The effects of atropine on brain

 

The effects of atropine on brain

The evolution of the finest brain on the planet must have taken millions of years to reach its present complexity.

The brain functions as a single unit but is made up of closely knit “discrete” structures communicating with each other with mindboggling agility.

The “discrete” structures  are nothing but the cerebrum, cerebellum, brainstem, basal ganglia and others.

The neural processing within the “discrete” structures and the communication of neural information between them, are both dependent on neurotransmitters.

The balance between the two ubiquitous neurotransmitters- acetylcholine and dopamine is of paramount importance in maintaining CNS physiology.

Atropine, a non-selective muscarinic blocker (read acetylcholine receptor blocker) crosses the blood brain barrier and therefore, has widespread CNS effects.

Part of the brain	Effect of atropine	Possible explanation
Cerebral cortex	Cognitive impairment manifested as memory loss, inability to perform skilful mental tasks, indecision etc	Projections to the cerebrum from other parts of the brain and the inter-neuronal communication within the cerebrum for cognitive processing are mediated by acetylcholine. Atropine blocks the muscarinic receptors (M1)  in the CNS and therefore causes cognitive impairment.
Basal ganglia	Motor hyperactivity	Tone and movement of muscles depends on the delicate balance between acetylcholine and dopamine in the striatum. Atropine, by blocking acetylcholine action, promotes the unimpeded action of dopamine in the striatum, resulting in hyperkinesia and motor incoordination.
Mesolimbic pathway	Disorientation, hallucination, confusion, excitement	Tilting of balance towards dopaminergic transmission because of cholinergic blockade. Dopamine excess in the striatum has been shown to cause psychotic behaviour.
Vestibular Nuclei	Loss of balance and equilibrium at very high doses	Suppression of cholinergic transmission in the vestibular apparatus in inner ear. This action has therapeutic use in motion sickness.

 

Secondary adverse effects

 

Secondary adverse effects

·         Adverse effects are undesirable or unintended consequence of drug administration

·         In most cases, adverse effects are due to direct effects of drugs

·         In few cases, adverse effects can occur due to indirect effects of drugs

·         For example- tetracycline induced superinfection of gut

·         Explanation

·         Tetracycline is a broad spectrum antibiotic which is given orally

·         However, prolonged use can kill normal intestinal flora

·         In absence of normal intestinal flora, oppurtunistic bacteria like Clostridium difficile can proliferate and spread in the gut.

·         This is known as superinfection or pseudomembranous enterocolitis. In this condition, there is severe inflammation of the large gut. The patient presents with diarrhoea, pain abdomen and fever.

 

Ageing of acetylcholine esterase

 

Ageing of acetylcholine esterase

·         Acetylcholine is the endogenous cholinergic neurotransmitter.

·         Acetylcholine esterase is an enzyme present in the milieu of the synaptic cleft that degrades acetylcholine into acetyl and choline and terminates post synaptic muscarinic receptor stimulation.

·         Acetylcholine esterase inhibitors bind with acetylcholine esterase and prevent degradation of acetylcholine. So cholinergic transmission increases.

·         Acetylcholine inhibitors are of two types-Reversible and Irreversible

·         With reversible acetylcholine inhibitors, the enzyme is regenerated in reasonable time. So cholinergic stimulation is of short duration and shows time bound recovery

·         With irreversible acetylcholine inhibitors, the enzyme is regenerated very slowly. So cholinergic stimulation is prolonged and recovery depends upon synthesis of fresh enzyme.

·         Therefore, poisoning with irreversible inhibitors is much more dangerous than reversible inhibitors.

·         Among the irreversible inhibitors, the organophosphates may lose one of its alkyl groups and the enzyme-organophosphate becomes completely resistant to hydrolysis. The enzyme is not regenerated at all. This is known as “Ageing” of the enzyme. Recovery completely depends upon synthesis of fresh enzyme. Oximes, if administered as antidote, must be administered promptly because after “ageing”, even oximes cannot regenerate the enzymes.

