Transcript ppt - Drive

Reading assignments:
Katzung’s Basic & Clinical Pharmacology,
13th Edi ,Ch-7 ,p105-132 ;
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?
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
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.
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
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?
Cholinoceptor-Activating & CholinesteraseInhibiting Drugs
Drugs in this section mimic acetylcholine (cholinomimetic agents)
NBME
Cholinoceptor-Activating & CholinesteraseInhibiting 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
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)
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
Basic Pharmacology of the Direct-Acting
Cholinoceptor agonists
 Classified as either:
• Esters of choline (including acetylcholine)
• Alkaloids (such as muscarine and nicotine)
NBME
 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 Do not cross BBB
NBME
• 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
From: McGraw Hill’s AccessMedicine; Katzung; Table 7-2
Note methyl group blocks nicotinic activity
Note carbamoyl group blocks hydrolysis
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
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
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
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
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
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
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Clinical uses of choline esteres and alkaloid
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
NBME
Clinical uses
Muscarine
no clinical use,
toxological
importance
Nicotine
no clinical use,
toxological
importance
Lobeline
no clinical use,
toxological
importance
Pilocarpine
Rx-glaucoma
(topical),
xerostomia
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
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.
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.
Indirect-Acting Cholinomimetics:
Basic Pharmacology (Structures)
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 inhibitorenzyme complex
 Organophosphates (except for echothiophate)
• Are well absorbed both topically and orally
• Are distributed to all parts of the body, including the CNS
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)
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!)
NBME
• At NMJ:
• Low (therapeutic) concentrations increase force of contraction
• Higher doses produce depolarizing neuromuscular blockade
Cholinesterase Inhibitors: Clinical Uses
 Eye
• Glaucoma (closed & open angle)-(Physiostigmine,Ecothiophate)
• Reduce intraocular pressure
• Contraction of the ciliary body
NBME
• 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
NBME
• Insufficient salivary secretion
 Reversal of Non-depolarizing Neuromuscilar blockers (Neostigmine
,pyridostigmine)
NBME
Cholinesterase Inhibitors: Clinical Uses
(cont’d)
 Neuromuscular Junction (Dx-Edrophonium ); T/t: Neostigmine,
pyridostigmine)
• Myasthenia gravis
• Autoimmune disease affecting NMJ
NBME
• 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.
Cholinesterase Inhibitors: Clinical Uses
(cont’d)
 Atropine intoxication (physostigmine)
• Reversal of competitive blockade by cholinomimetics
NBME
• 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
Cholinesterase Inhibitors: Acute Toxicity
“SLUDGE”
• Salivation
• Lacrimation
• Urinary incontinence
• Diarrhea
• Gastrointestinal cramps
• Emesis
DUMBBELSS
 Diarrhea
 Urination
 Miosis
 Bronchoconstriction
 Bradycardia
 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
NBME
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
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:
NBME
• 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
Cholinergic agents:
Direct muscarinic agonists:
Choline esters:
Acetylcholine
Bethanechol
Carbachol
Alkaloids:
Muscarine
Pilocarpine
Direct nicotinic agonists:
Nicotine
Lobeline
Cholinesterase Inhibitors
Indirect Parasympathomimetics
Reversible inhibitors:
Simple Alcohol ester:
Edrophonium
Alzheimer drugs:
Donepezil
Tacrine
Rivastigmine
Carbamates: (pseudo-reversible):
Neostigmine
Physostigmine
Pyridostigmine
Rivastigmine
Ambenonium
Demecarium
Carbaryl
Irreversible inhibitors:
Organophosphates:
Echothiophate
Soman
Sarin
Parathion
Malathion
Isoflurophate
Parasympathomimetics
Resting
Vegetative
Cholinoceptor Agonists
Eye
GI
Direct acting
GU
Indirect acting
(cholinesterase inhibitors)
Muscarinic
Nicotinic
Choline esters
Alkaloids
Ganglionic
Neuromuscular
Acetylcholine
Bethanechol
Carbachol
Methacholine
Muscarine
Pilocarpine
ACh
Nicotine
ACh
Nicotine
Succinylcholine
Physostigmine crosses BBB
Reversible
Irreversible
Neostigmine
Physostigmine
Edrophonium
Pyridostigmine
Tacrine
Donepezil
Sarin
Parathion
Malathion
Echothiophate
SLUDGE
DUMBBELSS
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?
