Download Cholinoceptor blocking drugs

Cholinoceptor blocking drugs:
Anti Muscarinic
M1, M2, M3, M4, M5,
Anti Nicotinic
Neuromuscular junction
blockers (NM)
Ganglion
blockers
(NN)
By: Dr. Sumbul
Cholino
ceptors
Other
names
location
Structural features
Postreceptor
mechanism
M1
M1a
Nerves
Seven transmembrane
segments, G protein
linked
IP3, DAG
cascade
M2
M2a’
Cardiac M2
Heart, nerves,
Smooth muscle,
Seven transmembrane
segments, G protein
linked
Inhibition of
cAMP
production
activation of K+
channel
M3
M2b’
Glands, smooth Seven transmembrane
Glandular M2 muscle,endotheli segments, G protein
um
linked
IP3, DAG
cascade
m41
CNS?
Seven transmembrane
segments, G protein
linked
Inhbition of
cAMP
production
m51
CNS?
Seven transmembrane
segments, G protein
linked
IP3, DAG
cascade
Basic Pharmacology of Muscarinic Receptor
blocking drugs:
PHARMCOKINETICS:
A.
B.
C.
D.
E.
Source and chemistry
Absorption
Distribution
Metabolism
Excretion
PHARMCODYNAMICS:
A. Mechanism of Action
B. Organ system effects
1.CNS
2.Eye
3.CVS
4. Respiratory system
5.GIT
6.Sweat glands
1.Pharmacokinetics:
1.Chemistry:
Tertiary: Atropine, hyoscine, hyoscyamine
Quaternary: propantheline, glycopyrrolate, pirenzepine, dicyclomine, tropicamide,
Ipratropium, Benztropine
2. Absorption:
• Natural alkaloids and tertiary antimuscarinic drugs well absorbed from GIT (lipid
soluble) and conjunctival membrane.
• Scoploamine absorbed from skin.
•Quaternary (less lipid soluble) only 10- 30% of a dose is absorbed from the oral
administration.
3. Distribution:
•Natural alkaloids and tertiary antimuscarinic drugs well distributed
•Significant levels are achieved within 30 min.- I hr.
4. Metabolism and excretion
• Atropine disappears from the blood after administration with a T1/2 of 2 hrs.
•60% excreted unchanged in the urine.
•Remaining is metabolized by hydrolysis and conjugation.
•In all organs except eye the drug declines rapidly.
•Effects on Iris and Ciliary muscles persists for hrs.
Absorption:
• Natural alkaloids and tertiary antimuscarinic drugs well absorbed from GIT (lipid
soluble) and conjunctival membrane.
• Scoploamine absorbed from skin.
•Quaternary (less lipid soluble) only 10- 30% of a dose is absorbed from the oral
administration.
Distribution:
•Natural alkaloids and tertiary antimuscarinic drugs well distributed
•Significant levels are achieved within 30 min.- I hr.
Metabolism and excretion
• Atropine disappears from the blood after administration with a T1/2 of 2 hrs.
•60% excreted unchanged in the urine.
•Remaining is metabolized by hydrolysis and conjugation.
•In all organs except eye the drug declines rapidly.
•Effects on Iris and Ciliary muscles persists for hrs.
Organ system effects of Anti muscarinic drugs and their
Clinical Uses:
I. central nervous system
II. Eyes
III. Cardiovascular system
IV. Respiratory system
V. Gastrointestinal tract
VI. Genitourinary tract.
• I. Central nervous system
•
•
•
•
Linger lasting sedation by action on parasympathetic medullary centres.
Scopolamine has marked central effects include drowsiness and amnesia in
sensitive individuals in recommended doses.
Used in Parkinson’s disease as adjunctive therapy with levodopa.
Normal:
Substantia
nigra
Parkinsonism:
corpus
striatum
dopamine
dopamine
Ach
GABA
Ach
GABA
• In motion sickness and vestibular disorders.
•Scopolamine by mouth or injection, or transdermal patches.
•Patch formulation produces significant blood levels over 48-72 hrs
II. Eye and Ophthalmogical Disorders:
• Muscarinic cholinergic activation on pupillary constrictor muscle is blocked by
topical atropine and other antimuscarinic drugs.
•This results in unopposed sympathetic dilator activity and mydriasis.
