Autonomic Nervous System 6-Anticholinergic Drugs

اليوزبكي. 0م0أ بشير وحدة د

ObjectivesObjectivesAt end of this lecture, the students should be able toAt end of this lecture, the students should be able to : :

11-- Identify nicotinic antagonists drugsIdentify nicotinic antagonists drugs . .22-- Discuss ganglionic blocking drugsDiscuss ganglionic blocking drugs . .

33-- Discuss neuromuscular blocking drugsDiscuss neuromuscular blocking drugs . .  

- -At a level consistence with standards scientific curriculum At a level consistence with standards scientific curriculum for the College of Medicine/ University of Mosulfor the College of Medicine/ University of Mosul..

Nicotinic AntagonistsNicotinic Antagonists

Antinicotinic agentsAntinicotinic agents

1 -Ganglionic Blocking agents

2-Neuromuscular Blocking agents

Non Depolarizingcompetitive

blocking agents

Depolarizing Non-competitive blocking

agents

11 - -Ganglionic Blocking AgentsGanglionic Blocking Agents

- -Hexamethionin, mecamylamineHexamethionin, mecamylamine and other and other ganglion-blockers were mainly used in the ganglion-blockers were mainly used in the treatment of hypertensiontreatment of hypertension..

- -But unfortunately, the adverse effect of ganglion blocked are But unfortunately, the adverse effect of ganglion blocked are so severe (both sympathetic and parasympathetic divisions so severe (both sympathetic and parasympathetic divisions are blocked), so that patients are unable to tolerate long are blocked), so that patients are unable to tolerate long term treatment with themterm treatment with them..

11 - -Ganglionic Blocking agentsGanglionic Blocking agentsTrimethaphanTrimethaphan

- -It is the only Ganglion-blocker still in clinical use. Its It is the only Ganglion-blocker still in clinical use. Its poorly lipid solublepoorly lipid soluble . .

- -Inactive orally and has a short half-lifeInactive orally and has a short half-life.. - -It is used IV to treat severe accelerated hypertension It is used IV to treat severe accelerated hypertension

(malignant hypertension)(malignant hypertension)..NoteNote::Because the ganglion-blocking agents interrupts Because the ganglion-blocking agents interrupts sympathetic control of venous-pooling, so so these sympathetic control of venous-pooling, so so these drugs cause drugs cause postural hypotensionpostural hypotension . .

22 - -Neuromuscular Blocking Neuromuscular Blocking DrugsDrugs

- -These drugs are important for These drugs are important for producingproducing complete sk-complete sk-m relaxationm relaxation in in surgery surgery, by specific blockade of the N-, by specific blockade of the N-M junctionM junction..

--They enable light level of anesthesia to be employed They enable light level of anesthesia to be employed with adequate relaxation of the muscles of the with adequate relaxation of the muscles of the abdomen and diaphragmabdomen and diaphragm..

- -They also relax the vocal cords and allow the passage They also relax the vocal cords and allow the passage of a tracheal tubeof a tracheal tube..

NoteNote:: - -Patients who have received a M-relaxant should always Patients who have received a M-relaxant should always

have their respiration assisted or controlled until the have their respiration assisted or controlled until the drug have been inactivated or antagonizeddrug have been inactivated or antagonized..

Non Depolarizing Competitive Non Depolarizing Competitive N-M blocking agentsN-M blocking agents

ActionAction:: - -Drugs of this group cause N-M block by competing with Drugs of this group cause N-M block by competing with

Ach at the receptor site at the N-M junction so prevent Ach at the receptor site at the N-M junction so prevent depolarization of muscle cell membrane and inhibit depolarization of muscle cell membrane and inhibit muscle contraction so causing complete SK- M muscle contraction so causing complete SK- M relaxationrelaxation..

PKPK:: - - Most non depolarizing agents have relatively long Most non depolarizing agents have relatively long

t1/2 ranging from 20 min to several hourst1/2 ranging from 20 min to several hours . . - -These drugs are given parentally (by injection)These drugs are given parentally (by injection) . .

