Download Clinical Uses of Cholinomimetics

II. BASIC
PHARMACOLOGY OF THE
INDIRECT-ACTING
CHOLINOMIMETICS
Structure
Three chemical groups:
1. simple alcohols bearing a quaternary
ammonium group, eg, edrophonium
2. carbamic acid esters of alcohols bearing
quaternary or tertiary ammonium groups
(carbamates, e.g. neostigmine,
physostigmine);
3. organic derivatives of phosphoric acid
(organophosphates, eg, ecothiophate).
insecticide
Cholinestrase inhibitors
Safe for
general
public use
B. Absorption, Distribution, and
Metabolism
organophosphates (except for
echothiophate):
- well absorbed from the skin, lung, gut, and
conjunctiva → dangerous to humans
- relatively less stable than the carbamates
when dissolved in water → have limited t1/2
in the environment
Mechanism of Action
AChE is the primary target of these drugs,
but butyrylcholinesterase is also inhibited.
AChE is an extremely active enzyme.
- 1st step: ACh binds to the enzyme's active
site and is hydrolyzed, yielding free choline
and the acetylated enzyme.
2nd step: the covalent acetylenzyme bond is
split, with the addition of water (hydration).
The entire process takes place in
approximately 150 microseconds.
The duration of their effect is
determined chiefly by the stability of
the inhibitor-enzyme complex, not by
metabolism or excretion.
Mechanism of Action
1) Quaternary alcohols (edrophonium):
reversibly bind electrostatically and by
hydrogen bonds to the active site→ preventing
access of ACh → enzyme-inhibitor complex is
short-lived (2-10 min).
2) Carbamate esters (neostigmine and
physostigmine):
undergo a two-step hydrolysis similar to ACh.
the covalent bond of the carbamoylated
enzyme is more resistant to the second
(hydration) process, and this step is prolonged
(30 min - 6 hrs).
Mechanism of Action
3) Organophosphates:
undergo initial binding and hydrolysis by the
enzyme, resulting in a phosphorylated active
site.
the covalent phosphorus-enzyme bond is
extremely stable and hydrolyzes in water at a
very slow rate (hundreds of hours).
phosphorylated enzyme complex may
undergo aging: breaking of one of the
oxygen-phosphorus bonds of the inhibitor →
further strengthening of the phosphorusenzyme bond.
“Cholinestrase regenerator”
pralidoxime: able to split the phosphorusenzyme bond and can be used in reversal of
organophosphate insecticide poisoning
once aging has occurred, the enzyme-inhibitor
complex more stable and is more difficult to split,
even with oxime regenerator compounds.
organophosphate inhibitors are sometimes
referred to as "irreversible" cholinesterase
inhibitors, and edrophonium and the carbamates
are considered "reversible" inhibitors.
Why pralidoxime should be always administered with
atropine?
Therapeutic uses and durations of action of cholinesterase inhibitors
http://www.myasthenia.org.
au/html/symptoms.htm
myasthenia gravis
Usually, weakness of the eye muscle is the first
noticeable symptom
"Sleepy" (© Disney) of Snow White and the Seven Dwarfs was
supposedly based on a friend of Walt Disney who had MG
myasthenia gravis
Three different serial pictures to demonstrate fatigue of eyelid
muscles as the patient keeps looking up.
After a few minutes of rest, the eyelids have returned to
near-normal position.
ptosis
Fatigue (Ptosis) in a patient with MG
Organ System Effects
3. Cardiovascular system:
AChE inhibitors can increase activation in both:
1. sympathetic and parasympathetic ganglia
supplying the heart;
2. at the Ach receptors on neuroeffector cells
(cardiac and vascular smooth muscles) that
receive cholinergic innervation;
Organ System Effects
3. Cardiovascular system:
Compare with the
direct acting
cholinomimetics!!
heart: parasympathetic effects predominate: →
negative chronotropic, dromotropic, and some
inotropic effects → ↓cardiac output (CO) ( pre and
post junctional modulation of sympathetic activity).
