Pharmacological Actions & Pharmacokinetics

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Chapter: Essential pharmacology : Anticholinergic Drugs And Drugs Acting On Autonomic Ganglia

The actions of atropine can be largely predicted from knowledge of parasympathetic responses. Prominent effects are seen in organs which normally receive strong parasympathetic tone. It blocks all subtypes of muscarinic receptors.


PHARMACOLOGICAL ACTIONS

(Atropine As Prototype)

 

The actions of atropine can be largely predicted from knowledge of parasympathetic responses.

Prominent effects are seen in organs which normally receive strong parasympathetic tone. It blocks all subtypes of muscarinic receptors.

 

1. CNS

 

Atropine has an overall CNS stimulant action. However, these effects are not appreciable at low doses which produce only peripheral effects because of restricted entry into the brain. Hyoscine produces central effects (depressant) even at low doses.

 

o   Atropine stimulates many medullary centres —vagal, respiratory, vasomotor.

 

o   It depresses vestibular excitation and has antimotion sickness property. The site of this action is not clear—probably there is a cholinergic link in the vestibular pathway, or it is exerted at the cortical level.

 

o   By blocking the relative cholinergic overactivity in basal ganglia, it suppresses tremor and rigidity of parkinsonism.

 

o   High doses cause cortical excitation, restlessness, disorientation, hallucinations and delirium followed by respiratory depression and coma.

 

Majority of the central actions are due to blockade of muscarinic receptors in the brain, but some actions may have a different basis.

 

2. CVS

 

Heart The most prominent effect of atropine is to cause tachycardia. It is due to blockade of M2 receptors on SA node through which vagal tone decreases HR. Higher the existing vagal tone— more marked is the tachycardia (maximum in young adults, less in children and elderly). On i.m./s.c. injection transient initial bradycardia often occurs. Earlier believed to be due to stimulation of vagal centre, it is now thought to be caused by blockade of muscarinic autoreceptors (M1) on vagal nerve endings augmenting ACh release. This is suggested by the finding that selective M1 antagonist pirenzepine is equipotent to atropine in causing bradycardia as are atropine substitutes which do not cross bloodbrain barrier. Atropine abbreviates refractory period of AV node and facilitates AV conduction, especially if it has been depressed by high vagal tone. PR interval is shortened.

 

BP Since cholinergic impulses are not involved in maintenance of vascular tone, atropine does not have any consistent or marked effect on BP. Tachycardia and vasomotor centre stimulation tend to raise BP, while histamine release and direct vasodilator action (at high doses) tend to lower BP.

 

Atropine blocks vasodepressor action of cholinergic agonists.

 

3. Eye

 

The autonomic control of iris muscles and the action of mydriatics as well as miotics is illustrated in Fig. 8.1. Topical instillation of atropine causes mydriasis, abolition of light reflex and cycloplegia lasting 7–10 days. This results in photophobia and blurring of near vision. The ciliary muscles recover somewhat earlier than sphincter pupillae. The intraocular tension tends to rise, especially in narrow angle glaucoma; conventional systemic doses produce minor ocular effects.



 

4. Smooth Muscles

 

All visceral smooth muscles that receive parasympathetic motor innervation are relaxed by atropine (M3 blockade). Tone and amplitude of contractions of stomach and intestine are reduced; the passage of chyme is slowed—constipation may occur, spasm may be relieved. However, peristalsis is only incompletely suppressed because it is primarily regulated by local reflexes and other neurotransmitters (5HT, enkephalin, etc.) as well as hormones are involved. Enhanced motility due to injected cholinergic drugs is more completely antagonised than that due to vagal stimulation.

 

Atropine causes bronchodilatation and reduces airway resistance, especially in COPD and asthma patients. Inflammatory mediators like histamine, PGs and kinins increase vagal activity in addition to their direct action on bronchial muscle and glands. Atropine attenuates their action by antagonizing the reflex vagal component.

 

Atropine has relaxant action on ureter and urinary bladder; urinary retention can occur in older males with prostatic hypertrophy. However, the same can be beneficial for increasing bladder capacity and controlling detrusor hyperreflexia in neurogenic bladder/enuresis. Relaxation of biliary tract is less marked and effect on uterus is minimal.

 

5.   Glands

 

Atropine markedly decreases sweat, salivary, tracheobronchial and lacrimal secretion (M3 blockade). Skin and eyes become dry, talking and swallowing may be difficult.

 

Atropine decreases secretion of acid, pepsin and mucus in the stomach, but the primary action is on volume of secretion so that pH of gastric contents may not be elevated unless diluted by food. Since bicarbonate secretion is also reduced, rise in pH of fasting gastric juice is only modest. Relatively higher doses are needed and atropine is less efficacious than H2 blockers in reducing acid secretion. Intestinal and pancreatic secretions are not significantly reduced. Bile production is not under cholinergic control, so not affected.

 

6.   Body Temperature

 

Rise in body temperature occurs at higher doses. It is due to both inhibition of sweating as well as stimulation of temperature regulating centre in the hypothalamus. Children are highly susceptible to atropine fever.

 

7.    Local Anaesthetic Atropine has a mild anaesthetic action on the cornea.

 

Atropine has been found to enhance ACh (also NA) release from certain postganglionic parasympathetic and sympathetic nerve endings, and thus produce paradoxical responses. This is due to blockade of release inhibitory muscarinic autoreceptors present on these nerve terminals.

 

The sensitivity of different organs and tissues to atropine varies and can be graded as—

Saliva, sweat, bronchial secretion > eye, bronchial muscle, heart > smooth muscle of intestine, bladder > gastric glands and smooth muscle.

 

The above differences probably reflect the relative dependence of the function on cholinergic tone vis a vis other influences, and variation in synaptic gaps in different organs. The pattern of relative activity is nearly the same for other atropine substitutes except pirenzepine which inhibits gastric secretion at doses that have little effect on other secretions, heart and eye. This is probably because atropine equally blocks M1, M2 and M3 receptors whereas pirenzepine is a selective M1 antagonist.

 

Atropine more effectively blocks responses to exogenously administered cholinergic drugs than those to parasympathetic nerve activity. This may be due to release of ACh very close to the receptors by nerves and involvement of cotransmitters.

 


 

Hyoscine The other natural anticholinergic alkaloid differs from atropine in many respects, these are tabulated in Table 8.1.

 

PHARMACOKINETICS

 

Atropine and hyoscine are rapidly absorbed from g.i.t. Applied to eyes they freely penetrate cornea. Passage across blood-brain barrier is somewhat restricted. About 50% of atropine is metabolized in liver and rest is excreted unchanged in urine. It has a t½ of 3–4 hours. Hyoscine is more completely metabolized and has better blood-brain barrier penetration.

 

Atropine sulfate: 0.6–2 mg i.m., i.v. (children 10 μg/kg), 1–2% topically in eye. ATROPINE SULPHATE: 0.6 mg/ ml inj., 1% eye drop/ointment; ATROSU LPH 1% eye drop, 5% eye oint.

 

Hyoscine hydrobromide: 0.3–0.5 mg oral, i.m.; also as transdermal patch.

Combinations of atropine with analgesics and antipyretics are banned in India.

 

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