Anticholinergic drugs

Also known as muscarinic receptor antagonists.

Muscarinic blockers block the muscarinic receptors. These include the naturally occurring alkaloids (Belladonna alkaloids), and have two prototype drugs:

1. Atropine from atropa belladonna
2. Hyoscine from hyoscyamus niger

Once the antagonist binds receptors, it prevents binding of agonist. This binding does not depend on the affinity of the receptor in muscarinic receptors, it depends on:

1. Parasympathetic tone and innervations and the functions regulated to parasympathetics.
2. Constitutively active receptors and their own intrinsic activity.

They prevent the binding of acetyl choline and shift equilibrium from active to inactive form. These are known as inverse agonists and include atropine, M1 selective drugs, Pirenzepine, methyl derivatives of Scopolamine (Hyosine) and trihexphenydle.

In smaller therapeutic doses, these drugs cause decreased salivary and bronchial secretions and decreased sweating. In larger doses, they cause dilated pupils, loss of accommodation and increased parasympathetic tone in young adults.

Classification

Muscarinic Antagonists/Antimuscarinics

1.      Non-selective

a.      Natural

Atropine

Hyoscine (Scopolamine)

b.      Semi-synthetic/Synthetic

Tertiary amines

Quaternary amines

2.      Selective

a.      M1 antagonists

Pirenzepine

Telenzepine

Dicyclomine (irritable bowel syndrome)

b.      M2 antagonists

AF-DX 116

Methoctramine

Gallamine

Tripitramine

Himbacine

c.       M3 antagonists (urinary incontinence)

Darifenacin

Oxybutanin

Solefencicin

Tolterodine

Quaternary amines

Trospium, Ipratropium, Propanetheline, Methanetheline, Glycopyrrolate, Anisotropine, Isopropamide

Tertiary amines

Homatropine, Eucatropine, Tropicamide, Cyclopentolate, Oxybutynin, Dicylcomine

Chemistry
Tertiary amine alkaloids esters of tropic acid

Organic acid  + Base  =   esterification

Tropic acid + tropine    =    Atropine

Tropic acid + scopine    =   Scopolamine (Hyoscine)

Mandelic acid + Tropine  =  Homatropine (non-selective, longer duration, semi-synthetic)

Mechanism of action

• Antimuscarinic drugs block  the muscarinic receptors, which can be reversed by increasing the concentration of muscarinic  agonist.
• Antimuscarinic drugs prevents:
  a. the release of inositol triphosphate (IP3)

b. the inhibition of adenylcyclase (caused by muscarinic agonist)

Pharmacokinetics

• Tertiary amines are well absorbed from GIT
• Quaternary amines 10-30% absorbed from GIT
• Tertiary amines are widely distributed in the body
• Quaternary amines limited in their distribution
• Atropine is excreted largely as unchanged drug in urine
• Only about  1% of the oral dose of scopolamine is excreted in urine as unchanged
• Atropine effects in body remain only for a few hours but in the eye its effects persist for about 72 hours

Normally it is applied topically, as eye drops and ointments can get absorbed and through nasolacrimal gland, causing toxicity.

Pharmacological Properties Of Anticholinergics

Atropine is a competitive antagonist of acetyl choline and other muscarinic agonists on muscarinic receptors, it selectively reduce s or abolishes the muscarinic effects of acetyl choline. Actions are more marked in organs with high parasympathetic innervation.

Atropine and Hyosine are natural alkaloids which differ quantitatively, main differences being in the action on CNS.

• Atropine has stimulant effect initially in therapeutic doses
• Hyosine is CNS depressant
• In higher doses, both drugs have stimulant effect.

Effects on CNS

Scopolamine causes drowsiness, amnesia, fatigue and dreamless sleep.  It is effective in motion sickness. It has good absorption from skin, thus skin packs may be applied behind the ear.