Non Depolarizing Competitive Non Depolarizing Competitive N-M blocking agentsN-M blocking agents

TubocurarineTubocurarine - -Is the Is the prototypeprototype it produces a competitive block at it produces a competitive block at

the at the motor endplate of the muscle causing the at the motor endplate of the muscle causing flaccid paralysis lasts 30-60 minflaccid paralysis lasts 30-60 min..

- -Tubocurarine blocks autonomic ganglia and causes an initial Tubocurarine blocks autonomic ganglia and causes an initial transient drop in blood pressure & cause histamine release transient drop in blood pressure & cause histamine release which may induce bronchospasmwhich may induce bronchospasm..

Pancuronium, AtracuriumPancuronium, Atracurium are short acting non-depolarizing are short acting non-depolarizing agentsagents..

Non Depolarizing Competitive Non Depolarizing Competitive N-M blocking agentsN-M blocking agents

NoteNote::The action of competitive N-M blocking drugs is The action of competitive N-M blocking drugs is antagonized byantagonized by anticholinesterases, like anticholinesterases, like NeostigmineNeostigmine which which is usually givenis usually given IV, IV, and preceded by and preceded by atropineatropine to prevent the parasympathetic autonomic effect to prevent the parasympathetic autonomic effect of Neostigmine (such as bradycardia and salivation)of Neostigmine (such as bradycardia and salivation)..

Depolarizing Non competitive Depolarizing Non competitive N-M blocking agentsN-M blocking agents

Suxamethonium (Succinylcholine)Suxamethonium (Succinylcholine)Mechanism of actionMechanism of action : :

- -It attaches to the nicotinic receptors and acts like Ach to It attaches to the nicotinic receptors and acts like Ach to depolarize the N-M junctiondepolarize the N-M junction..

- -Unlike acetylcholine, which is rapidly destroyed by Unlike acetylcholine, which is rapidly destroyed by Achesterase, the depolarizing agent persists at high Achesterase, the depolarizing agent persists at high concentrations in the synaptic cleft, remaining attached to concentrations in the synaptic cleft, remaining attached to the receptor for a relatively long time & providing a constant the receptor for a relatively long time & providing a constant stimulation of the receptor. Initially this produces short-stimulation of the receptor. Initially this produces short-lasting muscle fasciculation, followed within a few minutes lasting muscle fasciculation, followed within a few minutes by muscle paralysisby muscle paralysis . .

Suxamethonium (succinylcholine)Suxamethonium (succinylcholine)

- -The drug does not produce a ganglionic block, except in The drug does not produce a ganglionic block, except in high doses, although it does have weak histamine-high doses, although it does have weak histamine-

releasing actionreleasing action..

- -Normally, the Normally, the duration of actionduration of action of of succinylcholinesuccinylcholine is is extremely short extremely short (Total paralysis last up to 4 min)(Total paralysis last up to 4 min)

- -succinylcholine succinylcholine It is particularly It is particularly usedused during anesthesia during anesthesia for for brief procedures?brief procedures? such as such as tracheal intubations tracheal intubations oror electroconvulsive therapy (ECT)electroconvulsive therapy (ECT)..

PK of Suxamethonium (succinylcholine)PK of Suxamethonium (succinylcholine)

- -SuccinylcholineSuccinylcholine is injectedis injected intravenously intravenously.. - -Unlike the non depolarizing muscle relaxants Unlike the non depolarizing muscle relaxants

(tubocurarine), the succinylcholine action cannot be (tubocurarine), the succinylcholine action cannot be reversed by other drug. Instead of this its brief reversed by other drug. Instead of this its brief duration of action (several minutes) ended by rapid duration of action (several minutes) ended by rapid hydrolysis by plasma pseudo cholinesterase enzymehydrolysis by plasma pseudo cholinesterase enzyme..

  

PK of Suxamethonium (succinylcholine)PK of Suxamethonium (succinylcholine) - -It is hydrolyzed by plasma pseudo cholinesterase and It is hydrolyzed by plasma pseudo cholinesterase and

its persistence in the body is increased byits persistence in the body is increased by: : 1- Neostigmine1- Neostigmine, which inactivate that enzyme., which inactivate that enzyme.

