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Pharmacology notes

Autonomic Nervous System

-functions largely as an automatic modulatiny system for many bodily functions including the regulation of blood pressure, heart rate, gastrointestinal tract motility, salivary gland secretions, and bronchial smooth muscle.

-This system relies on specific neurotransmitters and a variety of receptors to initiate functional responses in the target tissues.

-The autonomic nervous system agents fall into four groups – including both stimulation (+) and inhibition (-) of the parasympathetic (P) and the sympathetic (S) nervous systems [ P+, P-, S+, S- ]

-Action of autonomic nervous system

*Maintains the integrated function of the body.

1.      regulation of resting blood pressure.

2.      Heart rate

3.      GI tract motility & secretion.

4.      Regulates bronchial smooth muscle.

5.      Regulates thermal temperature of body.

6.      Regulates endocrine system

7.      Regulates visual adaptation.

Parasympathetic Nervous System (PANS)

-Cell bodies in the CNS gives rise to the preganglionic fibers of the parasympathetic division.

-They originate in the nuclei of the third, seventh, ninth, and tenth cranial nerves (CN III, VII, IX, and X), as well as the second through fourth sacral segments (s2 to s4) of the spinal cord.

-The preganglionic fibers of the PNS are relatively long and extend near to or into the innervated organ.

-The distribution is relatively simple for the third, seventh, and ninth cranial nerves, whereas the tenth or vagus nerve has a complex distribution.

-There is usually a low ratio of synpatic connections between preganglionic and postganglionic neurons, which lead to a discrete response when the PANS is stimulated.

-The postganglionic fibers, originating in the ganglia, are usually short and terminate on the innervated tissue.

-Action of the parasympathetic nervous system called vegatative.

-Parasympathetic Nervous System (PANS) – “vegatative”; discrete response originate from CN III, VII, IX, X and sacral segments (2-4) of spinal cord.

-Parasympathetic

1.      nerves maintain physiologic status quo & respond to internal needs.

2.      Activation allows for end-organ regulation on an organ to organ basis.

3.      Clinically useul agents

a.      ones that inhibit acetylcholinesterase (AchE)

Cholinergic Agents

-Cholinergic agents or parasympathomimetics mimic the effects of the parasympathetic nervous system.

-classified as direct acting or indirect acting depending on their mechanism of action.

-The direct-acting agents include the choline derivatives and pilocarpine.

-The choline derivatives include both acetyl choline and other more stable choline derivatives.

-These derivatives of acetylcholine possess activity similar to PNS stimulation but have a longer duration of action and are more selective.

-The indirect-acting parasympathetic agents or cholinesterase inhibitors act by inhibiting the enzyme cholinesterase.  When this enzyme, which normally destroys acetylcholine is inhibited, the concentration of acetylcholine builds up, resulting in action that resembles PNS stimulation.

-P+ “mimic” the action of the parasympathetic autonomic nervous system (PANS), PANS stimulation.

-Receptors

1.      “Muscarinic” receptor stimulated by the compund found in the poisonous mushroom Amarita muscaria.

a.      areas affected (A)

(1)     smooth muscle

(2)     cardiac muscle

(3)     gland cells

b.      Neurotransmitter – acetylcholine (Ach)

c.      Location – synapse between postganglionic fiber and the neuroeffector organ in the PANS.

d.      Stimulated by muscarine

e.      Blocked by atropine

2.      “Nicotinic” – receptor stimulated by nicotine; found in cigarettes.

a.       areas affected

(1)     postganglionic neurons

(2)     skeletal muscle end-plates

b.      Neurotransmitter – acetylcholine (Ach)

c.      Location – autonomic ganglia (B) and neuromuscular junction (C)

d.      Stimulated by nicotine

e.      Blocked by hexamethonium (B) and d-turbocurarine (C).

B.      Acetylcholine – synthesis and inactivation.

C.      Classification/mechanism of action

1.      direct acting – drug acts at the receptor just like acetylcholine

a.       choline derivatives

b.      pilocarpine (salagen)

2.      Indirect acting – drug increases the amount of acetylcholine indirectly; blocks acetylcholine inactivation by inhibiting acetylcholinesterase (AchE, enzyme that normally destroys acetylcholine)

a.       Reversible cholinesterase inhibitors- drugs that block action of AchE; but whose action is terminated (Ach) then destroyed.

(1)    Edrophonium (Tensilon)

(2)    Physostigmine (Eserine)

(3)    Negostigmime (Prostigmin)

b.      “irreversible” cholinesterase inhibitors- drugs attach to and inactivate AchE; e.g., organophosphates used as insecticides (malathion, parathion)

-Cholinergic agents (parasympathomimetics, muscarinic agonists)

-direct acting are choline derivatives; indirect acting inhibit AchE enzyme.

