A.U .C N S

Indirect Acting Agents used to treat Alzheimer’s disease Anticholinesterase with specific CNS. Donepezil (Aricept)—said to delay progression of the disease by up to 55 weeks. Does not cause liver toxicity.Rivastigmine long acting. Twice a day dosing. Tacrine (Cognex)—hepatoxic. Elevated liver enzymes usu.

Irreversible cholinestrase inhibitors

1- organophosphorus ;; (malathion & parathion) :used in insecticide 2- Tabun & Sarin : nerve gas (chemical war agent )


Irreversible Inhibitors Compounds containing phosphoryl or phosphonic group that can react with ChE to form ChE-phosphate complexes stable to hydrolytic cleavage. Mainly used as agricultural insecticides and nerve gas agents.

Mechanism of action

Combined of o.p.c with choline esterase enzyme irreversible & formation anew compound O.p.c + chE -------------- o.p—chEO.p.c highly lipid soluble

Adverse effects of organophosphate compounds:

Miosis , Rhinorrhea Frontal headache , Bronchoconstriction Emesis,Diarrhea, Involuntary micturition Bradycardia Lacrimation ,Salivation. Muscle weakness confusion ,paralysis of respiratory muscle.(DUMBBLES) Death

treatment

1- stop exposure 2-wash skin 3-oxygen supply . 4 replace fluid . 5-atropine 6-Diazepam is also administered to reduce the persistent convulsion caused by these agents. 7- 2-PAM(Pralidoxime)


Reactivation of acetylecholinestrase
Pralidoxime synthetic compound that can reactivate the acetylcholinestrase if its given before aging of enzyme ((aging mean: loss of an alkyl gp from the structure of enzyme)).Pralidoxime :Effective antidote for poisoning by parathion • Most effective by intramuscular, intravenous, or subcutaneous administration • Treatment is effective if initiated within few hours

Parasympathlytic

(Cholinergic antagonists) (Anticholinergic ) (Cholinergic Blockers)

Agents with high binding affinity for muscarinic receptors but no intrinsic activity. Pharmacologic effects opposite of the muscarinic agonists. Competitive (reversible) antagonists of Ach
A- antimuscarinic agents(Muscarinic Antagonists):

Antagonistic responses include: decreased contraction of GI and urinary tract smooth muscles, dilation of pupils, reduced gastric secretion, decreased saliva secretion.
A- antimuscarinic agents(Muscarinic Antagonists):

A- antimuscarinic agents(Muscarinic Antagonists):

1-Atropine (belladonna alkaloid) (Competitive inhibitors) . bind to M receptors and preventAch binding. reversible blockade of ACh at muscarinic receptors by competitive binding. Cross CNS (atropine is central & peripheral) muscarinic blocker. reversal effect of atropine by increasing ACh or agonist ----> decreased blockade

Muscarinic receptor blockade does not interfere with transmission at autonomic ganglionic sites, the adrenal medulla, or skeletal muscle fibers. Sympathetic adrenergic functions are not affected.
X
X



MUSCARINIC RECEPTOR BLOCKADE ALLOWS SYMPATHETIC DOMINANCE IN DUAL INNERVATED ORGANS
X

Atropine actions

Eye: *mydriasis *unresponsiveness to light *cycloplegia *increase IOP

GIT: reduce activity of GIT. Urinary system: reduce hyper motility. Cardiovascular system: at low dose bradycardia at high dose tachycardia Secretions: reduce secretions

Therapeutic uses of atropine

1-Ophthalmic: Ophthalmologic examinations. mydriatic & cycloplegic effects. 2-Antispasmodic agent effect: relax GIT(Treatment of smooth muscle spasms). Hyoscene(buscopan) and anti diarrheal Diphenoxylate + atropine(lomotil)

3-antidot for cholinergic agonists: Rx of over dose of organophosphate 4-antisecretory agent: reduce secretions of respiratory tract and salivary gland (prior to surgery). (Reduction of nasal and upper respiratory tract secretions in cold and flu)

5. Cardiovascular: The drug is used to treat bradycardia of varying etiologies.

Pharmacokinetics of atropine
Absorbed & metabolized by liver. Eliminated by urine. Half life/4hr. Parenteral preparations (derivatives) are more potent than the parent compounds and short action than atropine.

Adverse effects of atropine

Dryness of mouth Blurred vision(“sandy eyes,”)Increase in IOPAttack of glaucomaTachycardiaConstipationCNS effectsCollapse of circulatory & respiratory systemsUrine retention


Treatment of atropine poisoning
Ventilation Cold spongy Diazepam physostigmine

Antimuscarinic agents

2-scopolamine: greater actions on CNS (than atropine) Low doses of scopolamine produce CNS effects that are not seen with equivalent doses of atropine. (longer duration of action than atropine)

The therapeutic use of scopolamine is limited to prevention of motion sickness and postoperative nausea and vomiting. side effects : sedation , amnesic action

Antimuscarinic agents

3-ipratropium bronchodilators for maintenance treatment of bronchospasm associated chronic 1.obstructive pulmonary disease and 2.asthma Administration: by inhalation as aerosol (to provide maximal concentration at the site of action)