vascular smooth muscle and BP: they have less
marked effects than direct-acting muscarinic agonists
(few vascular beds receive cholinergic innervation)
net cardiovascular effects: modest bradycardia, ↓
CO, and no change or a modest↓ BP.
toxic doses: more marked bradycardia (occasionally
tachycardia) and hypotension
Organ System Effects
4. Neuromuscular junction:
Low/therapeutic doses moderately prolong and
intensify the actions of physiologically released
ACh →↑ strength of contraction;
higher concentrations, the accumulation of ACh
may result in fibrillation of muscle fibers;
with marked inhibition of AChE, the initial
phase of depolarizing neuromuscular blockade
may be followed by a phase of nondepolarizing
blockade;
Fibrillation= uncoordinated contraction
Clinical Uses of Cholinomimetics
Eye: glaucoma, accomodative estropia
GIT: postoperative atony
UT: neurogenic bladder
neuromuscular junction: myasthenia
gravis, curare-induced neuromuscular paralysis
heart (rarely): certain atrial arrhythmias
Treatment of atropine (antimuscarinic)
overdosage
Treatment of Alzheimer’s disease
ptosis
estropia
Curare
Clinical Uses of Cholinomimetics
A. The Eye:
Glaucoma (↑intraocular pressures, IOP)
- In past: either muscarinic stimulants
(pilocarpine, methacholine, carbachol) or
cholinesterase inhibitors (physostigmine,
demecarium, echothiophate) ↓ IOP
- For chronic glaucoma, these drugs have been replaced
by -blockers and prostaglandin derivatives
Accomodative estropia in young children
(diagnosis and treatment)
Clinical Uses of
Cholinomimetics
Acute angle-closure glaucoma: a medical
emergency, usually treated initially with drugs
but frequently requires surgery for permanent
correction;
Initial therapy often consists of a combination
of a direct muscarinic agonist and a
cholinesterase inhibitor (eg, pilocarpine plus
physostigmine
Once IOP is controlled and the danger of
vision loss is diminished corrective surgery
(iridectomy or iridotomy)
Clinical Uses of Cholinomimetics
Open-angle glaucoma:
chronic disease (not amenable to traditional surgical
correction- NOW LASER!) → therapy is based on the
use of
1) parasympathomimetics
humor )
( outflow of aqueous
2)  agonists: epinephrine, ( outflow)
3) β-adrenoceptor-blocking drugs, Timolol,
betaxolol ( secretion)
4) carbonic anhydrase inhibitors,
acetazolamide
( secretion)
5) Prostaglandins, Latanoprost, unoprostone
outflow)
(
Where to store?
Clinical Uses of Cholinomimetics
GIT and UT:
Direct: of the choline esters, bethanechol is the most
widely used, usually 10-25 mg 3-4 t.d. or
subcutaneously 5 mg and repeated in 30 min if
necessary.
Indirect: of the cholinesterase inhibitors,
neostigmine is the most widely used subcutaneously
0.5-1 mg or orally 15 mg.
NB: if there is mechanical obstruction to outflow,
cholinomimetic may exacerbate the problem and may
even cause perforation as a result of ↑pressure
Clinical Uses of Cholinomimetics
Pilocarpine has long been used to increase
salivary secretion
Cevimeline: a NEW direct acting
muscarinic agonist used for the treatment of
dry mouth associated with Sjögren’s
syndrome
Sjögren’s syndrome: Syndrome characterized by dry
mouth, defective lacrimation and rheumatoid arthritis
(dryness of mucous membranes in the body)
Clinical Uses of Cholinomimetics
C. Neuromuscular Junction:
1. Myasthenia gravis: autoimmune processproduction of antibodies →↓the number of
functional nicotinic receptors on the skeletal
muscle → ptosis, diplopia, difficulty speaking
and swallowing, extremity weakness (in
extreme cases may interfere with respiration).
Cholinesterase inhibitors—but not directacting acetylcholine receptor agonists—are
used
Also, immunosuppressants and thymectomy
Clinical Uses of Cholinomimetics
Edrophonium is sometimes used as (1) a
diagnostic test I.V.: an improvement in muscle
strength that lasts about 5 min. will usually be
observed in myasthenia gravis. (2) to
distinguish between myasthenic crisis and
cholinergic crisis
Chronic long-term therapy: neostigmine,
pyridostigmine: require frequent dosing
(every 4 hours for neostigmine and every 6
hours for pyridostigmine).
