ANTI-MUSCARINIC DRUGS

BySYED MASOOD AHMED QUADRI

Classification Of Anti-Cholinergic’s

Characteristics of important subtypes of Muscarinic receptor By pharmacological as well as molecular cloning

techniques, muscarinic receptors have been divided into 5 subtypes M1, M2, M3, M4 and M5.

The major subtype that are present on effector cells as well as on prejunctional nerve endings, and are expressed both in peripheral organs as well as in the CNS.

The M4 and M5 receptors are present mainly on nerve endings in certain areas of the brain and regulate the release of other neurotransmitters.

Most organs have more than one subtype, but usually one subtype predominates in a given tissue.

Three main types of Muscarinic receptor M1 :- The M1 is primarily

a neuronal receptor located on ganglion cells and central neurones, especially in cortex, hippocampus and corpus striatum. It plays a major role in mediating gastric secretion, relaxation of lower esophageal sphincter (LES) on vagal stimulation and in learning, memory, motor

functions, etc. M2 :- Cardiac muscarinic

receptors are predominantly M2 and mediate vagal bradycardia.Autoreceptors on cholinergic nerve endings are also of M2 subtype. Smooth muscles express some M2 receptors well which, like M3,media contraction.

M3 :- Visceral smooth

muscle contraction and glandular secretions are elicited through M3 receptors, which also mediate vasodilatation . Together the M2 and M3 receptors mediate most of the well-recognized muscarinic actions including contraction of LES.

Some Anti-muscarinic Drugs Tertiary amines - atropine, scopolamine,

homatropine, tolterodine, trihexyphenidyl.

Quaternary ammonium compounds - glycopyrrolate, Ipratropium.

Effect of Muscarin on different tissues

Some short notes on Anti-Muscarinic action

Muscarinic drugs mechanism of action

competitively block muscarinic receptors. Atropine and scopolamine block all M receptors. Other antimuscarinic drugs are selective. Tertiary antimuscarinics don't block Nn. Quarernary block muscarinic but also Nn.

Anti-muscarinics on CNS

Antimuscarinic on CNS high dose :- Amnesia, malaise, restlessness, irritability, disorientation,

halluciations, delirium. Coma.

Antimuscarinics on CNS intermediate dose :- Mild vagal stimulation. Fatigue, sedation, drowsiness, depression of

vestibular, reduction in parkinsonian tremor and rigidity.

Antimuscarinics on Heart

Antimuscarinics on heart intermediate dose :- Tachycardia. Many types of reflex vagal cardiac slowing can be

abolished. Atria - increase in automaticity and contractility. AV node - increase in conduction and automaticity, decrease in refractoriness. Ventricles - minimal direct effect.

Antimuscarinics on heart low dose :- Decrease in heart rates (due to blockade of M2 presynaptic

autoreceptors and to central vagal stimulation.

Antimuscarinics on Cardiovascular (CV) vessels

Antimuscarinics on CV vessels after high dose :- Dilation of cutaneous blood vessels (unknown mechanism) in

children can cause atropine flush.

Antimuscarinics on Cardiovascular vessels therapeutic dose :- Negligible effects (but vasodilation and hypotension caused by

choline esters are antagonized).

Antimuscarinics on GASTROINTESTINAL TRACK

Antimuscarinics on GIT :- Decreased gastric secretion, decreased tone, contractions,

peristaltic activity. Relaxation of LES, gallbladder, bile ducts.

Antimuscarinics on Genitourinary System

Antimuscarinics on Genitourinary system :- Relaxation of pelves, calyces, ureters. Decreases peristalsis,

relaxation of detrusor muscle (increased capacity).

Antimuscarinics on respiratory system

Antimuscarinics on respiratory system :- Bronchial relaxation, decreased secretions, decreased mucociliary

clearance (except ipratropium).

Antimuscarinics on eyes

Antimuscarinics on eyes :- Relaxation of sphincter of iris (mydriasis), relaxation of ciliary

muscle (cycloplegia, accommodation is lost) hinders outflow of aqueous humor thru schlemm's canal. When atropine is given locally, these effects last for 3 days. Decreased lacrimal gland secretion.

Antimuscarinics on skin

Antimuscarinics on skin :- Decreased sweat. Raises body temperature. Infants and children

are prone to atropine fever.