Another amtimuscarinic agent

4.Benztropine is useful as adjuncts with other antiparkinsonian agents to treat Parkinson’s disease.5. Tropicamide and cyclopentolate These agents are used as ophthalmic solutions for mydriasis and cycloplegia. C/IGlaucomaStomach obstruction Cardiac disturbance

B- anti nicotinic agent

Nicotinic Antagonists: Agents that bind to cholinergic nicotinic receptors but do not have efficacy.(Competitive antagonists). Antinicotinic include : 1- Ganglion blockers 2- Neuromuscular blockers 1-ganglionic blockers e.g nicotinic

Pharmacological effects of ganglionic blockers:

Eye: mydriasis , paralysis of accommodation Respiratory tract: reduce secretions Salivary glands: xerstomia GIT: reduce secretions & motility Cardiovascular: decrease blood pressure Urinary tract : urinary retention Sweat glands: decrease sweating CNS: no direct effects



Ganglionic blockers specifically act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. ganglionic blockade is rarely used therapeutically, but often serves as a tool in experimental pharmacology.

Nicotine

Depending on the dose, nicotine depolarizes autonomic ganglia, resulting first in stimulation and then in paralysis of all ganglia. The stimulatory effects are complex and result from increased release of neurotransmitters due to effects on both sympathetic and parasympathetic ganglia

2- Neuromuscular blocking drugs

which block Ach at N-M-J(neuromuscular junction), classified as: A- Non-Depolarizing Agent:- Tubocurarine Pancuronium B- Depolarizing Agent:- Suxamethonium succinylcholine

Neuromuscular blockers:

Neuromuscular blockers: Drugs used during surgical procedures and in intensive care units to cause paralysis. Since skeletal muscle contraction is elicited by nicotinic (NM) cholinergic mechanisms. Neuromuscular blockers interfere with transmission at the neuromuscular end plate and lack CNS activity.

Action Potential

Ca2+
Motor neuron
Na+
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
ACH
a
a
b
a
a
b
a
a
b
ACH
ACH
ACH
ACH
Na+
Skeletal Muscle
ACHEsterase
Neuromuscular Blockers

A-non depolarizing:

First drug is curarine(d- tubocurarine)(Plant alkaloid). They act as competitive antagonists at the ACh receptors of the endplate(act by blocking nAChR). Blockade by these agents (such as tubocurarine and pancuronium) can be reversed by increasing the amount of ACh in the synaptic cleft, for example, by the administration of a cholinesterase inhibitor.

Mechanism of action

1- at low dose : combine with nicotinic receptors & prevent the binding of Ach(competitive blockers) 2-at high dose: block the ion channels of the end plate. Result in. Causes muscle paralysis

action

Small, rapidly contracting muscles of the face and eye are most susceptible and are paralyzed first, followed by the fingers, limbs, neck, and trunk muscles. Next, the intercostal muscles are affected and, lastly, the diaphragm

Tubocurarine

Therapeutic Use: As a muscle relaxant in various surgical procedures. (Rapid onset of action) The neuromuscular-blocking agents have significantly increased the safety of anesthesia, because less anesthetic is required to produce muscle relaxation, allowing patients to recover quickly and completely after surgery.

B-depolarizing agents

Depolarizing agents: Agonists at the nAChR (i.e., they act by stimulating the nAChR) Mechanism of action: Drugs like succinylcholine attach to nicotinic receptors & act like Ach to depolarize the junction, it cause opening of sodium channel associated with nicotinic receptor which result in fasciculation leading to paralysis.

Action of depolarizing agents

Fasciculation's followed by paralysis Weak histamine releasing action.

Theraputic uses

1- Endotracheal intubation during induction of anesthesia (Muscle relaxant). 2- Rx of electroconvulsive shock. 3- Suitable for short or long periods of relaxation.


pharmacokinetic
IV injection (continuous infusion) Short duration of action since this drug rapidly Brocken down by choline esterase enzyme. Rapid recovery (fast hydrolysis). Adverse effects: Hyperthermia Apnea(Administration of succinylcholine to a patient who is deficient in plasma cholinesterase) lead to prolonged apnea due to paralysis of the diaphragm.

Drug interaction

Anticholinesterase :antagonist action General anesthesia: enhance action Antibiotics:aminoglycoside:reduce Ach release Lithium: prolong the action

Application in dentistry

Mandibular fracture TMJ disorder: centrally acting Reduce patients stress to stop grinding of the teeth


Botulinum Toxin (Botox): Toxin produced by the bacterium Clostridium Botulinum. purified & highly diluted for therapeutic use Prevents Acetylcholine release from the nerve terminal. Produces flaccid paralysis of skeletal muscle , Inhibition lasts from several weeks to 3 to 4 months. Immuno resistance may develop with continued use.

Botulinum toxin

The acetylcholine vesicle release process is blocked by botulinum toxin

Therapeutic use botulinum toxin

Dermatological / Cosmetic Uses: Local facial injections of botulinum toxin are widely used for the short-term treatment (1–3 months per treatment) of wrinkles associated with aging around the eyes; neck and mouth to control muscle spasms and to facilitate muscle relaxation . Local injection of botulinum toxin has also become a useful treatment for generalized spastic disorders (eg, cerebral palsy). Most studies have used type A botulinum toxin, but type B is also available. Prevent excessive sweating (palm).