Anticholinergics

Question 1

What kind of drug are anticholinergics?

Answer 1

competitive antagonists
-competitive and reversible

Question 2

ACh neurotransmission: M antagonists

Answer 2

ACh binds to cholinoceptors on the postsynaptic cell
-M receptor antagonists (antimuscarinics)
-agents are competitive antagonists for M receptors (M1, M2, M3): smooth muscle, cardiac muscle, exocrine glands

atropine: oldest and most well known antimuscarinic agent that’s an antagonist at M1, M2, and M3

Question 3

atropine

Answer 3

general considerations: muscarinic receptor blockade
-competitive antagonism at the M receptor (M1, M2, M3)-mediated actions of ACh on autonomic effectors innervated by postganglionic cholinergic nerves, as well as smooth muscles

ganglia: little effect on ACh binding to nicotinic receptor

CNS: widespread distribution of muscarinic receptors throughout brain
-therapeutic doses are attributable to central muscarinic blockade
-atropine can produce partial block (M1) only at relatively high doses

Question 4

effects of atropine

Answer 4

low to high dose: exocrine glands, eye, CVS, respiratory tract, urinary bladder, GI smooth muscle, CNS

Question 5

antimuscarinics: general chemical properties

Answer 5

mechanism: competitive and reversible inhibition of M receptor activation by preventing the binding of ACh

Question 6

classes of antimuscarinics

Answer 6

tertiary amines: mainly used in ocular and CNS applications
-no charge: can cross BBB
-ex. atropine
quaternary amines: mainly used in GI tract and peripheral applications
-positive charge: can’t cross BBB
-ex. anisotropine

Question 7

muscarinic antagonists: tertiary amine examples

Answer 7

belladonna alkaloids (long lasting)
-atropine
-scopolamine
tertiary amine derivatives (short acting)
-homatropine
-tropicamide
tertiary amine derivatives (antiparkinson use)
-benztropine
-trihexyphenidyl

Question 8

muscarinic antagonists: quaternary amine examples

Answer 8

derivatives of belladonna alkaloids
-ipratropium
-tiptropium

Question 9

long lasting tertiary amines

Answer 9

atropine and scopolamine
-M1/M2/M3 nonselective
-treat GI/urinary conditions, motion sickness
-tertiary compounds can affect CNS
–scopolamine has higher penetration, induces greater drowsiness (low doses) or hallucinations (high doses)
-naturally occuring
–belladonna from Italy, used to dilate eyes
–deadly nightshade
–historically used as hallucinogen: confusion, dilated pupils, tachycardia

Question 10

scopolamine

Answer 10

action: antimuscarinic with relatively more CNS action than atropine (highly lipophilic)
-has an extra O on it
clinical use: effective Tx of motion sickness (oral, transdermal administration)
SE: dry mouth, blurred vision, sedation
-high doses: confusion, psychosis

Question 11

short acting tertiary amines

Answer 11

homatropine, tropicamide
-used in optical applications due to short duration of action
-cycloplegia and mydriasis
homatropine is less toxic, tropicamide has shorter duration of action

Question 12

tertiary amines for Parkinson’s Disease

Answer 12

benztropine
-sedative activity
-used as adjunct therapy with L-DOPA in PD patients (achieve better balance between dopaminergic and cholinergic neurotransmission)
-similar potency to atropine (less SE)

Question 13

quaternary amines for COPD

Answer 13

ipratropium
-action: antimuscarinic with receptor activity similar to atropine, M3 antagonist blocks ACh-mediated constriction and open the airways
-clinical use: Tx of COPD, occasionally asthma
–less effective as monotherapy but enhances therapeutic effect of b-adrenergic agonists in COPD
–combivent or duoneb: combination of ipratropium and albuterol in treating COPD
-problems: few because of poor absorption, toxic doses can cause hypotension (ganglionic blockade), muscle weakness (neuromuscular blockade)

triotropium: longer acting analog

Question 14

quaternary amines for GI disorders

Answer 14

glycopyrrolate, propantheline bromide
-used to treat gastric disorders (GI spasms, peptic ulcers)
-glycopyrrolate: pre-op to reduce secretions, charged N makes crossing the gut difficult = fewer SE
-propantheline bromide isn’t available in the US

