Autonomic Nervous System 6-Anticholinergic Drugs أ0م0د.وحدة بشير اليوزبكي

Objectives At end of this lecture, the students should be able to: 1- Identify nicotinic antagonists drugs. 2- Discuss ganglionic blocking drugs . 3- Discuss neuromuscular blocking drugs.   - At a level consistence with standards scientific curriculum for the College of Medicine/ University of Mosul.

Nicotinic Antagonists

1- Ganglionic Blocking Agents - Hexamethionin, mecamylamine and other ganglion-blockers were mainly used in the treatment of hypertension. - But unfortunately, the adverse effect of ganglion blocked are so severe (both sympathetic and parasympathetic divisions are blocked), so that patients are unable to tolerate long term treatment with them.

1- Ganglionic Blocking agents Trimethaphan - It is the only Ganglion-blocker still in clinical use. Its poorly lipid soluble. - Inactive orally and has a short half-life. - It is used IV to treat severe accelerated hypertension (malignant hypertension). Note: Because the ganglion-blocking agents interrupts sympathetic control of venous-pooling, so so these drugs cause postural hypotension.

2- Neuromuscular Blocking Drugs - These drugs are important for producing complete sk-m relaxation in surgery, by specific blockade of the N-M junction. -They enable light level of anesthesia to be employed with adequate relaxation of the muscles of the abdomen and diaphragm. - They also relax the vocal cords and allow the passage of a tracheal tube. Note: - Patients who have received a M-relaxant should always have their respiration assisted or controlled until the drug have been inactivated or antagonized.

Non Depolarizing Competitive N-M blocking agents Action: - Drugs of this group cause N-M block by competing with Ach at the receptor site at the N-M junction so prevent depolarization of muscle cell membrane and inhibit muscle contraction so causing complete SK- M relaxation. PK: - Most non depolarizing agents have relatively long t1/2 ranging from 20 min to several hours. - These drugs are given parentally (by injection).

Non Depolarizing Competitive N-M blocking agents Tubocurarine - Is the prototype it produces a competitive block at the at the motor endplate of the muscle causing flaccid paralysis lasts 30-60 min. - Tubocurarine blocks autonomic ganglia and causes an initial transient drop in blood pressure & cause histamine release which may induce bronchospasm. Pancuronium, Atracurium are short acting non-depolarizing agents.

Non Depolarizing Competitive N-M blocking agents Note: The action of competitive N-M blocking drugs is antagonized by anticholinesterases, like Neostigmine which is usually given IV, and preceded by atropine to prevent the parasympathetic autonomic effect of Neostigmine (such as bradycardia and salivation).

Depolarizing Non competitive N-M blocking agents Suxamethonium (Succinylcholine) Mechanism of action: - It attaches to the nicotinic receptors and acts like Ach to depolarize the N-M junction. - Unlike acetylcholine, which is rapidly destroyed by Achesterase, the depolarizing agent persists at high concentrations in the synaptic cleft, remaining attached to the receptor for a relatively long time & providing a constant stimulation of the receptor. Initially this produces short-lasting muscle fasciculation, followed within a few minutes by muscle paralysis.

Suxamethonium (succinylcholine) - The drug does not produce a ganglionic block, except in high doses, although it does have weak histamine-releasing action. - Normally, the duration of action of succinylcholine is extremely short (Total paralysis last up to 4 min) - succinylcholine It is particularly used during anesthesia for brief procedures? such as tracheal intubations or electroconvulsive therapy (ECT).

PK of Suxamethonium (succinylcholine) - Succinylcholine is injected intravenously. - Unlike the non depolarizing muscle relaxants (tubocurarine), the succinylcholine action cannot be reversed by other drug. Instead of this its brief duration of action (several minutes) ended by rapid hydrolysis by plasma pseudo cholinesterase enzyme.  

PK of Suxamethonium (succinylcholine) - It is hydrolyzed by plasma pseudo cholinesterase and its persistence in the body is increased by : 1- Neostigmine, which inactivate that enzyme. 2- In patient with hepatic disease or severe malnutrition, whose plasma concentration of enzyme may be lower than normal. 3- Procaine also is destroyed by this enzyme and so by competing with suxamethonium for the enzyme, may prolong its action. 4- There are persons with hereditary defects in amount or kind of enzyme, who cannot destroy the drug as rapidly as normal, so paralysis (Apnea) then prologed for hours. - Here treatment consist of ventilation until recovery, and may need fresh blood transfusion.

Adverse effects of Succinylcholine 1- Hyperthermia: When halothane is used as an anesthetic, administration of succinylcholine has occasionally caused malignant hyperthermia (with muscular rigidity and hyperpyrexia) in genetically susceptible people. - Treated by rapidly cooling the patient and by administration of dantrolene which blocks release of Ca++ from the sarcoplasmic reticulum of muscle cells, and so reducing heat production and relaxing muscle tone. 2- Apnea: A genetically related deficiency of plasma cholinesterase or presence of an atypical form of the enzyme can lead to apnea due to paralysis of the diaphragm.

Adverse effects of Succinylcholine 3- Cardiovascular: a- Repeated injections of suxamethonium can cause bradycardia and even cardiac arrest these probably due to activation of cholinoceptors in the heart and this can be prevented by atropine. b- It causes release of K from muscle which can be enough to cause cardiac arrest in patients with already hyperthermia.

Adverse effects of Succinylcholine 4- Muscle pain lasting 1-3 days due to muscle fasciculation preceded the paralysis by Suxamethonium. - The pain can largely prevented by a small dose of a competitive N-M blocking agent (tubocurarine) before giving succinylcholine. 5- High dose can stimulate the uterus and can cause premature labour in pregnant patient.

Contraindication of succinylcholine 1- Hypersensitivity to suxamethonium. 2- Severe liver disease. ?? 3- Burned patient. ?? 4- Pregnancy. ??

Uses of N-M blocking agents - The main use of these drugs is the producing complete skeletal muscle relaxation in surgery. Other uses: 1- Control Ventilation: - In respiratory failure due to obstructive airway disease. 2- Treatment of convulsion: - By decrease peripheral manifestation of convulsion (As these drugs not cross BBB so has no effect on the central processes involved).

The End