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Chapter 5_ Cholinomimetics _Cholinergic Agnoist_

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Chapter 5_ Cholinomimetics _Cholinergic Agnoist_ Powered By Docstoc
					Chapter 5

Cholinomimetics
(Cholinoceptor agonists & Anticholinesterase agents)

Ⅰ Cholinoceptor agonists
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M ,N -R agonists: acetylcholine(ACh), metacholine, bethaechol M-R agonists: pilocarpine, muscarine, oxotremorine N-R agonists: nicotine, dimethylphenypiperazinium(DMPP), lobeline,

Acetylcholine(ACh)
[Pharmacological actions] Directly activate M,N-R  muscarinic actions: small dose  nicotinic actions: large dose

1.muscarinic actions: small dose

 


 

Vessel dilate, BP decrease Heart depress: negative effect Gastrointestinal tract: contraction Urinary bladder: contraction Glands secrete increasingly Sphincter muscle of iris contract: miosis Ciliary muscle contract: near vision (myopia)

2.nicotinic actions: large dose
N1-R: dominant nerve actions heart increased, vessel contract, BP↑ gastrointestinal smooth muscle contract

glands secretion increase
N2 -R: skeletal muscle contraction

Pilocarpine
[Pharmacological actions]
selectively activate M-R Eyes and glands are particularly sensitive to this drug. It is primarily used in ophthalmology.

1.Eye
(1)miosis Pilocarpine makes circular muscle (sphincter muscle) of the iris contract, which result in miosis.

The eye is a good example of an organ with multiple ANS functions, controlled by several different autonomic receptors. the anterior chamber is the site of several tissues controlled by the ANS. These tissues include three different muscles (pupillary dilator and constrictor muscles in the iris and the ciliary muscle) and the secretory epithelium of the ciliary body.

Muscarinic cholinomimetics mediate contraction of the circular pupillary constrictor muscle and of the ciliary muscle. Contraction of the pupillary constrictor muscle causes miosis, a reduction in pupil size. Miosis is usually present in patients exposed to large systemic or small topical doses of cholinomimetics, especially organophosphate cholinesterase inhibitors.



Ciliary muscle contraction causes accommodation of focus for near vision. Marked contraction of the ciliary muscle, which often occurs with cholinesterase inhibitor intoxication, is called

cyclospasm.

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Ciliary muscle contraction also puts tension on the trabecular meshwork, opening its pores and facilitating outflow of the aqueous humor into the canal of Schlemm. Increased outflow reduces intraocular pressure, a very useful result in patients with glaucoma. All of these effects are prevented or reversed by muscarinic blocking drugs such as atropine.

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Alpha adrenoceptors mediate contraction of the radially oriented pupillary dilator muscle fibers in the iris and result in mydriasis. This occurs during sympathetic discharge and when alpha agonist drugs such as phenylephrine are placed in the conjunctival sac.

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Beta-adrenoceptors on the ciliary epithelium facilitate the secretion of aqueous humor. Blocking these receptors (with â-blocking drugs) reduces the secretory activity and reduces intraocular pressure, providing another therapy for glaucoma.

cholinergic nerve
noradrenergic nerve

Ciliary smooth muscle Schlemm’s canal Anterior/posterior chamber lens mydriasis

Far vision

Iris Zonules Anterior chamber angle Ciliary

Near vision miosis

1.Eye
(2)decrease intraocular pressure Through miosis, the iris is pulled away from the angle of the anterior chamber, and the trabecular meshwork at the base of the ciliary muscle is opened up, which facilitate the outflow of aqueous humor into the canal of Schlemm and reduces intraocular pressure.

Ciliary smooth muscle Schlemm’s canal Anterior/posterior chamber lens mydriasis

Far vision

Iris

Near vision miosis

Zonules
Anterior chamber angle Ciliary

1.Eye
(3)spasm of accommadation Pilocarpine makes ciliary muscles contract, which makes suspensory ligaments relax and diopter of lens increase, and results in myopia (spasm of accommodation).

Ciliary smooth muscle Schlemm’s canal Anterior/posterior chamber lens mydriasis

Far vision

Iris Zonules Anterior chamber angle Ciliary

Near vision miosis

2. Glands
secrete increasingly Sweat and salivary glands are increased markedly.

Clinical uses of pilocarpine
1.Glaucoma Glaucoma is a disease complex characterized chiefly by an increase in intraocular pressure which can cause headache, poor eyesight and irreversible blindness.  angle-closure glaucoma  open-angle glaucoma

Clinical uses
angle-closure glaucoma there is physical obstruction (iris) to the entry to the trabecullar meshwork. The aqueous outflow is facilitated by the freeing of the entrance to the trabecullar space from blockade by the iris, as the result of the drug-induced contraction of the sphincter muscle of the iris.