A. Carbaryl
B. Donepezil
C. Parathion
D. Pilocarpine
E. Sarin
Answer: C
Only for organophosphates;
Sarin ages to rapidly
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
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
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)
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")
Cholinoceptor-Blocking Drugs (anti
muscarinics): Therapeutic Applications
Figure out Receptor subtypes for each indication
 Parkinson's Disease (benztropine, trihexphenidyl)
 Motion Sickness (scopolamine)
Patch behind the ear
NBME
NBME
 Preoperative medication – prevents laryngospasm
(glycopyrrolate); some are also amnestic (scopalamine)
 Relieves bronchodilation – asthma and COPD (ipratropium,
tiotropium)
NBME
 Relief of vagal syncope
 Traveler's diarrhea, mild GI hypermotility
• Combined with an opioid antidiarrheal (abuse deterrent)
Cholinoceptor-Blocking Drugs:
Therapeutic Applications
 Urinary urgency, frequency, incontinence (Oxybutynin;
Tolterodine – M3 selective)
NBME
Oxybutynin available as a patch
 Reversal of cholinergic poisoning
• Requires a tertiary (not quaternary) drug
• Large doses of atropine may be needed
• Drug may have to be repeated
NBME
 Ophthalmology (homatropine, cyclopentolate, tropcainamide,
scoplolamine, atropine)
NBME
• Retinal examination
• Prevention of synechiae after surgery
 Hyperhidrosis
• Relief is incomplete at best
• Understand ecccrine (cholinergic) vs. apocrine (adrenergic) glands
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 succinylcholineinduced arrhythmias during surgery
Non-anticholinergic drugs
with Anticholinergic properties
-H1 antihistaminics
-TCAs
-Antipsychotics
-Quinidine
-Amantidine
-Meperidine
-many others
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
Dose dependent effect of
Atropine
49
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?
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
Ganglion-Blocking Drugs:
Organ system effects
 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)
NBME
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
Algorithm: Reflex control of Heart Rate
Muscarinic antagonists
Tertiary amines
Atropine
Scopolamine
Homatropine
Oxybutynin
Pirenzepine (M1 selective)
Anticholinergic
Tropicamide
Agents
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)
Parasympatholytics
Eye
GI
GU
Dry mouth
Urinary retention
constipation
Cholinoceptor antagonists
ACh release inhibitors
Postsynaptic inhibitors
Botulinus toxin
Muscarinic
Antagonists
Atropine
Scopolamine
Ipratropium
Glycopyrrolate
Pirenzepine (M1 selective)
Oxybutynin
Tolterodine (M3)
Nicotinic
antagonists
Ganglionic
Hexamethonium
Mecamylamine
Trimethaphan
Used for eye exams
Homatropine
Cyclopentolate
Tropocainamide
Neuromuscular
(Muscle relaxants)
Nondepolarizing
Atracurium
Pancuronium
Tubocurarine
Vecuronium
Depolarizing
Succinylcholine
Dry as a bone
Red as a beat
Hot as a hare
Mad as a hatter
Tachycardia
Histamine release
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?
A. Botulinum toxin
B. Hemicholinium
C. Scopolamine
D. Tetrodotoxin
E. Vesamicol
Answer: A
LEARNING OBJECTIVES
Neuromuscular Blocking Agents
 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)
NBME
Effects of Neuromuscular Blocking
Agents
NBME
Competitive
Depolarizing
Antagonist
Agonist
Effect on motor end
plate depolarization
None
Partial persistent
depolarization
Initial effect on
striated muscle
None
Fasciculation
Small muscles
Skeletal muscle
Respiratory muscles
Respiratory muscles
Effect of inhaled
anesthetics
Increase potency
No or little effect
Effect of antibiotics
Increase potency
No or little effect
Action at receptor
Muscles affected
first
Muscles affected last
Neuromuscular Blocking Agents:
Adverse Effects
NBME
 Many paralytics cause histamine release leading
to hypotension and bronchospasm
 Most pronounced with d-Tubocurarine.
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
Parasympatholytics
Eye
GI
GU
Dry mouth
Urinary retention
constipation
Cholinoceptor antagonists
ACh release inhibitors
Postsynaptic inhibitors
Botulinus toxin
Muscarinic
Antagonists
Atropine
Scopolamine
Ipratropium
Glycopyrrolate
Pirenzepine (M1 selective)
Oxybutynin
Tolterodine (M3)
Nicotinic
antagonists
Ganglionic
Hexamethonium
Mecamylamine
Trimethaphan
Used for eye exams
Homatropine
Cyclopentolate
Tropocainamide
Neuromuscular
(Muscle relaxants)
Nondepolarizing
Atracurium
Pancuronium
Tubocurarine
Vecuronium
Depolarizing
Succinylcholine
Dry as a bone
Red as a beat
Hot as a hare
Mad as a hatter
Tachycardia
Histamine release
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?
A. Botulinum toxin
B. Hemicholinium
C. Scopolamine
D. Tetrodotoxin
E. Vesamicol
Answer: A
PowerPoint Slides
 Several of the PowerPoint slides are Copyright © 2002-04,
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