Competitive and non-competitive antagonism

 

Feature	Competitive antagonism	Non-competitive antagonism (equilibrium type)	Non-competitive antagonism (Non-equilibrium)
Site of receptor binding	Same as that of agonist (orthosteric)	Different from that of agonist (Allosteric)	Same as that of agonist (orthosteric)
Reversibility of binding	Reversible	Reversible	Irreversible (strong covalent bonds)
Dose response curve at increasing concentration of antagonist	Rightward shift	Flattening	Flattening
Maximal response	Reached with increase in concentration of agonist (surmountable)	Not reached with increase in concentration of agonist (Unsurmountable)	Not reached with increase in concentration of agonist (Unsurmountable)
Duration of action	As long as antagonist is above the threshold concentration	As long as antagonist is above the threshold concentration	Action persists even if plasma is cleared of the antagonist. Action returns after fresh receptors are synthesized which bind the agonist

 

Congestive heart failure and lower drug absorption

 

Congestive heart failure and lower drug absorption

·        Inability of the heart to pump adequate blood in the circulation leads to congestive heart failure

·        In this condition, blood reaching systemic circulation is inadequate. As a compensatory mechanism there is vasodilation in vital organs like brain, kidneys and vasoconstriction in less vital organs like skin, gut, muscles. Vasoconstriction in blood vessels supplying the gut and allied organs is known as splanchnic vasoconstriction.

·        Venous return also decreases because the pressure build up in the failing heart is transmitted backwards resulting in increase in central venous pressure

·        Increase in venous pressure causes oozing of plasma into the interstitial space causing oedema including the intestinal mucosal oedema.

·        Absorption occurs when drug molecules in the gut lumen move across the gut mucosa into the capillaries and reaches systemic circulation via the portal vein.

·        As venous return is decreased in congestive heart failure, the absorption of drugs from the gut is also decreased.

BOOSTED PI REGIMEN: AN EXAMPLE OF ENZYME INHIBITION USED FOR THERAPEUTIC PURPOSE

 

BOOSTED PI REGIMEN: 

AN EXAMPLE OF ENZYME INHIBITION USED FOR THERAPEUTIC PURPOSE

Protease inhibitors (PIs) are a class of anti-HIV drugs

PIs have high first pass metabolism. They are mainly metabolised by CYP3A4

PIs when indicated, have to be given as 6-18 tablets daily for months. Patient acceptability and compliance are low.

Ritonavir is also a PI which is a CYP3A4 inhibitor.

Low dose of ritonavir in patients receiving PI based regimen, reduces first pass metabolism of the PIs.

Therefore, the dose of PIs can be reduced and the number and frequency of tablets can also be reduced. The side effects are also reduced.

This provides some relief to the people living with HIV infection receiving PI regimen. 

MECHANISM OF ACTION OF IRRITANT DRUGS

 

MECHANISM OF ACTION OF IRRITANT DRUGS

With the advancement in molecular pharmacology, the mechanism of action of drugs have been elucidated at the level of receptors, enzymes and genes. Irritant drugs, on the other hand, act by local mechanism, and by their irritant and stimulant action on nerves, mucosal epithelium or muscle fibres produce effects which can be best understood with some examples.

·         Purgatives like bisacodyl, sodium picosulphate etc irritate the mucosa and stimulate the myenteric neurones, resulting in increased watery secretion and vigorous muscle contractions of the gut wall.

·         Capsaicin, a component of chili, is a chemical irritant and acts on peripheral nerves. It is used for relief of pain in muscles and joints in arthritis, sprain and injury.

·         Certain chemicals which when introduced intrauterine can cause vigorous uterine contractions and abortion by irritant action. It is misused by miscreants for illegal abortion.

·         Ipecacuanha: The dried root of Cephaeliv ipecacuanha contains emetine and is used as syrup ipecac for inducing vomiting. It acts by irritating gastric mucosa as well as through CTZ.

Initial Bradycardia with Atropine

 

MECHANISM OF INITIAL BRADYCARDIA WITH ATROPINE

Normal cholinergic transmission

Acetylcholine is stored in vesicles in the presynaptic neuron

When impulse reaches the pre-synaptic neuron, acetylcholine is released in the synaptic cleft.

Cholinergic receptors are present both on the presynaptic (auto-receptors)  and post-synaptic neuron.

Cholinergic action occurs when acetylcholine binds with the post-synaptic neuron.

Acetylcholine also binds with the auto-receptors causing “feedback” inhibition of the release of acetylcholine from the pre-synaptic neuron.

Atropine blockade

Atropine is a non-selective competitive muscarinic antagonist

Auto-receptors are more sensitive to atropine than the post-synaptic receptors

At low dose of atropine (or initial dose), the auto-receptors are more actively blocked than the post-synaptic receptors.

Inhibition of the “feedback” inhibition at the auto-receptors, results in increase in release of acetylcholine from the pre-synaptic neuron. This increases cholinergic effect and is the cause of initial bradycardia.