Both may be used to treat extra pyramidal side effects of antipsychotic drugs (used in Parkinsonism, depression).

Toxic doses of both alkaloids produce CNS excitation- restlessness, irritability, disorientation, hallucination or delirium.  Stimulation is followed by depression, coma, medullary paralysis and death.

Effects on Eye

M1 receptors are present in the eye. Mydriasis produced due to blockade of the cholinergic stimulation of sphincter, this will allow adrenergic action on the radial muscles to dominate, resulting in unopposed dilator activity and weakness of contraction of ciliary muscles. Loss of ability to accommodate occurs.

Photophobia is due to mydriasis. Light reflex is lost.

Cycloplegia is the paralysis of ciliary muscles.

Reduction of lacrimal secretion occurs. The patient complains of dry and sandy eye when receiving large doses of anticholinergic drugs.

Intraocular pressure is increased in patients having narrow angle glaucoma.

Atropine has limited role therapeutically.

Effects on GIT

Therapeutic dose of atropine produce a decrease in tone, amplitude and frequency of peristalsis, and causes constipation

Large doses decrease secretion of (HCl) mucin and proteolytic enzymes in gastric juice.

The action is non-selective.

Effects on Respiratory & Genitourinary Tract

Respiratory tract:

Inhibition of secretions of upper respiratory tract, prevention of  laryngospasm, induced by excessive secretions due to certain general anesthetics

Inhibition of bronchoconstriction produced by parasympathetic stimulation

Genitourinary Tract:

No Effect on uterus.

Urinary Tract:

Decrease in tone and contraction of urethra and bladder

Sweat Glands

Sweat secretions are decreased, thus hyperthermia blush may occur.

Cutaneous vasodilatation causes atropine flush in neck and upper areas. Hyperthermia may be fatal in children.

Effects on CVS

Heart

Small dose – bradycardia due to blockade of M1 receptors

Larger dose – tachycardia due to blockade of M2 receptors

Ventricles are less affected because less vagal tone has less effect (dilate coronary artery)

Atropine blocks the vasodilatation due to endothelial muscarinic receptors.

Blood Vessels

Majority of blood vessels are not affected.

In toxic doses vasomotor paralysis occurs leading to fall in blood pressure.

Dilatation of cutaneous blood vessels may occur causing flushed skin

Exocrine Secretions

Salivary and bronchial secretions are inhibited – dry mouth

Sweating is inhibited – hot skin.

Antagonists  For Three Types Of Muscarinic Receptors

M1.  Pirenzepine (peptic ulcer, M1 receptor effect), telenzepine

M2.  AF-DX116, methoctramine, himbacine, tripitramine.

Tripitramine is used to block  cholinergic bradycardia.

M3.  Hexa hydro siladifenidiol and darifenacin.

Darifenacin is used for overactive bladder

Atropine is used in the eyes. It is not used in elderly because they are already prone to acute angle glaucoma and bladder actions (urinary retention).

Side Effects (through M2)

1. Blurring of vision
2. Constipation
3. Urinary retention in elderly

Atropine used for moderate tachycardia, may become severe (SA block)

GIT and bladder effects selective drugs are made. Non-selective antimuscarinic drugs block parasympathetic innervation. Thus more adverse effects are seen with non-selective drugs.

Antidepressant, antipsychotic, antihistamine and antimuscarinic effects may be seen so problems might arise when given in combination with these.

Therapeutic classification of Anticholinergics

Mydriatics

Tertiary amines: Homatropine, hydro bromide, eucatropine, cyclopentolate, tropicamide.

Their advantages over atropine are:

They are short acting and produce less cycloplegia.