Antimuscarinic toxicity

Antimuscarinic toxicity :- Skin rashes, urticarial, fever. Therapeutic index >100 adults, but a

dose of 5mg can be lethal to children. Serious atropine poisoning appears in 30 minutes, lasts for 2-7 days. Death due to respiratory failure may follow coma and collapse.

Poisoning by antimuscarinics :- mydriasis, blurring of vision, dryness conjunctiva, difficulty

speaking, dyspnea, respiratory depression, dry hot red skin, dryness of mouth, difficulty swallonging, no bowel sounds, difficulty in micturition, tachycardia, arrhythmias, fatigue, ataxia, restlessness, delirium, hallucinations, coma.

Diagnosis of antimuscarinic poisoning

Diagnosis of antimuscarinic poisoning :-

IM injection of physostigmine. If signs of muscarinic activation do not occur, poisoning with antimuscarinic drug is almost always certain.

Treatment for poisoning

Antimuscarinic treatment :- maintenance of vital signs, alleviation of convulsion with

diazepam, temp control with ice bag and alcohol sponges.

Contraindications of Anti-Muscarinics

Contraindications of antimuscarinics :- glaucoma, prostatic hypertrophy, urinary tract obstruction, GI tract

obstruction, a dynamic ileus, gastric ulcer, infectious diarrhea, UC, chron's disease, tachyarrhythmia’s, coronary artery disease, hyperthyroidism, children, elderly.

Therapeutic uses of antimuscarinics

Therapeutic uses of antimuscarinics :- Funduscopic exam (mydriasis), measurements of refractive

errors, iritis, chroiditis. IBS diahrea, renal colic, enuresis, urinary incontinence (to reduce frequency), preoperative lung surgery to reduce secretions, bronchial asthma and copd (ipratropium), cardio resuscitation (when vagal hyperactivity is the cause of cardiac arrest), sinus or nodal bradycardia, AV block due to increased vagal tone. CNS - prevention of motion sickness (scopolamine), parkinsons (triexyphenidyl). To counteract parasympathomimetic effects of neostigmine in myasthenic patients. Poisoning by AchE inhibitors or mushrooms containing muscarine.

Brief details on drug indication

Atropine- Visceral hypermotility and spasms, excessive salivation, cardio

disorders, cholinesterase inhibitor overdose, ophthalmology, preanesthetic medication.

  Scopolamine-

Motion sickness, ophthalmology, preanesthetic medication.  Homatropine-

Ophthalmology.

Ipratropium- bronchospastic disorders.

Ganglionic stimulating drugs- nicotine, tetramethylammonium (carbachol, cholinesterase

inhibitors, succinylcholine less used).

Ganglionic blocking drugs- hexamethonium, mecamylamine (glycopyrrolate, ipratropium,

tubocurarine less used).

Tolterodine- Neurogenic bladder, urinary urge incontinence.

Trihexyphenidyl- Parkinsons.

Glycopyrrolate- visceral hypermotility and spasms, cardiovascular disorders,

preanesthetic medication.

In Brief

Acetylcholine is the main contractile neurotransmitter of the detrusor muscle – it stimulates the muscarinic receptors. Anti-muscarinic medications are, therefore, used to treat overactive bladder, to :-

• reduce intravesical pressure,• reduce uninhibited contractions.

Available Medication’s

The available medications are:

• listed: oral oxybutynin IR (Ditropan),

propantheline (Pro-Banthine), imipramine (Tofranil) and, as a second-line, the oxybutynin transdermal patch (Oxytrol).

• private script: tolteridine IR (Detrusitol), solifenacin

(Vesicare), darifenacin (Enablex), and the oxybutynin transdermal patch (Oxytrol).

Medication in detail

Oxybutynin IR ( Ditropan XL, Urotrol )

1. This is an anticholinergic, antispasmodic and local anaesthetic.

2. It is more selective for the salivary gland than the bladder, so dry mouth and constipation are common.

3. However, most side effects are caused by an active metabolite from first pass mechanism in the gut.

4. It has well-documented effectiveness at doses of 2.5–5mg up to 4 times a day

Oxybutynin patch (oxytrol )

1. This has no more systemic side effects than placebo, with minimal discontinuation due to dry mouth.

2. It releases oxybutynin 3.9 mg/day and the patch is changed twice a week.

3. There may be redness at the application site.

Solifenacin Brand Name(s): 

India : Soliten (5 mg) | Bispec (10 mg) | Solicept (5mg) | Bispec (5 mg) | Soliten (10 mg) | Vesiact (5mg)

Foreign Names : VESIcare

1. Solifenacin is more selective for M3 receptors in the bladder than in the salivary glands, so there are low rates of dry mouth and a low discontinuation rate.