•Second effect is weakening of contraction of ciliary muscles or Cycloplagia i.e.,
loss of accomodation for near vision.
Third effect is reduction of lacrimal secretion
Pts. Complaining of dry or sandy eyes
When receiving large dose of antimuscarinic drug.
• Acuurate mesurement of refractive error in uncooperative patients eg., young
children requires ciliary paralysis.
•Ophthalmologic examination of retina is facilitated by mydriasis.
•Antimuscarinic agents are administered as eye drops or ointment.
•For adults and older children the shorter acting drugs are preferred eg. are
Drug
Duration of effect (days)
Usual conc.
Atropine----------- 7-10
0.5-1
Scopolamine------ 3-7
0.25
Homatropine------ 1-3
2-5
Cyclopentolate---- 1
0.5-2
Tropicamide-------- 0.25
0.5-1
•Tertiary amines have good penetration after conjunctival application.
• Glycopyrrolate a quaternary agent is as rapid and as long acting as Atropine.
•Antimuscarinic drugs should never be used in mydriasis unless cycloplagia or
prolonged action is required.
• alpha adrenoceptor stimulant drug eg., phenylephrine is sufficient for
fundoscopic examination
•Another use is to prevent Synechia (adhesion) formation in uveitis and iritis
longer lasting antimuscarinic drug especially Homatropine is valuable.
III. The Cardio vascular system:
a. Heart:
•SA node is very sensitive to Muscarinic receptor blockade.
•Moderate to high therapeutic doses of atropine
Blockade of vagal slowing
Relative tachycardia.
•Lower dose
Initial bradycardia before tachycardia.
•This slowing maybe due to the block of presynaptic muscarinic receptors on vagal
postganglionic fibers.
Heart cont….
•
•
•
•
•
These presynaptic muscarinic receptors normally limit the release of Ach in the
SA node and other tissues.
Because of presynaptic muscarinic block there is unlimited release of Ach leading
to bradycardia.
The same mechanism opeates in the control of AV node function in the presence
of high vagal tone.
Atropine can significantly reduce the PR interval of the ECG by blocking
muscarinic receptors in the AV node.
Muscarinic effects on the Atrial muscles are similerly blocked.
b. BLOOD VESSELS:
• Blood vessels receive no direct innervation from Parasympathetic N.S.
• Parasympathetic nerve stimulation dilates coronary Arteries and Paracympathetic
cholinergic nerves cause vasodilation in the skeletal muscle vascular bed.
• Atropine can block this dilation
• Almost all vessels contain endothelial muscarinic receptors that mediates vasodilation.
•These receptors are readily blocked by antimuscarinic drugs.
•At toxic doses and in some individuals at normal doses , antimuscarinic drugs cause
cutaneous vasodilation , especially in the upper portion of the body.
•NET CVS affects of Atropine in normal Hemodynamics are:
Tachycardia and little effects on Blood Pressure.
•Cardiovascular effects of Direct Acting muscarinic Innervation are easily prevented.
•Marked reflex vagal discharge sometimes accompanies the pain of MI and may result in
sufficient depression of SA- and AV- nodal functions to impair cardiac out put.
• In this condition Parenteral Atropine and a similar antimuscarinic agent is appropriate
therapy.
• Circulating antibodies against the second extracellular loop of cardiac muscarinic
receptors have been detected, these antibodies have prasympathomimetic action
on Heart.
• Their action is prevented by Atropine.
III. Respiratory system:
•
•
•
•
•
•
1.
2.
3.
•
•
Both Muscles and secretary glands receive vagal innervation and contain
muscarinic receptors.
Atropine causes bronchodilation and reduction of secretion
Effectiveness of unselective, antimuscarinic drugs in ASTHMA and COPD is
limited because of block of auto inhibitory M2 receptors on Postganglionic
Parasympathetic nerves can oppose the bronchodilation caused by block of
M3 receptors on airway smooth muscles.
These antmuscarinic agents are frequently given prior to the administration of
imhalant anaesthetics to reduce the accumulation of secretion in trachea and
the possibity of Laryngospasm.
Atropine or scopolamine can reduce these hazards as preanesthetic
medication.