Question 15

antimuscarinics for overactive bladder

Answer 15

tolterodine
-action: no apparent selectivity for different M receptor subtypes, therapeutically seems to act somewhat selectively on M3
-clinical use: OAB
-problems: still causes typical anticholinergic effects, but significantly lower than with previous antimuscarinic drugs

newer M3-selective muscarinic antagonists to treat OAB
-solifenacin, darifenacin, oxybutynin
-proposed advantages: lower incidence of constipation and confusion

b3 receptor agonist: mirabegron

Question 16

antimuscarinic poisoning

Answer 16

over 600 meds prescribed and OTC have drugs with antimuscarinic properties
-H1 receptor antagonists (diphenhydramine)
-older antipsychotics (chlorpromazine)
-tricyclic antidepressants (amitriptyline)
often see antimuscarinic effects at therapeutic dose (ex. dry mouth)
Tx: change med/decrease dose, supportive care (sodium bicarb for prolonged QRS or arrhythmias, benzodiazepines for agitation/delirium), physostigmine (acetylcholinesterase inhibitor)
identify potentially inappropriate meds for elderly
-est. 30-60% of nursing home residents receive meds with signigicant antimuscarinic effects
-Beers Criteria
-STOPP (screening tool of older persons’ potentially inappropriate prescriptions)

Question 17

nicotinic receptor antagonists

Answer 17

Na+ channel receptor

Question 18

effects of nicotine on muscle: stimulation

Answer 18

normal operation of nicotinic receptors is the rapid degradation of synaptically released ACh
-allows neuronal membrane/muscle endplate to repolarize and fast Na+ channels (responsible AP) to reset
-next ACh release causes another depolarization that triggers opening of rested Na+ channels and AP
–use AChE to block

Question 19

effects of nicotine on muscle: desensitization

Answer 19

nicotinic receptors are specifically adapted to transient nature of ACh as a neurotransmitter
-agonist remains bound to receptor: persistent depolarization means fast Na+ channels can’t reset to active state

Question 20

blocking the nicotinic receptor

Answer 20

non-depolarizing blockade (normal antagonist): tubocurarine
depolarizing blockade (first activates then blocks): succinylcholine
neuromuscular blocking agents look like ACh

Question 21

tubocurarine

Answer 21

action: nicotinic receptor competitive antagonist producing non-depolarizing blockade
clinical use: skeletal muscle relaxation during anesthesia, particularly useful for intubation
problems: minor

Question 22

succinylcholine

Answer 22

mechanism of action: binds to nicotinic ACh receptor
-agonist nicotinic receptor, initial depolarization
-persistent depolarization makes muscle fiber resistant to further stimulation by ACh (prevents resetting of voltage-gated Na+ channels)
-metabolized to choline by plasma butyrylcholinesterase
–slower than AChE, choline increases BP, muscle fasciculation precedes paralysis, arm, neck, leg then respiratory muscles, rapid onset, short duration

clinical use: skeletal muscle relaxation during anesthesia, particularly useful for intubation, electro-convulsant therapy

problems: muscle soreness (avoid in hyperkalemia, cause of cardiac arrest), malignant hyperthermia, prolonged paralysis can result in people with atypical plasma cholinesterases

Question 23

hexamethonium

Answer 23

action: antagonist at nicotinic receptors in autonomic ganglia thus blocking all SNS and PSNS activity
use: originally for hypertension, not used clinically due to adverse effects
problems
-blood vessels (SNS): hypotension
-sweat glands (SNS): decreased perspiration
-other glands (PSNS): dry mouth, decreased secretions
-heart rate (PSNS): tachycardia (if SNS is active you’ll see bradycardia)
-eye (PSNS): pupillary dilation, blurred vision
-gut (PSNS): decreased tone and motility, constipation
-bladder (PSNS): urinary retention

Question 24

inhibition of ACh release: botulinum toxin

Answer 24

action: inhibit release of ACh
clinical use: dystonias (uncontrolled muscle spasms), cerebral palsy, spasm of ocular muscles, anal fissure, hyperhidrosis (excessive sweating)
problems: spread form injection site