Autonomic Nervous System (ANS) Cholinergic Drugs -3
أ.م.د.وحدة بشير اليوزبكيObjectives
At end of this lecture, the students should be able to: 1- State the indirect acting cholinergic drugs. 2- Identify the individual indirect acting cholinergic drugs. 3- Discuss the organophosphorous poisoning. In a way, consistence with standards scientific curriculum for the College of Medicine/ University of Mosul.2. Indirect acting cholinergic agents Cholinesterase inhibitor or Anticholinesterase
Mechanism of action: - Achesterase is an enzyme that specifically cleaves Ach to acetate and choline. - Inhibitors of Ach esterase enzyme indirectly provide a cholinergic action by accumulation of Ach in the synaptic space instead of being destroyed so prolonging the lifetime & the clinical effects of Ach produced endogenously at the cholinergic nerve endings.a- Indirect acting Cholinesterase inhibitor, Reversible
1- Short acting: Edrophonium: Used parentrally ( by injection). - Short duration of action (10-20 minutes). Clinical uses: 1- Drug of choice for diagnosing Myasthenia gravis (MG). 2- Used to differentiate M.G (which is weakness due to severe disease or inadequate anticholinesterase treatment) from cholinergic crisis (which is weakness due to over treatment with anticholinesterase).2- Intermediate & long acting
Physostigmine Actions: It has a wide range of actions because it stimulates not only muscarinic and nicotinic sites of the ANS but also the NR of the neuromuscular junction (skeletal muscle). PK: 1- Its duration of action is about 2-4 hours. 2- Physostigmine can enter and stimulate the CNS.Therapeutic uses of Physostigmine
1- Used topically in the eye (but pilocarpine is more effective), it produces meiosis and spasm of accommodation and a decrease of IOP in glaucoma. 2- The drug increases intestinal and bladder motility in case of atony of either organ. 3- Used in the treatment of overdoses of drugs with anticholinergic actions such as atropine, phenothiazines and tricyclic antidepressants.2- Intermediate & long acting
Neostigmine - Its effect more on skeletal muscle (N-M junction) and GIT than CVS & eye. - It has a moderate, duration of action, usually 2-4 hours. Clinical Uses: 1- Symptomatic chronic treatment of myasthenia gravis. 2- As an antidote for tubocurarine and other competitive neuromuscular blocking agents. 3- It is used to stimulate the bladder & GlT after surgery.
2- Intermediate & long acting
Pyridostigmine - It is another cholinesterase inhibitor similar to neostigmine. - Its duration of action (3-6 hours) is longer than that of neostigmine (2-4 hours). - Used orally & paranterally. Clinical uses: 1- Chronic management of myasthenia gravis. 2- As an antidote to competitive neuromuscular blocking agents.Note
- Neuromuscular blockade is frequently produced as an adjunct to surgical anesthesia, using nondepolarizing neuromuscular blocking drugs (muscle relaxants) such as tubocurarine. - Following the surgical procedure, it is usually desirable to reverse this pharmacologic muscle paralysis rapidly. This can be easily accomplished with cholinesterase inhibitors (neostigmine or pyridostigmine) which are the drugs of choice. They are given intravenously or intramuscularly for rapid effect.b- Indirect acting Cholinesterase inhibitor, Irreversible (Very long acting)
Isoflurophate & Echothiophate Therapeutic uses of Isoflurophate: - The drug is used topically in the eye for the chronic treatment of open-angle glaucoma. The effects may last for up to one week after a single administration. Echothiophate: is a newer drug. Its use is the same as Isoflurophate.b- Indirect acting Cholinesterase inhibitor, Irreversible (Very long acting)
- A number of synthetic organophosphate compounds. Used in agriculture or pesticides & insecticides. - Many of these drugs are extremely toxic & were developed by the military as nerve gases. - Of these substances GA (Tabun); GB (Sarin) and GD (Soman) called Nerve gases, although they are volatile liquids.Poisoning with cholinesterase inhibitors (Organophosphorous poisoning)
Mechanism of action: - An organophosphate that covalently binds to a serine-OH at the active site of Achesterase. Once this occurs, the enzyme is permanently inactivated, and restoration of Achesterase activity (recovery) requires the synthesis of new enzyme molecules, this process may take weeks, although clinical recovery is usually evident within days.Clinical Features of Organophosphorous poisoning
1- Excessive salivation, nausea, vomiting. abdominal cramps, diarrhea & lacrimation. 2. Excessive bronchial secretion, bronchoconstriction, cough, wheezing and dyspnea. 3. Bradycardia. 4. Involuntary micturation.5. Sweating . 6. M-weakness, twitching. 7. Meiosis (small size pupil) , anxiety, headache, convulsion, respiration failure. - Death is due to actions on CNS, paralysis of respiratory m. and excessive bronchial secretion & constriction.