Post surgical effects of Scopolamine are:
Amnesia
Urinary retention
Intestinal Hypomotality
Ipratropium (a synthetic analog of Atropine) is used as Inhalation drug
in ASTHMA and COPD.
Aerosole route of administration provides the advantage of maximal
concentration at the bronchial target tissue with reduced systemic effects.
IV.Gastro Intestinal Tract:
• Blockade of Muscarinic receptors has dramatic effects on motility and some of the
secretary functions of the gut.
•
Even complete muscarinic blockade can not abolish the activity in this organ system
since local hormones and noncholinergic neurons in the enteric nervous system.
•
Antimuscarinic drugs have marked effects on salivary secretion
dry mouth
in patients of Parkinson’s disease or urinay conditions taking antimuscarinic drug.
•
Gastric secretion is blocked less effectively: the volume and amount of acid, pepsin,
and mucin are reduced in large doses.
•
The drugs like Pirenzepine and telenzepine more selectively and potently
reduce the gastric secretions but with fewer side effects than of atropine and other
less selective agents.
•
•
•
Pancreatic and intestinal secretions are less effectively blocked by Atropine.
These processes are primarily under hormonal than vagal control.
Walls of the viscera are relaxed, and both the tone and propulsive movements
are diminished
Gastric emptying is prolonged
Intestinal transit time is
lengthened
• Diarrhea due to over dosage of parasympathomimetic drug is readily stopped. And even
is caused by non autonomic drug, can temporarily be stopped.
•After 1-3 days of antimuscarinic therapy the paralysis can be reversed by the
local mechanism.
•Used in the treatment of motion sickness or traveler's diarrhea.
•Clinically given in combination with the opioid antidiarrheal agents to enhance
effectiveness.
•A classic example is LOMOTIL (tablet or liquid form) that is combination of atropine with
diphenoxylate, a non analgesic congener of meperidine.
V. Genito urinary tract:
• Relaxes smooth muscles of ureters and bladder walls and slows voiding.
• useful in the treatment of spasm caused by mild inflammation, surgery and certain
neurological conditions.
•Anti muscarinic drugs have no significanr action on the uterus .
•They are used for the symptomatic relief from the urinary urgency, however certain anti
Bacterial drugs are prescribed for the treatment of infections (bacterial cystitis).
• OXYBUTYNIN is used for the relief of bladder spasm after the urologic surgery
and prostectomy.
• Also valuable to reduce the involuntary voiding in patients with neurologic diseases
eg., in pts. with Meningomyelocele.
• In such conditions Oral Oxybutynin or instillation of the drug by catheter into the
bladder
improves bladder capacity and continence to reduce infection and
renal damage.
• IMIPRAMINE a tricyclic antidepressant is used to reduce incontinence in
institutionalized elderly patients.
• PROIVERINE, is also used for this purpose.
•These antimuscarinic agents are also used in urolithiasis to reduce muscular spasm
caused by passage of stone.
VI. Sweat gland:
•Atropine reduces thermoregulatory sweating by muscarinic receptors
Atropine Fever.
•Sympathetic cholinergic fibers innervate eccrine sweat galnds and their muscarinic
receptors are easily accessible by antmuscarinic drugs
SUMMARY:
Organ
system
Drugs
Application
CNS
Benztropine,trihexyphenidyl,
biperiden,
To treat parkinson’s disease
manifestations
scopolamine
To prevent or reduce motion
sickness
Eye
Atropine,homatropine,
cyclopentolate,tropicamide.
To produce mydriasis and
cycloplagia. Cyclopentolate is well
absorbed from conjunctival sac
into the eye
bronchi
Ipratropium
To cause bronchodilation in
asthma and chronic obstructive
pulmonary diseases
GIT
Glycopyrrolate, dicyclomine,
methscopolamine
To reduce transient hypermotality
GenitoOxybutynin,
urinary tract glycopyrrolate,dicyclomine,tolte
rodine
To treat transient cystitis,
postoperative bladder spasm, or
incontinence
Summary continued….
organ
effects
mechanisms
CNS
Sedation, anti motion sickness,
Anti parkinson’s,amnesia,delirum
Block of muscarinic receptor,
Unknown subtype.