2. Again, there is well-

documented effectiveness with doses of 5–10 mg once a day.

Darifenacin ( Enablex )

1. Darifenacin is a relatively selective M3 receptor antagonist with low discontinuation rates and good effectiveness.

2. It is given as a once daily oral dose of 7.5–15 mg.

Tolterodine IR ( Detrol LA )

1. Tolterodine in a nonselective muscarinic receptor antagonist with more affinity for the bladder than the salivary gland.

2. It is effective at 1–2 mg twice a day.

Propantheline (Spastheline ) Foreign Names

• Propanthelini Bromidum (Latin)• Propanthelin bromid (German)• Propanthéline bromure de (French)• Propantelina, bromuro de (Spanish)

1. Propantheline is a nonselective muscarinic receptor antagonist with poor GIT absorption, a short half-life, a poor side-effect profile, and varying effectiveness.

Imipramine ( Tofranil )

1. Imipramine has systemic antimuscarinic actions and blocks reuptake of serotonin and noradrenaline.

2. It therefore has cardiovascular side effects and can cause drowsiness in therapeutic antidepressant dosages.

3. Use low dosage to benefit nocturnal enuresis and nocturia

Side Effects

The side effects of antimuscarinic drugs include: dry mouth with difficulty swallowing and thirst dilation of the pupils with difficulty accommodating and

sensitivity to light - i.e. blurred vision increased intraocular pressure hot and flushed skin dry skin bradycardia followed by tachycardia, palpitations and

arrhythmias difficulty with micturition - urinary retention Constipation More rarely: fever confusion, mania, hallucinations rashes

Summary

For many years, antimuscarinic drugs have been the first-line pharmacological treatment for urgency, frequency, and urge incontinence, all symptoms of the disorder termed overactive bladder.

Antimuscarinic treatment is not always effective and is associated with side-effects that limit its clinical use.

They may not be the perfect treatment for all patients with this disorder, but their value for individual patients should not be underestimated.

Further clinical trials with improvement in quality of life as the primary endpoint are needed and may give a fair reflection of the clinical value of antimuscarinic drugs.

Some short notes on Anti-Nicotinic Action

Nicotinic receptors are selectively activated by nicotine and blocked by tubocurarine or hexamethonium.

They are rosette-like pentameric structures which enclose a ligand gated cation channel; their activation causes opening of the channel and rapid flow of cations resulting in depolarization and an action potential.

On the basis of location and selective agonists and antagonists two subtypes NM and NN (previously labelled N 1 and N 2) are recognized.

Two types of Nicotinic receptors NM: These are present at skeletal

muscle end plate are selectively stimulated by phenyl trimethyl ammonium (PTMA) and blocked by tubocurarine. They mediate skeletal muscle contraction.

NN: These are present on

ganglionic cells (sympathetic as well as parasympathetic), adrenal medullary cells (embryologically derived from the same site as ganglionic cells) and in spinal cord and certain areas of brain. They are selectively stimulated by dimethyl phenyl piperazinium (DMPP), blocked by hexamethonium, and constitute the primary pathway of transmission in ganglia.

NEUROMUSCULAR BLOCKERS

About NEUROMUSCULAR BLOCKERS Neuromuscular junction blocking agents

(NMBA’s) act on cholinergic receptors on the skeletal muscle endplate to produce muscle paralysis.

They are used during anaesthesia to facilitate endotracheal intubation and provide surgically required muscle relaxation.

NEUROMUSCULAR BLOCKING DRUGS Depolarizing

Succinylcholine (short acting) Non-depolarizing

Short acting Mivacurium

Intermediate acting Atracurium Cisatracurium Vecuronium Rocuornium

Long acting Doxacurium Pancuronium Pipecuronium

Medication in detail

Atracurium (Tracrium ® )   May be given undiluted by IV bolus.  Dosing (Adults): 

initially 0.4 to 0.5 mg/kg IV bolus, followed by 0.08 to 0.1 mg/kg every 20 to 45 minutes after initial dose. 