Clinical uses
open-angle glaucoma
there is no physical obstruction (iris) to the entry to the trabecullar meshwork,. Contraction of the sphincter muscle of the iris and the ciliary muscle enhances tone and alignment of the trabecular network to improve resorption and outflow of aqueous humor.

Clinical uses
2. iritis Alternative using with atropine and pilocarpine is employed to prevent or break the development of adhesions between the iris and the lens.

Adverse reactions
sweating , salivation, etc.

Anticholinesterase(AchE) Agents / Cholinesterase inhibitor
Anticholinesterases are classified as
Reversible inhibitor Neostigmine, Physostigmine Short, moderate duration of action Uses: Therapeutic agents
AchE in this compound can be reactivated.

Irreversible inhibitor Organophosphorus compound Long duration of action Uses: Agricultural insecticide & nerve gases
AchE in this compound is not easily be reactivated

Neostigmine, organophosphate
(-) Ach (+) M,N-R

AchE

Choline + acetate Effects

Reversible Anticholinesterase agent
Neostigmine, Physostigmine

Neostigmine
[Pharmacological actions]
1.Skeletal muscle It induces increased skeletal muscle activity. This effect is based on a combination of its anti-ChE activity and direct cholinergic stimulation. 2.Smooth muscle It increases the motility of gastrointestinal and urinary smooth muscles. 3.Heart negative effects: HR↓ , contractility↓ , CO↓

Neostigmine
[Clinical Uses ] 1. Myasthenia gravis: Skeletal muscle contraction 2. Postoperative abdominal distension; Urinary retention 3. Intoxication of tubocurarine and atropine 4. Supraventricular tachyarrhythmias

Neostigmine
[Adverse reaction] Nausea, vomiting, abdominal pain, airway resistance increased

Physostigmine (Eserine)
Low ionization and high lipid solubility 1.Eye- more potent & longer effect than pilocarpine (1) Miosis: treatment of glaucoma (2) Myopia, headache (side reactions)- ciliary muscle contraction 2.CNS (1) Treatment of Alzheimer’s disease

(2) Treatment of atropine intoxication

Chapter 8
Organophosphate Cholinesterase Inhibitor & Cholinesterase Reactivators

Irreversible Anticholinesterase agents


Organophosphorus compound

Organophosphates (OPP)
[Pathway of intoxication]
skin , mucosa respiration oral ingestion These agents have been used frequently for homicidal and suicidal purpose.

Organophosphates
[signs of acute intoxication] 1.Mild intoxication: M signs  2.Moderate intoxication: M+N signs 3.Severe intoxication: M+N +CNS signs

signs of acute intoxication
1.Mild intoxication: M signs
Vessel dilate, BP decrease Heart depress: negative effect Gastrointestinal tract: contraction Urinary bladder: contraction Glands secrete increasingly Sphincter muscle of iris contract: miosis Ciliary muscle contract: near vision (myopia)

signs of acute intoxication
2.Moderate intoxication: M+N signs M signs N signs

N1-R: dominant nerve actions heart increased, vessel contract, BP↑ Gastrointestinal smooth muscle contract glands secretion increase N2 -R: skeletal muscle contraction

signs of acute intoxication 3.Severe intoxication: M+N +CNS signs
CNS signs

Excitation

inhibition

failure

source of intoxication






The major source of intoxication is from the use and manufacture of organophosphorus compounds as agricultural insecticides. Occupational exposure occurs most commonly by the dermal and pulmonary routes. Oral ingestion is most common in case of nonoccupational poisoning.

Treatment of acute organophosphates intoxication


The return of AchE activity depends on synthesis of new enzyme, which requires 15-30days.So,once intoxication occurs, emergency treatment should be given immediately and continuously.

Treatment of acute organophosphates intoxication
1.Termination of exposure by removal of the patient of a gas mask if the atmosphere remains contaminated, removal and destruction of c o nt amin at e d clo thin g , c op iou s w a s hi ng contaminated skin or mucous membranes with water, gastric lavage or catharsis.

Treatment of acute organophosphates intoxication
2.Supporting respiration by endobronchial aspiration or artificial respiration. 3.Blocking the muscarinic effects by atropine 4.Reactivating the inhibited cholinesterase by PAM (pyraloxime methoiodide --cholinesterase reactivators)

Cholinesterase Reactivators --Pyraloxime Methoiodide( PAM)


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PAM reverses the effects of the organophosphate anticholinesterase agents. PAM combines with and splits off the phosphorus from the esteratic site on cholinesterases such that the enzyme is restored. with the reactivation of the enzyme ,the effects of Ach begin to disappear. The treatment must be within hours, because the phospharylated enzyme slowly changes to a form that can not be reversed.

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PAM and atropine have synergism in the treatment. slowly reversal effects PAM ----Atropine rapidly block M receptor Less effective for M symptom effective for myoclonus PAM ----Atropine is ineffective for myoclonus effective for CNS symptom
Atropine is ineffective for myoclonus


				
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