Cholinoceptor blocking drugs:

Anti Muscarinic Anti Nicotinic

Neuromuscular junction blockers (NM)

Ganglion blockers (NN)

M1, M2, M3, M4, M5,

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’

Glandular M2

Glands, smooth muscle,endothelium

Seven transmembrane segments, G protein 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 Receptorblocking drugs:

PHARMCOKINETICS:A. Source and chemistryB. AbsorptionC. DistributionD. MetabolismE. Excretion

PHARMCODYNAMICS:A. Mechanism of ActionB. Organ system effects1.CNS2.Eye3.CVS4. Respiratory system5.GIT6.Sweat glands

1.Pharmacokinetics:

1.Chemistry:

Tertiary: Atropine, hyoscine, hyoscyamine

Quaternary: propantheline, glycopyrrolate, pirenzepine, dicyclomine, tropicamide,

Ipratropium, Benztropine2. 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 systemII. EyesIII. Cardiovascular systemIV. Respiratory systemV. Gastrointestinal tractVI. 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: Parkinsonism:

dopamine

AchGABA

dopamine

GABAAch

corpus corpus striatumstriatum

Substantia Substantia nigranigra

• In motion sickness and vestibular disorders.In motion sickness and vestibular disorders.•Scopolamine by mouth or injection, or transdermal patches.Scopolamine by mouth or injection, or transdermal patches.•Patch formulation produces significant blood levels over 48-72 hrsPatch formulation produces significant blood levels over 48-72 hrs

II. Eye and Ophthalmogical Disorders:II. Eye and Ophthalmogical Disorders:• Muscarinic cholinergic activation on pupillary constrictor muscle is blocked by Muscarinic cholinergic activation on pupillary constrictor muscle is blocked by topical atropine and other antimuscarinic drugs.topical atropine and other antimuscarinic drugs.•This results in unopposed sympathetic dilator activity and mydriasis.This results in unopposed sympathetic dilator activity and mydriasis.•Second effect is weakening of contraction of ciliary muscles or Second effect is weakening of contraction of ciliary muscles or CycloplagiaCycloplagia i.e., i.e., loss of accomodation for near vision.loss of accomodation for near vision.Third effect is reduction of lacrimal secretion Pts. Complaining of dry or sandy eyesThird effect is reduction of lacrimal secretion Pts. Complaining of dry or sandy eyesWhen receiving large dose of antimuscarinic drug.When receiving large dose of antimuscarinic drug.• Acuurate mesurement of refractive error in uncooperative patients eg., young Acuurate mesurement of refractive error in uncooperative patients eg., young children requires ciliary paralysis.children requires ciliary paralysis.•Ophthalmologic examination of retina is facilitated by mydriasis.Ophthalmologic examination of retina is facilitated by mydriasis.•Antimuscarinic agents are administered as eye drops or ointment.Antimuscarinic agents are administered as eye drops or ointment.•For adults and older children the shorter acting drugs are preferred eg. areFor adults and older children the shorter acting drugs are preferred eg. are Drug Duration of effect (days) Usual conc.Drug Duration of effect (days) Usual conc.Atropine----------- 7-10 0.5-1Atropine----------- 7-10 0.5-1Scopolamine------ 3-7 0.25Scopolamine------ 3-7 0.25Homatropine------ 1-3 2-5Homatropine------ 1-3 2-5Cyclopentolate---- 1 0.5-2Cyclopentolate---- 1 0.5-2Tropicamide-------- 0.25 0.5-1Tropicamide-------- 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 systemIII. The Cardio vascular system:: a. a. Heart:Heart:

•SA node is very sensitive to Muscarinic receptor blockade.SA node is very sensitive to Muscarinic receptor blockade.•Moderate to high therapeutic doses of atropine Blockade of vagal slowing Moderate to high therapeutic doses of atropine Blockade of vagal slowing Relative tachycardia.Relative tachycardia.•Lower dose Initial bradycardia before tachycardia.Lower dose Initial bradycardia before tachycardia.•This slowing maybe due to the block of presynaptic muscarinic receptors on vagal This slowing maybe due to the block of presynaptic muscarinic receptors on vagal postganglionic fibers.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: • 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:

1. Amnesia

2. Urinary retention

3. 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

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

Genito-

urinary tract

Oxybutynin, glycopyrrolate,dicyclomine,tolterodine

To treat transient cystitis, postoperative bladder spasm, or incontinence

SUMMARY:

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

Summary continued….

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 THERAPY2. 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 type,end plate receptor)

Skeletal muscle neuromuscular junction

Pentamer (α2βδγ)2

Na+,K+ depolarizing ion channel

NN (Neuronal type, ganglion receptor)

Post ganglionic sell bodies, dendrites

α and β subunits only as α2β2 or α3β3

Na+,K+ depolarizing ion channel

NM antagonists: Tetramethylammonium, Hexamethonium, Decamethonium,

NN antagonists:

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.

S.No Generic names Trade names & dosage form Doses

Antimuscarinic

1 Atropine

2 Belladona alkaloid, extract, tincture

3 cyclopentolate

4 Dicyclomine

5 Flavoxate

6 Glycopyrrolate

7 Homatropine

8 Hyoscyamine

9 Ipratropium

Generic and Trade names of Anti cholinergic drugs

( HOME WORK...?)

S.No Generic names Trade names & dosage form Doses

10 Scopolamine

11 Methscopolamine

12 oxybutynin

13 Tropicamide

Ganglion blockers

14 Mecamylamine

15 Trimethaphan

Cholinestrase regenerator

16 Pralidoxime

HOMEWORK CONTINUED…..?