Continuous infusion: initially 0.4 to 0.5 mg IV bolus, followed by 9 to 10 mcg/kg/min. Maintenance infusion rates of 5 to 9 mcg/kg/min are usually adequate. (Range: 2 to 15 mcg/kg/min). 

Toxic metabolite (laudanosine) may accumulate in renal failure. [Supplied: 50 mg/5 ml ; 100 mg/10ml vial]

Cisatracurium  (Nimbex ® )   Dosing (Adults):

Intermittent: initial dose: 0.15 to 0.2 mg/kg IV bolus followed by 0.03 mg/kg IV every 40 to 60 minutes. 

Continuous infusion: 0.15 to 0.2 mg/kg IV bolus followed by 1 to 3 mcg/kg/min. The average infusion rate for long term use in the ICU is at 3 mcg/kg/min (range: 0.5 to 10.2 mcg/kg/min). In some cases, re-administration of the bolus dose may be req'd while titrating. Dosage reductions are not required in renal or hepatic failure.

Drug of choice in the following cases: (1) hemodynamically significant increases in HR (eg

>20%) while paralyzed with pancuronium or MAP>110. (2) Concurrent corticosteroid administration (>72hrs) (3) Significant renal dysfunction (CRCL < 30 ml/min) (4)History of asthma or bronchospasm.

Doxacurium  (Nuromax OD ® )   Dosing (Adults): (usual) 

Anesthesia adjunct: initial, 0.05 mg/kg and 0.08 mg/kg IV to provide neuromuscular block for an average 100 min and 160 min, respectively. Maintenance, 0.005 mg/kg and 0.01 mg/kg IV to provide neuromuscular blockage for an average of 30 min and 45 min, respectively. 

Endotracheal intubation: 0.05 mg/kg IV. Endotracheal intubation: (with succinylcholine)

initial, 0.025 mg/kg IV. [ Supplied: 1 mg/ml Solution]

Mivacurium  (Mivacron ® )   Short-acting arizing neuromuscular

blocking agent.  Dosing (Adults)

Endotracheal intubation: 0.15 mg/kg IV bolus. For extended neuromuscular block, IV average infusion rates of 6 to 7 mcg/kg/min are used. Recovery from muscular paralysis occurs within 15 to 30 minutes.

Pancuronium  (Pavulon ® )   Non-depolarizing skeletal muscle

blocker--competes with acetylcholine at the neuromuscular junction. 

Dosing (Adults) Intermittent dosing: 0.1 to 0.2 mg/kg

(usually 0.1) every 1 to 3 hours (range: 0.04 to 0.2 mg/kg). 

Continuous infusion: Loading dose: 0.04 to 0.10 mg/kg , followed by 1 to 1.7 mcg/kg/min or 0.06 to 0.1 mg/kg/hr

Rocuronium  (Zemuron ® )   Dosing (Adults)  (usual): 

Intubation(rapid sequence intubation): initial, 0.6-1.2 mg/kg IV. tracheal intubation: initial, 0.6 mg/kg IV. Maintenance, 0.1-0.2 mg/kg IV repeated as needed. 

Maintenance (continuous IV infusion): 0.01-0.012 mg/kg/minute.

Skeletal muscle relaxation: initial, 0.6 mg/kg IV. Maintenance: 0.1-0.2 mg/kg IV repeated as needed. Alternatively: maintenance (continuous IV infusion): 0.01-0.012 mg/kg/minute

Succinylcholine    Depolarizing skeletal muscle blocker.

Indications: procedures of short duration such as endotracheal intubation. 

Dosing (Adults):  Intermittent: 0.6 mg/kg (0.3 to 1.1) over

10-30 seconds, up to 150mg total dose. Maintenance: 0.04 to 0.07 mg/kg every 5-10 minutes as needed.

Continuous infusion: 2.5 mg/min (0.5 to 10 mg/min).  Dilute to 1-2 mg/ml.

Vecuronium  (Norcuron ® )   Dosing (Adults)

Intermittent dosing: initially 0.08 to 0.1 mg/kg IBW IV bolus. (Higher initial doses-up to 0.3 mg/kg-may be used for rapid onset. Maintenance: 0.01 to 0.015 mg/kg every 25 to 45 minutes as needed. 