Eye
Cycloplagia, mydriasis
Block of M3 receptors
Bronchi
Bronchodilation especially if
constructed
Block of M3 receptors
GIT
Relaxation, slowed peristalsis
Block of M1, M3 receptors
Genitourinary
Relaxation of bladder wall, urinary
retention
Block of M3 receptors
Heart
Initial bradycardia, especially at low
doses; then tachycardia
Tachycardia from Block of
M3 receptors in the heart
Blood vessels
Block of muscarinic vasodilatation;
not manifested unless a muscarinic
agonist is present.
Block of M3 receptors on
endothelium of vessels
Glands
Reduction of salivation, lacrimation
and sweating; less reduction of
gastric secretion
Block of M1, M3 receptors
Skeletal
muscles
none
TOXICITY OF ANTIMUSCARINIC DRUGS:
A traditional mnemonic for atropine toxicity is “Dry as a bone, red as a beet,
mad as a hatter”.
Predictable toxicities
Unpredictable toxicities
1. Predictable toxicities:
•
•
•
•
•
Blockade of thermoregulatory sweating
hyperthermia or Atropine fever
Tachycardia or arrhythmias (dry as bone)
Most important toxicity in elderly patients include Acute angle closure glaucoma
and urinary retention particularly in pats. of prostatic hyperplasia.
Constipation
Blurred vision.
2. Unpredictable toxicities:
a. CNS
•
Sedation, amnesia, delirium and hallucination, convulsions. (mad as hatter)
b. Cardiovascular
•
•
I.V conduction blockade.
Dilation of coetaneous vessels of arms, head, neck and trunk leading to “Atropine
flush.” (red as beet)
CHOLINERGIC POISONING:
1. ANTIMUSCARINIC THERAPY
2. CHOLINESTERASE REGENERATOR COMPOUNDS.
3. PRETREATMENT WITH REVERSIBLE INHIBITOR OF ENZYME
1. ANTIMUSCARINIC THERAPY:
• Large doses of Atropine are needed to reverse the muscarinic effect of extremely
potent agents l
•
For Parathion and chemical warfare nerve Gases: 1-2 mg of atoropine I. V
every 5 min until signs of antimuscarinic effects are observed (dry mouth,
reversal of miosis).
2. CHOLINESTERASE REGENERATOR COMPOUNDS.
• Used for the treatment of organophosphorus poisoning.
• They are known as oxime agents and include Pralidoxime (PAM) & diacetylmonoxime
• The oxime group has a high affinity for binding with Phosphorus atom and hydrolyze
the phosphorylated enzyme.
pralidoxime i.v.1-2 g for over 15-30 min. and for several days in severe poisoning.
• This drug may cause neuromuscular weakening
• Pralidoxime is not recommended in reversal of inhibition of acetylcholineestrase
by carbamte inhibitors.
• B/c of its positive charge it does not enter the CAN and is ineffective in reversing the
central of effects of organophosphate poisoning.
• Diacetylmonoxime does cross the BBB.
3. PRETREATMENT WITH REVERSIBLE INHIBITOR OF ENZYME:
• To protect against excessive AchE inhibition, pretreatment with reversible inhibitors
of the enzzyme to prevent binding of the Irreversible organophosphate inhibitor.
• This prophylaxis can be achieved with pyridostigmine or physostigmine, but is
reserved for situations in which possibly lethal poisoning is anticipated eg,
chemical warfare. .
• Simultaneous use of atropine is required to control muscarinic excess.
•
MUSHROOM POISONING:
1. Rapid onset :15-30min following ingestion. Parentral atropine 1-2mg is effective
in treatment. Signs are of Muscarinic excess.
2. Delayed onset :6-12 hrs.atropine is not used in such poisoning
•
•
ATROPINE POISONING:
Manifestations are dry mouth, mydriasis, tachycardia, hot and flushed skin,
agitation, delirium and hyperthermia.
• CONTRAINDICATIONS OF ANTIMUSCARINIC DRUGS:
1. Glaucoma, especially angle-closure glaucoma.
2. Elserly men, especially of prostatic hyperplasia.
3. Non selective antimuscarinic drugs should never be used to treat acid-peptic disease.
PHARMACOLOGY AND CLINICAL USES OF THE
GANGLION BLOCKING DRUGS.
These agents block the action of Ach and similar agonist at the nicotinic
receptors of both parasympathetic and sympathetic autonomic ganglia.
