Transcript Cholinoceptor blocking drugs

Clinical importance of anticholinesterases
 Ophthalmologic
applications
 Diagnosis and treatment of myasthenia
gravis
 Treatment of atropine and curare type
poisoning
 Some chemicals (from agricultural or
military sources) are themselves
significant sources of poisoning.
Physostigmine (Eserine, Antilirium)
 Non-quaternary,
well absorbed and
distributed to CNS and other tissues.
 Pharmacological effects result from the
increase in concentration of acetylcholine
at muscarinic and nicotinic sites following
inhibition of cholinesterases.
Physostigmine
CNS:
 eye:
 bronchioles:
 glands:

GIT:
 bladder:
 CV:


NMJ:
restlessness, convulsions
miosis, accommodation
constriction, increased secretions
increased lacrimation, salivation,
sweating
increased tone and motility
increased tone,
effect variable, low doses decrease
HR; higher could increase HR and BP.
fasciculations and tremor; paralysis
Physostigmine
Clinical uses reserved for reversal of serious
atropine or scopolamine type poisoning where
CNS is involved.
 Not routinely used for overdose of drugs with
anticholinergic side effects (e.g., may
exacerbate arrhythmia in tricyclic
antidepressant overdose)
 Toxicity is predictable based upon ANS effects.
CNS stimulation and coma often result.

Edrophonium (Tensilon, Reversol)

Brief duration of action, rapid onset

Uses
–
–
–
–

Diagnostic aid for myasthenia gravis (not primary
diagnostic, but useful for distinguishing MG from other
neurological disorders)
Differentiation of myasthenia crisis from cholinergic crisis
during therapy for MG
Antidote for non-depolarizing neuromuscular blockers
Treatment for paroxysmal atrial tachycardia (PAT)
Toxicities limited because of brief action
Irreversible Cholinesterase Inhibitors

Highly lipid soluble (except echothiopate)
Bind covalently to and inhibit cholinesterases
 Have muscarinic and nicotinic actions
 Readily penetrate the CNS


Absorbed by all routes

Hydrolyzed slowly in the body by
phosphorylphosphatases
Organophosphates: Clinical relevance

Treatment of open angle glaucoma
–

Insecticides (malathion; parathion)
–
–

Echothiopate and isoflurophate (DFP) are used but not preferred
because of potential for development of cataracts and other
side-effects.
In insects, parathion is converted to paraoxon; malathion to
malaoxon.
Mammals can preferentially oxidize these chemicals to less
toxic compounds. Parathion and malathion are only
preferentially toxic to insects.
Nerve gas (soman, tabun, sarin)
–
Developed for volatility, rapid absorption and “aging”
Organophosphates: Toxicity

Muscarinic, nicotinic and CNS manifestations:
Muscarinic
Nicotinic
CNS
Bronchoconstriction
Muscular fasciculation
Restlessness
Bronchial secretion
Sweating
Salivation
Lacrimation
Bradycardia
Hypotension
Tachycardia
Hypertension
Insomnia
Tremors
Confusion
Ataxia
Convulsions
respiratory
depression
circulatory
collapse
Miosis
Blurring of vision
Urinary incontinence
Organophosphates: Toxicity

Limited reversibility if treated rapidly

Enzyme/drug bond becomes increasingly
irreversible with time. “Aging” is related to loss of
alkoxy groups which result in more stable bonds.

Aging rate varies with compounds

Treatment [Atropine; pralidoxime (2-PAM)]:
–
–
–
support respiration
large doses of atropine
cholinesterase reactivator pralidoxime
Cholinergic Receptor Antagonists
Cholinoceptor blocking drugs: Overview
 Definition
and classification
Alkaloids
– Quaternary and non-quaternary synthetics
–
 Sites
of action
 Prototypes: atropine; scopolamine
 Therapeutic uses
 Toxicity
 Contraindications
Cholinergic Receptor Antagonists
Cholinoceptor blocking drugs
 DEFINITION:
Drugs which occupy muscarinic receptors
and prevent the muscarinic actions of
endogenous acetylcholine or other
muscarinic agonists.
Often referred to as anticholinergics or
antimuscarinics
Anticholinergic drugs
Antimuscarinic
M 1- selective
Nonselective
Antinicotinic
Ganglion
blockers
Neuromuscular
blockers
Naturally occurring compounds
(Belladonna alkaloids)
plant
Atropa belladonna
Dautura stramonium
Hyosacyamus niger
drug
atropine
scopolamine
atropine
scopolamine
Synthetic/semisynthetic compounds
Quaternary
compounds:
Ipratropium (Atrovent)
Propantheline (Pro-Banthine)
Synthetic/semisynthetic compounds
 Non-quaternary
compounds
Dicyclomine (generic, Bentyl)
Homatropine (Isopto Homatropine)
Tropicamide (Nydriacyl)
Prototypes: Atropine & scopolamine
 The
actions of these drugs upon
peripheral tissue/organ activity are
similar to that which would occur
following reduction of activity in
postganglionic, parasympathetic and
postganglionic cholinergic
sympathetic nerves.
 Both drugs also block CNS
muscarinic receptors
Pharmacokinetics of atropine and other tertiary amines
Atropine is relatively lipid soluble and readily crosses membrane
barriers. The drug is well distributed into the CNS and other organs
and is eliminated partially by metabolism in the liver and partially
by renal excretion. The elimination half-life is approximately
2 hours, and the duration of action of normal doses is 4-8 hours
except in the eye, where effects last for 72 hours or longer.
Other tertiary amines are able to enter the eye after conjunctival
administration. Similar ability to cross lipid bariers is important
for the agents used in parkinsonism.
Cardiovascular system effects
 Heart:
low dose
high dose
bradycardia
tachycardia
 Vascular
– no
(direct) effect
– except, dilate cutaneous vessels (red as a
beet)
– block hypotensive effect of muscarinic
agonists
Extravascular smooth muscle
 Eye:
–
–
mydriasis
cycloplegia
 Bronchial:
 GIT:
 Urinary:
 Glands
(dilation of iris sphincter)
(relaxation of ciliary muscle)
dilation
decreased tone, motility
(antispasmodic effect)
relaxation of detrusor, ureter;
constriction of sphincter
decrease in all secretions
Eye Fluid Production and Pressure
Cornea
Iris
Anterior chamber angle
Trabecular meshwork
Schlemm’s canal
(out)
Pupil
Posterior chamber
Ciliary body
(in)
Lens
Vitreous
Zonule
Cassel, Billig, Randall Fig 8-2
Types of Glaucoma
Open-Angle Glaucoma
Blocked drainage of aqueous
Blocked drainage of aqueous
Anterior chamber open
Blockage at trabecular
meshwork
Cassel, Billig, Randall
Closed-Angle Glaucoma
Fig 8-4
Anterior Chamber
angle closure
Cassel, Billig, Randall
Fig 8-3
Central nervous system
 Slowing
of heart after therapeutic doses (??)
 Action at respiratory center
therapeutic dose:
– larger doses:
–
 Cerebral
centers:
low doses:
– high doses:
– higher doses:
–
 Note:
faster deeper breathing
depression of respiration
sedation
restlessness, amnesia, delirium
stupor; coma
with therapeutic doses, atropine
generally has less CNS sedative effects
Tissue organ specificity of antimuscarinics
Order of appearance of physiological
effects with increasing dosage:
 Salivary, bronchial, sweat secretions
  Micturition

