergic drugs with Anticholinergic properties
-H1 antihistaminics -TCAs -Antipsychotics -Quinidine -Amantidine -Meperidine -many others

48. Cholinoceptor-Blocking Drugs: Adverse Effects
Atropine poisoning
Dry mouth, mydriasis, tachycardia, flushed skin, delirium
“Dry as a bone, blind as a bat, red as a beet, mad as a hatter."
Can be treated with physostigmine or symptom management
Contraindications are relative:
Glaucoma (especially narrow angle-closure glaucoma)
Prostatic hyperplasia
May increase gastric ulcer symptoms
NBME

49. Dose dependent effect of Atropine49
Dose dependent effect of Atropine

50. B. Ganglion Blocking Drugs
+ What is the selectivity of ganglion-blocking drugs for sympathetic vs. parasympathetic nervous systems?
+ For nicotinic vs. muscarinic receptors?
+ For autonomic ganglia vs. neuromuscular junction?
+ Even though ganglion blockers are very effective in lowering blood pressure in patients with malignant hypertension, why are they used rarely today?

51. Nicotinic Cholinoceptor-Blocking Drugs: Adverse Effects
Block actions of ACh and other agonists at nicotinic receptors
Receptors located on both PNS and SNS autonomic ganglia
Non-selectivity produces array of adverse effects
All are synthetic amines
First was tetraethylammonium (TEA) – short duration of action

52. Ganglion-Blocking Drugs: Organ system effects
NBME
Effects depend on predominant ANS tone at specific end-organ
Quaternary amines, like trimethaphan or hexamethonium
Lack central effects
Mecamylamine readily enters CNS
Sedation, tremor, choreiform movements, mental aberrations
Eye
Ciliary muscle (mostly PNS tone) – cycloplegia
Pupil (both PNS and SNS, but PNS dominates slightly)
Moderate dilation of the pupil
Cardiovascular System
Blood vessels (SNS tone)
Decrease in arteriolar and venomotor tone
Reduced blood pressure
Orthostatic hypotension
Moderate tachycardia (removal of PNS tone at SA node)
GB are often used in tracings of ANS

53. Ganglion-Blocking Drugs: Organ system effects: (cont’d)
Gastrointestinal Tract
Tone is PNS – reduced secretion and motility
Can produce constipation
Genitourinary system
Hesitancy or urinary retention (esp. with prostatic hyperplasia)
Sexual function is impaired (requires both SNS and PNS)
Blocks thermoregulatory sweating
Responses to Autonomic Drugs are altered!!
Effector cell receptors are not blocked
End-organ effects are present
Homeostatic reflexes are absent!
Can dramatically alter responsiveness to drugs
Example – NE and heart rate
How to predict a/es associated with ganglionic blocker on various organs?
Answer:A/E of gang.blockers on particular organ would be opposite to predominant physiological tone on that organ.
Q.What are the predominat physiological tone on various organs supplied by both SNS & PNS?
Answer:All organs receives autonomic supply by both divisions have predominant physiological tone as parasympathetic except Blood vessel which is sympathetic.

54. Algorithm: Reflex control of Heart Rate

55. Anticholinergic Agents Muscarinic antagonists Tertiary amines Atropine
Scopolamine
Homatropine
Oxybutynin
Pirenzepine (M1 selective)
Tropicamide
Tolterodine (M3 - bladder)
Quaternary amines
Atropine methyl nitrate
Methscopolamine
Ipratropium
Tiotropium
Propantheline
Glycopyrrolate
Ganglionic blocking drugs
Hexamethonium
Trimethaphan (lacks CNS effects)
Mecamylamine
Cholinesterase regenerator
Pralidoxime (2-PAM)
Anticholinergic
Agents

56. Parasympatholytics Eye GI GU Dry mouth Urinary retention constipation
Histamine release
Dry as a bone
Red as a beat
Hot as a hare
Mad as a hatter
Tachycardia

57. Botulinum toxin Hemicholinium Scopolamine Tetrodotoxin Vesamicol
Which of the following medications blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, entering nerve terminals, and inhibiting the release of acetylcholine and would be appropriate for the treatment of cervical dystonia in a 46-year-old woman?
Botulinum toxin
Hemicholinium
Scopolamine
Tetrodotoxin
Vesamicol
Answer: A

58. LEARNING OBJECTIVES

59. Neuromuscular Blocking Agents
NBME
Competitive – nicotinic antagonists
d-TUBOCURARINE
potency altered by pH
causes large increase in
histamine release
ATRACURIUM
CISATRACURIUM
MIVACURIUM
PANCURONIUM
ROCURONIUM
Depolarizing –
nicotinic agonists
SUCCINYLCHOLINE
short duration of action (<8 min)

60. Effects of Neuromuscular Blocking Agents
NBME
Effects of Neuromuscular Blocking Agents
Competitive
Depolarizing
Action at receptor
Antagonist
Agonist
Effect on motor end plate depolarization
None
Partial persistent depolarization
Initial effect on striated muscle
Fasciculation
Muscles affected first
Small muscles
Skeletal muscle
Muscles affected last
Respiratory muscles
Effect of inhaled anesthetics
Increase potency
No or little effect
Effect of antibiotics

61. Neuromuscular Blocking Agents: Adverse Effects
NBME
Many paralytics cause histamine release leading to hypotension and bronchospasm
Most pronounced with d-Tubocurarine.

62. Neuromuscular Blocking Agents: Drug Interactions
Numerous – alter potency of paralytics
Opioids
Local anesthetics - increases potency of both competitive and depolarizing agents
Anticonvulsants
Cardiovascular drugs
Antibiotics, esp. aminoglycosides
Inhalable anesthetics

63. Skeletal Muscle Relaxants
Curare was used by natives of the Amazon basin of South America as arrow poison that produced death by skeletal muscle paralysis.

64. Parasympatholytics Eye GI GU Dry mouth Urinary retention constipation
Histamine release
Dry as a bone
Red as a beat
Hot as a hare
Mad as a hatter
Tachycardia

65. Which of the following medications blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, entering nerve terminals, and inhibiting the release of acetylcholine and would be appropriate for the treatment of cervical dystonia in a 46-year-old woman?
Botulinum toxin
Hemicholinium
Scopolamine
Tetrodotoxin
Vesamicol
Answer: A

66. PowerPoint Slides
Several of the PowerPoint slides are Copyright © , the  American Society for Pharmacology and Experimental Therapeutics (ASPET). All rights reserved.
Some of slides in this session are from the above mentioned format and are free for use by members of ASPET. 
Some others are from various sources like text book, recommended books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA), Dr. S. Kacker (co-professor , Clinical Pharmacology & Therapeutics, MUA)
Core concepts of various USMLE High yield review series like Kaplan ,BRS etc. are thoroughly explored & integrated whenever necessary