Receptor type
location
Structural feature Postreceptor
mechanism
NM (muscle
Skeletal muscle
neuromuscular
junction
Pentamer
(α2βδγ)2
Na+,K+
depolarizing ion
channel
Post ganglionic
sell bodies,
dendrites
α and β subunits
only as α2β2 or
α3β3
Na+,K+
depolarizing ion
channel
type,end plate
receptor)
NN (Neuronal
type, ganglion
receptor)
NM antagonists: NN antagonists:
Tetramethylammo
nium,
Hexamethonium,
Decamethonium,
Mechamylamine,
Trimethaphan.
ORGAN SYSTEM EFFECTS AND CLINICAL USES OF
GANGLIONIC BLOCKERS:
1. CNS:
•
Quarternary amine and trimethophan lack CNS effects because of
inability to cross BBB.
•
Mechamylamine readily enters the CNS. Sedation, Tremor,Choreiform
movements and mental aberrations are the side effects of this drug.
•
Mechamylamine is studied for use in reducing nicotinic craving in pts. To
quit smoking and some other central indications.
2. EYE:
•
As the ciliary muscles receive innervation primarily from parasympathetic
NS, the ganglion blocking drugs cause predictible cycloplagia with loss of
accomodation.
•
Their effects on pupil is not easily predicted because the IRIS receives
both sympathetic and Prasympathwtic innervations.
•
As Parasympathetic tone is usually dominant in this tisssue, Ganglionic
blockade usually causes moderate dilation of pupil.
3. CVS:
•
The blood vessels receive vaso constrictor fibers from the sympathetic
nervous system therefore Ganglionic blockade causes a very important
decrease in arteriolar and venomotor tone.
•
The blood pressure may drop precipitiously, because both peripheral
vascular resistance and venous return are decreased.
•Hypotension is especially marked in the upright position (orthostatic or postural
hypotension), because postural reflexes that normally prevent venous pooling are
Blocked.
•Cardiac effects include diminished contractility and because the SA-node is usually
dominated by Parasynpathetic nervous system
moderate tachycardia.
•Trimethaphan is ocassionally used in the treatment of hypertensive emergencies
and dissecting Aortic aneurism, to produce controlled hypotension, which can be of
value in neurosurgery to reduce bleeding in the operative field, and in pts. undergoing
electroconvulsive therapy.
3. GIT:
•Secretion is reduced although not enough to treat peptic disease.
•Motility is inhibited
constipation.
4. OTHER SYSTEMS:
•Urinary retention.
•Impaired sexual function both in erection and ejaculation
•Thermoregulatory sweating is blocked.
5.RESPONSE TO AUTONOMIC DRUGS:
As the effector receptors (muscarinic and α, β) are not blocked, pts. receiving ganglion
blocking drugs are fully responsive to drugs acting on these receptors.
NUROMUSCULAR BLOCKING DRUGS:
•Are imp. For producing complete muscle relaxation in surgery.
Nondepolarizing
Depolarizing
Nondepolarizing:
• Tubocurarine is prototype
•Produces competitive blockade at the end plate nicotinic receptor.
•Causing flaccid paralysis lasting for 30-60 min.
•Other drugs are Pancuronium, Atracurium, vancuronium are short acting.
Depolarizing:
• Although these are nicotinic agonists, not antagonists.
•They cause flaccid paralysis.
•Succinylcholine is the only agent.
•The drug is hydrolysed by pseudocholinestrase (plasma cholinestrase and has a T1/2 of
few minutes in persons with normal plasma cholinestrase.
Generic and Trade names of Anti cholinergic drugs
( HOME WORK...?)
S.No
Generic names
Antimuscarinic
1
Atropine
2
Belladona
alkaloid, extract,
tincture
3
cyclopentolate
4
Dicyclomine
5
Flavoxate
6
Glycopyrrolate
7
Homatropine
8
Hyoscyamine
9
Ipratropium
Trade names & dosage form
Doses
HOMEWORK CONTINUED…..?
S.No
Generic names
10
Scopolamine
11
Methscopolamine
12
oxybutynin
13
Tropicamide
Ganglion
blockers
14
Mecamylamine
15
Trimethaphan
Cholinestrase
regenerator
16
Pralidoxime
Trade names & dosage form
Doses