Anti Spasmodic

Quaternary ammonium compounds:

Propantheline, methantheline, oxyphenonium, glycopyrrolate, hyosine butyl bromide (drug of choice for abdominal cramps)

Tertiary amines:

Dicyclomine (irritable bowel syndrome, bowls of constipation and diarrhea), oxyphencyclimine, piperidolateamprotropine, oxybutynin chloride

Anti-Parkinsonian Agent

These are tertiary amines, e.g. trihexyphenidyl, benztropine, orphenadrine, biperidine, procyclidine, cycrimine, ethopropazine

Anticholinergics were used for Parkinsonism before L dopa.

Anti ulcer

Telenzepine, Pirenzepine

Anti-Asthmatics

Ipratropium, Oxytropium (route of administration is inhalational)

Pre anesthetics

Atropine, Hyosine, Glycopyronium

Motion sickness

Hyosine

Urinary Incontinence

Non- selective: Trospium

Selective M3 antagonists: Darifenacin, Oxybutynin, Solefenacin, Tolterodine

Selective Anti-Muscarinic Drugs

Ipratropium and Oxitropium relieve bronchospasm in asthma/COPD by inhalational route (beta 2 agonists most potent), also given to smokers when cilia are damaged and mucous cannot be removed

Oxybutynin and Tolterodine :

1. Relieve bladder spasm after surgery

2.Urteral spasm due to ureolithiasis

Clinical Uses Of Anticholinergics

Use In GIT

Pirenzepine acts synergistically with H2 blockers in the treatment  of peptic ulcer

Increased tone and motility of GIT

Irritable bowel syndrome

To reduce salivary secretion in heavy metal poisoning, Parkinsonism and esophageal stricture.

Eye

Topical use of mydriatic for fundoscopic examination

Topical use of cycloplegic for iritis, iridocyclitis, choroiditis

Alternating with miotic to prevent or break the adhesions between iris and lens

In open angle glaucoma, trabecular meshwork is broken, to increase the flow, contraction and dilatation breaks adhesions.

Respiratory Tract

Ipratropium inhalation in bronchial asthma and COPD

CVS

To antagonize reflex cardiac slowing

In hyperactive carotid sinus reflex

In patients with inferior or posterior wall infarction having decreased cardiac output, sinus or nodal bradycardia.

In AV block due to digitalis toxicity.

CNS

Benztropine, for treating extra pyramidal disorder due to antipsychotic drugs.

Scopolamine (oral transdermal) for prevention and treatment of motion sickness because of vestibular disturbances. It is taken orally half an hour before journey, thus has prophylactic use

General Anesthesia

Not used any more.

To inhibit excessive salivation and secretion of respiratory tract and to prevent reflex vagal stimulation of the heart

Atropine given with neostigmine to counter its muscarinic effect when given to end the effect of competitive type of neuromuscular blocking agent.

Neostigmine is given for reversal of effects now (anticholine esterase). There are chances of aggravation of bradycardia because of muscarinic effects. Atropine is given for blocking the unwanted blocking actions.

Genitourinary Tract

Atropine with an opioid in the treatment of renal colic to prevent abuse liability. Atropine is not given for antispasmatic actions.

To relieve ureteral spasm and irritability of bladder (urinary urgency) and after urologic surgery (e.g., prostatectomy) and also reducing involuntary voiding in patients with neurological diseases  oxybutynin is used.

Anticholinesterases And Mushroom Poisoning

• Antidote for organophosphate poisoning
•  To antagonize muscarinic effect of neostigmine in myasthenia gravis (symptomatic treatment)
•  Rapid type of muscarinic (inocybe) poisoning

Contraindications Of Atropine(Absolute and Relative)

• Narrow angle glaucoma
•  Enlarged prostate
•  Delayed type of mushroom poisoning
•  Pyloric stenosis
•  Congestive heart failure with tachycardia (blocks intraventricular conduction)
•  Patients over the age of 40 years as it may precipitate an acute attack of congestive glaucoma.
•  Chronic lung disease as this reduces respiratory tract secretions.

Vasodilatation is a diagnostic sign of atropine over dosage.

Blush area is due to hyperthermia, there is redness on cutaneous surface.

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