At higher dose of atropine, the post-synaptic receptors are completely blocked and are unsurmountable with the physiological amount of acetylcholine in the synaptic cleft. Thereafter, tachycardia prevails.

Mydriatics and Cycloplegics

 

Mydriatics and Cycloplegics

Mydriasis means pupillary dilatation

Cycloplegia means paralysis of the ciliary muscles

Iris has two types of muscles- The dilator pupillae (radial muscles) and the constrictor pupillae (circular muscles)

Muscle	Agonistic action	Antagonistic action	Receptor
Radial Muscles	Dilatation	Constriction	Alpha 1 adrenergic
Circular Muscles	Constriction	Dilatation	M3 muscarinic
Ciliary Muscles	Contraction	Relaxation (Cycloplegia)	M3 muscarinic

 

Therefore, topical application of alpha 1 adrenergic drugs like phenylephrine causes pupillary dilatation but no cycloplegia.

And anti-muscarinic drugs cause both pupillary dilatation and cycloplegia.

These drugs are used in two important procedures.

1.      Fundoscopy

2.     Refraction testing

In fundoscopy, the retina of the patient is viewed under magnification by observing through the pupil. Therefore, pupillary dilatation is required. Both adrenergic and anti-muscarinics can be used. But since cycloplegia is not required in this procedure, anti-muscarinics with strong cycloplegia effect are not preferred.

In objective determination of refractive error, the power of the eye is determined with instruments, in contrast to subjective refraction where the patient actively reads the Snellen chart with lens of different powers. Therefore, in objective refraction both pupillary dilatation and cycloplegia is required. So anti-muscarinics are used, especially in children where the sympathetic tone of the ciliary muscles is very high.

Drug	Class	Mydriasis	Cycloplegia
Homatropine	Anti-muscarinic	Yes	Yes
Cyclopentolate	Anti-muscarinic	Yes	Yes
Tropicamide	Anti-muscarinic	Yes	Weak
Atropine	Anti-muscarinic	Yes	Yes, strong
Phenylephrine	Adrenergic	Yes	No

 

 

REDISTRIBUTION

 

REDISTRIBUTION

The phenomenon of redistribution is seen with drugs which are highly lipid soluble.

After drug administration, when the drug reaches systemic circulation, the drug is preferentially distributed in tissues with the maximum blood supply.

The brain is 2% of the body weight but is highly vascular and receives 15-20% of  the total blood supply. So highly lipid soluble drugs quickly enter the brain and the onset of action is very fast.

The faster the drug molecules enter the brain, the quicker they exit because it is a two way process and remember the blood supply is high both for entry and exit (Voila! Yes it is so!). 

Simultaneously, the drug molecules are also moving into and out of the lesser vascular tissues like the fat but albeit at a slower rate. As the amount of drug in peripheral tissues (read fat) increases, the amount of drug in brain decreases. So the action is terminated. (This is up to which you have already understood O)

However, on repeated administration, the peripheral sites gets gradually filled up and redistribution from brain to adipose tissue slows down and prolonged action of the drug will be observed.

A schematic diagram herewith will help you understand.

First order to zero order in therapeutic range

 **With increase in dose rate, plasma concentration of the drug also increases.

·        **In first order kinetics, as the plasma concentration increases, the rate of elimination also increases.

·        


**So, there is a direct relationship between dose rate and plasma concentration ( linear relation)

·         **The process of metabolism and elimination are carried out by enzymes and transporters.

·        ** Most enzymes and transporters  in the body obey saturation kinetics.

·         **So theoretically, all drugs will show first order kinetics at low concentration in plasma and zero order kinetics at high concentration in plasma.

·        ** However, in clinical pharmacology, we are concerned only about the therapeutic range because the dose and dose interval are planned to keep the drug concentration in the therapeutic range.

·         **So, drugs for which the enzymes and transporters are yet not saturated in therapeutic range are said to obey first order kinetics. And drugs for which the enzymes are saturated in therapeutic range are said to obey zero order kinetics.

Fo**For drugs like phenytoin, the enzymes and transporters become saturated from non-saturated state in the therapeutic range, and the elimination kinetics also change from the first order to zero order in the therapeutic range.

**So if we plot a graph between dose rate and plasma concentration, it will be linear and less steep in the initial phase (first order kinetics), but steeply rising in the later phase (zero order kinetics)