Sustained-release preparations should be used
only at night and if needed.
Clinical Uses of Cholinomimetics
2. to reverse neuromuscular blockade after
surgery: neostigmine and edrophonium
are the drugs of choice (DOC): I.V. or I.M.
D. Heart:
In the past: edrophonium was used for
treatment of paroxysmal supraventricular
tachycardia (PSVT),
replaced by newer drugs (adenosine and the
calcium channel blockers verapamil and
diltiazem).
Clinical Uses of Cholinomimetics
E. Antimuscarinic Drug Intoxication
(atropine, tricyclic antidepressants)
physostigmine has been used for this
application, because it enters the CNS and
reverses the central as well as the peripheral
signs of muscarinic blockade.
It, however, itself can produce dangerous
CNS effects→ used only in patients with
dangerous ↑body temperature or very rapid
supra-ventricular tachycardia.
Clinical Uses of Cholinomimetics
F. CNS (Alzheimer’s Disease)
Tacrine X (withdrawn)
Donepezil, galantamine and rivastigmine
- more selective acetylcholinesterase inhibitor
- Donepezil: may be given once daily (long t1/2)
- lacks the hepatotoxic effect of tacrine
Toxicity of Cholinomimetics
A. Direct-Acting Muscarinic Stimulants (e.g
pilocarpine and the choline esters):
nausea, vomiting, diarrhea (N,V,D)
salivation,
sweating,
cutaneous vasodilation,
bronchial constriction.
all above toxicities are blocked competitively by atropine
Toxicity of Cholinomimetics
Certain mushrooms, especially those
of the genus Inocybe, contain
muscarinic alkaloids;
Ingestion of these mushrooms causes
typical signs of muscarinic excess within
15-30 minutes. Treatment is with
atropine, 1-2 mg parenterally;
Amanita muscaria: the 1st source of
muscarine, contains v low conc
Toxicity of Cholinomimetics
B. Direct-Acting Nicotinic Stimulants
(nicotine).
1. Acute toxicity-The fatal dose is ~40 mg
(how many cigarettes?), or 1 drop of the pure
liquid. (content of two regular cigarettes).
Ingestion of nicotine by infants and children
is usually followed by vomiting, limiting the
amount of the alkaloid absorbed.
nicotine is also used in a number of
insecticides.
Toxicity of Cholinomimetics
Why nicotine can be fatal?
(1) CNS stim.: convulsions, coma, and
respiratory arrest;
(2) skeletal muscle and respiratory paralysis;
(3) hypertension and cardiac arrhythmias.
Treatment is symptom-directed:
1. Muscarinic excess - atropine.
2. Central stimulation - diazepam.
3. Neuromuscular blockade may require
mechanical respiration.
Toxicity of Cholinomimetics
2. Chronic nicotine toxicity causes:
up to 30% of coronary heart disease
(CHD) deaths
nicotine contributes to the ↑ risk of
vascular disease and sudden coronary
death associated with smoking.
high incidence of ulcer recurrences in
smokers with peptic ulcer.
Methods of smoking cessation? (self
study) pp.157
Toxicity of Cholinomimetics
C. Cholinesterase Inhibitors: The major
source is pesticide use in agriculture and in
the home.
The dominant initial signs are those of
muscarinic excess:
miosis,
salivation,
sweating,
bronchial constriction,
vomiting,
diarrhea
Toxicity of Cholinomimetics
(cont’d)
→ CNS involvement + peripheral nicotinic
effects (depolarizing neuromuscular blockade).
Therapy always includes:
(1) maintenance of vital signs—respiration in
particular
(2) decontamination—removal of all clothing and
washing of the skin in cases of exposure to dusts
and sprays;
(3) atropine parenterally in large doses, given as
often as required to control signs of muscarinic
excess.
(4) pralidoxime