Cholinergic Drugs

• Cholinergic drugs are those which release acetylcholine as neurotransmitter. These are of two types;
• Cholinergic drugs which act directly on postsynaptic membrane receptors are called as direct acting drugs.
• Cholinergic drugs which stop the activity of acetyl cholinesterase thus increasing the Ach in the synaptic cleft are known as indirect acting drugs.

Direct Acting Drugs

Direct acting cholinergic drugs include two types of drugs;

Natural Alkaloids… Which Include nicotine, muscarine, pilocarpine and arecoline

Synthetic Drugs… which include Acetylcholine, carbachol, methacholine and bethanicol

If an additional methyl group attaches on β carbon, methacholine is formed.

If an NH2 group is attached instead of methyl group in Acetyl choline (Acetyl co-a portion), carbachol is formed.

If a methyl group is attached on β carbon in structure of Carbachol, Bethanichol is formed.

• Nicotinic receptors are only stimulated by Ach and Carbachol.
• Muscarinic receptors are stimulated by all.

Prototype Drugs
Drugs which are representative of groups. These drugs are studied thoroughly and then compared with other members of the group. E.g. Ach

Effects on Different organ Systems

Therapeutic Uses

Acetylcholine

• It is of no therapeutic use because it is degraded rapidly because of presence of PsuedoCholinesterase or Buterylcholinesterase in the plasma.
• It Hydrolyzes Ach rapidly
• Acetylcholinesterase is present in RBCs, grey matter of brain and nerve endings.
• Pseudocholinesterase is also present in liver and intestine.
• So, effect of Ach will not be observed intravenously or there will be short lived effect.

Methacholine

• It is slowly hydrolyzed so duration of activity will be greater.
• The primary clinical use of methacholine is to diagnose bronchial hyper reactivity. Which is the hallmark of asthma and also occurs in chronic obstructive pulmonary disease
• This is accomplished through the bronchial challenge test, in which a subject inhales aerosolized methacholine, leading to bronchoconstriction.
• Other therapeutic uses are limited by its adverse cardiovascular effects, such as bradycardia and hypotension, which arise from its function as a cholinomimetic.

Carbachol

• It is not hydrolyzed by enzymes.
• It increases motility of intestine and uterus.
• Carbachol is a parasympathomimetic that stimulates both muscarinic and nicotinic receptors. In topical ocular and intraocular administration its principal effects are miosis and increased aqueous humour outflow. Aqueous humour is a thich watery substance filling the space b/w lens and cornea.
• In the cat and rat, carbachol is well-known for its ability to induce rapid eye movement (REM) sleep when microinjected into the pontine reticular formation.
• Carbachol elicits this REM sleep-like state via activation of postsynaptic muscarinic cholinergic receptors (mAChRs).

Bethanicol

• Bethanechol is used clinically to treat post-op paralytic ileus (GI), urinary retention (GU) and glaucoma.  (In glaucoma the choline ester, bethanechol, is used to reopen the channels while the soon to be seen adrenergics will help decrease aqueous humor production.)
• It can also be used for the treatment of the gastro esophageal reflux.

Indirect Acting Drugs

These drugs are reversible or irreversible inhibitors of Acetylcholinestrase.

Reversible Inhibitors

• These inhibitors block enzyme and detach from it after some time. 
• These include Edrophonium, Physostigmine, Neostigmine, Pyridostigmine and Carbaryl.

Irreversible Inhibitors

• These block enzymes permanently but do not detach from it. 
• These include organophosphates (Di isopropylflourophosphate..DFP), Echothiophate, Melathion, Parathion (both are insecticides), soman, tabnum, cumaphos, trichlorofen and dichlorofen ( last 3 are used against ectoparasites).

Acetylcholinesterase

• This enzyme has two reactive sites which are used for hydrolysis of compounds like Ach.
• These sites are anionic and esteratic sites. Anionic site attaches to N portion of Ach and Esteratic site attaches to Carbon of Ach. So, complex is formed.
• After this, addition of water occurs and acetylated Enzyme and choline detaches.
• In the last step, choline detaches from esteratic site.

 

Edrophonium

Edrophonium first occupies anionic site and then OH covers the esteratic site and complex forms.

Its activity is short lived and again cholinesterase starts working after some time.

• Because its duration of action is only about 20 minutes, edrophonium (by the so-called Tensilon test) is used to differentiate myasthenia gravis from cholinergic crisis.
• In myasthenia gravis, where a person is not able to produce enough neuromuscular stimulation, edrophonium will reduce the muscle weakness by effectively supplying more acetylcholine.
• In a cholinergic crisis, where a person has too much neuromuscular stimulation, edrophonium will make the muscle weakness worse by inducing a depolarizing block.

Neostigmine

• When complex is formed, addition of water occurs.
• Anionic site become free but esteratic site remained occupied and carbamylated enzyme is formed.
• After some time, both sites become free.
• Neostigmine is converted into 3-HPTA (Hydroxy phenyl trimethyl acetate) and DMCA (dimethyl carbamic Acid) during the reaction.
• It is used to improve muscle tone in people with myasthenia gravis and routinely, in anesthesia at the end of an operation, to reverse the effects of non-depolarizing muscle relaxants such as rocuronium and vecuronium.
• It can also be used for urinary retention resulting from general anesthesia and to treat curariform drug toxicity.
• Another indication for use is the Ogilvie syndrome which is a pseudoobstruction of the colon in critically ill patients.
• Historically, it has been used as a test for early pregnancy. In a non-pregnant female whose menstrual period is delayed, administration of neostigmine can provoke menstrual bleeding. Modern tests which rely on detecting hCG in urine have rendered this application obsolete.
• Though one of only two treatments available for myasthenia gravis this drug is no longer available to anyone using the Medicare Part D program.

How Irreversible Inhibitors Act?

Organophosphates

• DFP interacts with esteratic site and occupies it. Enzyme becomes inactive.
• After some time, covalent bond if formed and it cannot be separated.
• Enzyme substrate complex in this reaction is phosphorylated enzyme.
• This enzyme is also called as aged enzyme and the process is called as aging of enzyme. This enzyme is long lived.
• Substances which reactivate the enzyme are called reactivators of enzyme. E.g. class Oximes which include paraladoxine and obidoxine.
• Paraladoxine first attaches itself to anionic site with N portion and then attaches to phosphate of DFP and separates it from Esteratic site. Then, 2-PAM itself detaches from anionic site and enzyme is free.
• Reactivation can only occur before the formation of covalent bond.

 

Signs of organophosphate poisoning

Signs of organophosphate poisoning include:

• Salivation
• Lacrimation
• Urinary incontinence
• Defecation
• GI upset/diarrhea
• Emesis
• miosis

Therapeutic uses of Organophosphates

• Several organophosphate agents are being tried therapeutically. Cholinesterase inhibition, which in large doses makes these agents effective pesticides, also may be useful in other doses for treating dementia. Metrifonate has been used to treat schistosomiasis and is undergoing trials for the treatment of primary degenerative dementia.
• The organophosphates pyridostigmine and physostigmine are carbamate anticholinesterases that have been used for many years for the treatment of myasthenia gravis. Although the short-duration anticholinesterases are generally safe, reports of their abuse are associated with a picture similar to pesticide intoxication.
• One of the author's patients had been diagnosed erroneously as a myasthenic. Long-term "therapeutic" doses of physostigmine chemically altered her neuromuscular junctions to the point where she had to be slowly weaned from the drug.
• Sung and others have reported on the ability of these substances to induce nicotinic receptor modulation. This explains the action of these drugs and may result in development of more effective agents.