2-2- In patient with In patient with hepatic disease hepatic disease oror severe malnutrition severe malnutrition, , whose plasma concentration of enzyme may be lower whose plasma concentration of enzyme may be lower

than normal.than normal.3-3- ProcaineProcaine also is destroyed by this enzyme and so by also is destroyed by this enzyme and so by

competing with suxamethonium for the enzyme, may competing with suxamethonium for the enzyme, may prolong its action.prolong its action.

4- 4- There are persons with There are persons with hereditary defects in amount or hereditary defects in amount or kind of enzymekind of enzyme, who cannot destroy the drug as rapidly , who cannot destroy the drug as rapidly as normal, so paralysis as normal, so paralysis ((Apnea)Apnea) then prologed then prologed for hours. for hours. - Here treatment consist of ventilation until recovery, - Here treatment consist of ventilation until recovery,

and may need fresh blood transfusion.and may need fresh blood transfusion.

Adverse effects of Adverse effects of SuccinylcholineSuccinylcholine

11 - -Hyperthermia:Hyperthermia: When When halothanehalothane is used as an anesthetic, is used as an anesthetic, administration of succinylcholine has occasionally caused malignant administration of succinylcholine has occasionally caused malignant hyperthermia (with muscular rigidity and hyperpyrexia) in genetically hyperthermia (with muscular rigidity and hyperpyrexia) in genetically susceptible peoplesusceptible people . .

- -Treated by rapidly cooling the patient and by administration of Treated by rapidly cooling the patient and by administration of dantrolenedantrolenewhich blocks release of Ca++ from the sarcoplasmic reticulum of which blocks release of Ca++ from the sarcoplasmic reticulum of muscle cells, and so reducing heat production and relaxing muscle muscle cells, and so reducing heat production and relaxing muscle tonetone..

22 - -Apnea:Apnea: A genetically related deficiency of plasma A genetically related deficiency of plasma cholinesterase or presence of an atypical form of the cholinesterase or presence of an atypical form of the enzyme can lead to apnea due to paralysis of the enzyme can lead to apnea due to paralysis of the diaphragmdiaphragm..

Adverse effects of Adverse effects of SuccinylcholineSuccinylcholine

33 - -CardiovascularCardiovascular::a- a- Repeated injections of suxamethonium can cause Repeated injections of suxamethonium can cause bradycardia and even cardiac arrest these probably bradycardia and even cardiac arrest these probably due to activation of cholinoceptors in the heart and due to activation of cholinoceptors in the heart and

this can be prevented by atropine.this can be prevented by atropine.

b-b- It causes release of K from muscle which can be It causes release of K from muscle which can be enough to cause cardiac arrest in patients with enough to cause cardiac arrest in patients with

already hyperthermia.already hyperthermia.

Adverse effects of Adverse effects of SuccinylcholineSuccinylcholine

44 - -Muscle pain lasting 1-3 daysMuscle pain lasting 1-3 days due to due to muscle fasciculation preceded the paralysis by muscle fasciculation preceded the paralysis by SuxamethoniumSuxamethonium . .

- -The pain can largely prevented by a small dose of a The pain can largely prevented by a small dose of a competitive N-M blocking agent (tubocurarine) before competitive N-M blocking agent (tubocurarine) before giving succinylcholinegiving succinylcholine..

55-- High dose can stimulate the uterus and can High dose can stimulate the uterus and can cause cause premature labour in pregnant premature labour in pregnant patientpatient..

Contraindication of succinylcholineContraindication of succinylcholine

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

Uses of N-M blocking agentsUses of N-M blocking agents - -The The main use main use of these drugs is the of these drugs is the producing producing

complete skeletal muscle relaxation in surgerycomplete skeletal muscle relaxation in surgery..

Other usesOther uses::1- Control Ventilation:1- Control Ventilation:

- In respiratory failure due to obstructive airway disease. - In respiratory failure due to obstructive airway disease. 2- Treatment of convulsion:2- Treatment of convulsion:

- By decrease peripheral manifestation of convulsion (As - By decrease peripheral manifestation of convulsion (As these drugs not cross BBB so has no effect on the central these drugs not cross BBB so has no effect on the central

processes involved).processes involved).