Continuous infusion: initial IV bolus (0.08 to 0.3 mg/kg), followed by (after 20-40min), 1 mcg/kg/min infusion (usual range: 0.8 to 1.2 mcg/kg/min). Dosage reductions are not req'd in renal failure.

Ganglionic blocking Drugs

Pharmacology of Ganglionic Blocker’s A ganglionic blocker (or ganglioplegic) is a

type of medication that inhibits postganglionic transmission, primarily by acting as a nicotinic antagonist .

Because ganglionic blockers block the parasympathetic nervous system and sympathetic nervous system, the effect of these drugs depends upon the dominant tone in the organ system.

Ganglionic blockers on CVS :-

Moderate HR increase, decreased CO (b/c of peripheral venous pooling decreases preload), marked decrease in venous tone and peripheral resistance (hypotension in upright position), skin blood flow is decreased, spanchnic and renal blood flow are decreased.

Ganglionic blocker on heart Ganglionic blocker on heart effect :-

Tachycardia (M2).

Ganglionic blocker on arterioles:- vasodilation, orthostatic hypotension .

Ganglionic blocker on veins :- vasodilation, venous pooling, decreased

cardiac output.

Ganglionic blocker on eye

Ganglionic blocker on iris :- Mydriasis.

Ganglionic blocker on ciliary muscle :- Cycloplegia.

Ganglionic blocker on GI tract

Ganglionic blocker on GI tract:-

Decreased motility and tone, constipation.

Ganglionic blocker on urinary bladder

Ganglionic blocker on urinary bladder:-

urine retention.

Ganglionic blocker on exocrine glands

Ganglionic blocker on exocrine glands:-

reduced secretion.

Ganglionic blocker on sweat glands

Ganglionic blocker on sweat glands:-

reduced secretion (anhydriosis).

Therapeutic Uses

- Ganglionic blockers are used less frequently now than they were in the past, because more selective agents are now available. However, they are still used in some emergency situations, such as aortic dissection or  autonomic dysreflexia.

Drug’s Available

The first ganglion-blocker to be used clinically was Tetraethylammonium, although it was soon superseded by better drugs.

Other examples include :-Hexamethonium, Pentolinium, Mecamy

lamine, Trimetaphan, and Pempidine.

Hexamethonium (Methium)

It was formerly used to treat disorders, such as chronic hypertension, of the peripheral nervous system, which is innervated only by the sympathetic nervous system. The non-specificity of this treatment led to discontinuing its use.

Pentolinium  (Ansolysen)

Is a ganglionic blocking agent which acts as a nicotinic acetylcholine receptor antagonist. It can be used as an antihypertensive drug during surgery or to control hypertensive crises. It works by binding to the acetylcholinereceptor of adrenergic nerves and thereby inhibiting the release of noradrenaline and adrenaline. Blocking this receptor leads to smooth muscle relaxation and vasodilatation. Pentolinium can be given orally, injected intramuscularly or administered intravenously.

Mecamylamine A nicotinic antagonist that is well

absorbed from the gastrointestinal tract and crosses the blood-brain barrier. Mecamylamine has been used as a ganglionic blocker in treating hypertension, but, like most ganglionic blockers, is more often used now as a research tool.

Brands of Mecamylamine

Inversine 2.5 mg

Vecamyl 2.5 mg

Trimetaphan camsilate  or trimethaphan camsylate (USA), trade name Arfonad, is a drug that counteracts cholinergic transmission at the ganglion type  of nicotinic receptors of the autonomic ganglia and therefore blocks both the sympathetic nervous system and the parasympathetic nervous system. It acts as a non-depolarizing competitive antagonist at the nicotinic acetylcholine receptor, is short-acting, and is given intravenously.

Pempidine  Is a ganglion-blocking drug, first

reported in 1958 by two research groups working independently, and introduced as an oral treatment for hypertension.

Pharmacokinetics of ganglionic blocker’s:-

Hexamethonoium is quaternary ammonium, mecamyalamine is secondary amine (active by oral and enters CNS).

Side Effects

Cardiovascular: Orthostatic(postural) hypotension, Tachycardia,

GIT: Dry-mouth, GIT atony,urine retention, digestive problems,

Sexual Dysfunction: Failure of erection and ejaculation.

Blocks baroreceptor reflex.

Blocks parasympathetic mediated pupil contraction and accommodation.

PREPARED BY

SYED MASOOD AHMED QUADRI

MESCO COLLEGE OF PHARMACY