Pharmacologic Effects

1.      Cardiovascular effects.  The cardiovascular effects associated with the cholinergic agents are the result of both direct and indirect action.  The direct effect on the heart produces a negative chronotropic and inotropic agent.  There is also a decrease in cardiac output associated with these agents.  The cholinergic agent’s effect on vessel results in smooth muscle relaxation and a decrease in the total peripheral resistance (TPR).  The indirect effect of these agents is an increase in heart rate and cardiac output.  Since the direct and indirect effects of these agents on the heart rate and cardiac output are opposite, the resulting effect will depend on the concentration of the drug present.  Generally, there is bradycardia and a decrease in blood pressure and cardiac output.

2.      Gastrointestinal effects.  The cholinergic agent excite the smooth muscle of the gastrointestinal tract, producing an increase in activity and secretion.  In the intestine this can produce diarrhea or even cramping.  Increased secretions can cause salivation, lacrimation, sweating, and increased stomach acid production.

3.      Effects on the eye.  The cholinergic agents produce miosis and cause a “spasm of accommodation” so that the eye becomes focused for near vision.  Since intraocular pressure is also decreased, these agents are useful in the treatment of glaucoma.

-similar to PANS stimulation

1.      smooth muscle stimulation

a.       increase in gastrointestinal (GI) motility- diarrhea may result; used to treat postoperative ileus (GI/GU – gastrointestinal/genitourinary)

b.      Bronchoconstriction – stimulates bronchial smooth muscle.

2.      Glands – increased secretion of saliva; used to treat xerostomia.

3.      Eye -  decreased intraocular pressure; used to treat glaucoma.

-Cardiovascular, gastrointestinal, eye, salivary glands, urinary tract, blood vessels

Adverse reactions

-The adverse reactions associated with the cholinergic agents are essentially extensions of their pharmacologic effects.

-When large doses of these agents are ingested, the resultant toxic effects are described by the acronym SLUD: salivation, lacrimation, urination, and defecation.

-With even larger doses, neuromuscular paralysis can occur as a result of the effect on the neuromuscular juntion.

-Central nervous system (CNS) effects such as confusion can be seen if toxic doses are administered.

-The treatment of a overdose of cholinesterase inhibitors such as the insecticides or organophosphates includes a combination of pralidoxime (2-PAM, protopam) and atropine.  Pralidoxime regenrates the receptor sites bound by the inhibitors, and atropine blocks the muscarinic effects of the excess acetylcholine present.

-Toxic reactions – extensions of the pharmacologic effects; “too much” effect

1.      SLUD – salivation, lacrimation (tearing), urination, and defecation (Bowel movement)

2.      Treatment of overdose

a.       Pralidoxime (2-PAM, protopam) – regnerates acetylcholinesterase

b.      Atropine – antimuscarinic; blocks the muscarinic effects of acetylcholine excess (not the nicotinic effects)

-diarrhea, diaphoresis, miosis, nausea, urinary urgency, broncho.

Contraindications

The contraindications to the use of cholinergic agents result from these agents’ pharmacologic effects and adverse reactions.  They include the following:

1.      Bronchial asthma

2.      Hyperthyroidism

3.      Mechanical obstruction of the gastrointestinal or urinary tract

4.      Severe cardiac disease

5.      Myasthenia gravis treated with neostigmime (These patients should not be given and irreversible cholinsterase inhibitor, since neostigmime would occupy the enzyme and the irreversible agent could not function.)

6.      Peptic ulcer.

-asthma, GI obstruction (mechanical), increased motility, peptic ulcers

Uses

-The direct-acting agents are used primarily in the treatment of glaucoma, a condition in which the intraocular pressure is elevated.

-Occasionally, they are used to treat myasthenia gravis, a disease resulting in muscle weakness.

-The urinary retention that occurs after surgery is also treated with the choline esters.

-An attemot to use these agents in the treatment of xerostomia has met with a limited degree of success.

-Oral administration of pilocarpine eye drops has been employed for this purpose.

-The indirect-acting agents, the cholinesterase inhibitors. Are divided into groups based on the degree of reversibility with which they are bound to the enzyme.

-Edrophonium is rapidly reversible, whereas physostigmine and neostigmine are slowly reversible.

-These agents are used to treat glaucoma or myasthenia gravis.

-The cholinesterase inhibitors developed for use are insecticides and chemical warfare agents are essnetially nonreversible.

-Physostigmine has been used to treat reactions caused by several different kinds of drugs.

-Acute toxicity from the anticholinergic agents (such as atropine), the phenothiazines, the tricyclic antidepressants, and the antihistamines has been treated with physostigmine.

-Dental use – treatment of xerostomia

          1. pilocarpine tablets may increase saliva flow

-Uses

          glaucoma-direct acting; since reduces intraocular pressure

          Myasthenia gravis (muscle weakness)

          Urinary retention

          Xerostomia (dry mouth)

          Insecticides, chemical warfare – irreversible CE inhibitors

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