Tachycardia, mydriasis, cycloplegia
  Intestinal motility
  Gastric secretion

Quaternary vs Non-quaternary antimuscarinics
 Absorption.
Quaternary compounds are
less well absorbed and lack CNS actions
 Nicotinic
actions. Quaternary compounds
can block nicotinic receptors and may
have ganglion or neuromuscular blocking
action
Therapeutic uses of antimuscarinics
 Anesthesiology
– Prevention
(partly historical)
of bronchial and salivary
secretions
– Prevent bronchospasm
– Reversal of reflex bradycardia or
hypotension during surgery
– Drugs:
Belladonna alkaloids, some
synthetics
Therapeutic uses of antimuscarinics
 Respiratory
– Ipratropium
disorders:
(Atrovent). Inhalational drug
to reverse bronchial constriction and
secretion
– Asthma, emphysema, chronic bronchitis (
Therapeutic uses of antimuscarinics
 Ophthalmology
– production
of mydriasis and cycloplegia
of long or short duration
– choice of agent depends upon
requirements.
– routine examination: short duration;
minimal cycloplegia.
– many appear in combinations with alpha
adrenergic drugs
Mydriatic antimuscarinics
Drug
Duration of Action Cycloplegia
Atropine
6-12 days
+++
Cyclopentolate 12-24 h
++
Homatropine
12-48 h
+
Scopolamine
3-7 days
+++
Tropicamide
1-2 h
++
Therapeutic uses of antimuscarinics
 Gastroenterology: Peptic ulcer treatment.
Can reduce basal and nocturnal acid secretion
(other drugs are better, e.g., H2 antagonists)
– Inhibit gastrointestinal motility
– Reduce pain and prolong actions of antacids
– Drugs:
atropine, dicyclomine, propantheline
–
Therapeutic uses of antimuscarinics
 Gastroenterology: Irritable bowel syndrome
– Reduce
motility for reduction of pain,
constipation, or diarrhea
– Drugs:
atropine, dicyclomine, propantheline
Therapeutic uses of antimuscarinics
 Urologic
disorders
– Detrusor
hyperreflexia, enuresis
– Increase bladder capacity
– Decrease bladder pressure
– Drugs: dicyclomine, oxybutynin
Therapeutic uses of antimuscarinics
 Motion
–
sickness
Scopolamine is useful in prophylactic
treatment via CNS action in vestibular
nuclei and reticular formation
 Muscarine
poisoning
poisoning with muscarinic mushrooms
(Inocybe) or cholinesterase inhibitors
– Drugs: Belladonna alkaloids or synthetics
(propantheline)
–
Sources of Belladonna Poisoning:
Nonprescription
 Plants
drugs
of the Solanaceae family
 Antiparkinsonian drugs
Classic symptoms of belladonna poisoning:
 Hot
as a hare
 Dry
as a bone
 Red
as a beet
 Blind
 Mad
as a bat
as a hatter
 Bloated
as a toad
Contraindications for Antimuscarinics
 Glaucoma
 Prostatic
hypertrophy
 Toxicity more severe in children
Toxicity
constipation
Urinary retention
Mydriasis
Blurred vision
Flushing, dry skin
Heart palpitation
hyperthermia
headache
Dizziness
Excitement
Mental confusion,
memory loss,
hallucinations
Drugs with anticholinergic side-effects
 Antihistamines
 Monoamine
oxidase inhibitors
 Antipsychotics
 Lithium
 Tricyclic
Antidepressants
 Antiparkinsonian
drugs