3rd lecture - parasympathomimetics Flashcards
another term for parasympathomimetics
cholinomimetics
What is required for synthesis of acetylcholiine?
Inflow of choline and glucose is required for synthesis.
acetylcholine is broken down by?
acetylcholinesterase
acetylcholine is a mediator between
nerve endings and innervated cells of autonomic ganglia, parasympathetic neuroeffector junction, some sympathetic neuroeffector junctions, the adrenal medulla and certain regions of the CNS.
Cholinoreceptors are called (2)
M – Muscarinic (Multiple subtypes (5), clinical relevance not clear.)
N – nicotinic
Nicotinic responsive sites are present in (3)
autonomic ganglia,
adrenal medulla chromaffin cells
and neuromuscular junctions of the somatic nervous system.
Muscarinic receptors are located at
postganglionic parasympathetic neuroeffector junctions,
also in some blood vessels.
Cholinomimetic drugs are divided into 2 main groups.
1) Direct-acting - act on the receptor. Acetylcholine, muscarine, pilocarpine, nicotine and arecoline.
2) Indirect-acting – act through acetylcholine metabolism. They are also referred to as cholinesterase inhibitors.
acetylcholine analogues
Choline esters: bethanechol and methacholine, carbachol.
Cholinomimetic effect is aimed at
the gastrointestinal tract, urinary tract and cardiovascular system.
Cholinomimetic effect on the gastric, intestinal and salivary glands
Increase in the secretion and motility
Cholinomimetic effect on bronchi
Bronchial contraction
in which species are sweat glands regulated by the parasympathetic system?
horses
they can sweat profusely when cholinergic receptors are stimulated
Cardiovascular effects of Cholinomimetics
Slowing of heart rate (activation of muscarinic receptors of blood vessels).
blood pressure decrease
at larger doses atrio-ventricular block, atrial fibrillation or flutter or even cardiac arrest.
what is methacholine
also known as acetyl-β-methylcholine, is a synthetic choline ester that acts as a non-selective muscarinic receptor agonist in the parasympathetic nervous system.
Methacholine is primarily used to diagnose bronchial hyperreactivity, which is the hallmark of asthma and also occurs in chronic obstructive pulmonary disease.
Carbachol causes
profuse salivation and an increase in peristaltic movements of the gut resulting in increased fluidity of feces and defecation (muscarinic receptors).
Carbachol and bethanecol are relatively more active on the GI and urinary tracts.
carbachol effect on uterine muscles
Uterine muscles are contracted by Carbachol, should not be used during pregnancy.
Carbachol (and Ach) is a
mixed nicotinic-muscarinic agonist, parasympathomimetic that mimics the effect of acetylcholine on both the muscarinic and nicotinic receptors.
Stimulating effect on autonomic ganglia and cromaffin cells of the adrenal medulla.
Carbachol Effect on adrenal medulla can cause
an increased discharge of epinephrine and norepinephrine, that could produce diffuse sympathomimetic effect.
Carbachol and ohter parasymathomimetics not used frequently in veterinary medicine.
Pilocarpine is
a drug that acts as a muscarinic receptor agonis, so cholinergic/parasympathomimetic.
used mainly in ophthalmic clinical medicine as causes miosis (pupil contraction)
How does pilocarpine stimulate the eye?
Pilocarpine stimulates the sphincter muscle of the iris and the ciliary muscle of the lens. Intraocular pressure first increases, followed by a persistent decrease. (Irritating!)
Nowadays mainly for stimulating tear production in case of specific oftalmologic pathologies (keratoconjunctivitis sicca, KCS)
Side effects of parasympathomimetics (5)
Colic, diarrhea
Miosis
Shortness of breath (vasoconstriction of bronchial vessels)
Phlegm retention in respiratory tract
Hypotension/extreme bradycardia
Contraindications of parasympathomimetics (5)
Gestation - risk of abortion.
Old and exhausted animals - inhibitory action on the heart.
Diseases of the respiratory organs
Heart diseases
Spastic colitis
Indirect-acting cholinomimetics cause
the accumulation of acetylcholine at synapses and parasympathomimetic effects appear.
Cholinesterase inhibitors, also known as anticholinesterase agents, impact the action of acetylcholine at all cholinergic synapses across the entire organism.
pharmacologic effects of Indirect-acting cholinomimetics (3)
Stimulation of postganglionic muscarinic receptors, resulting in typical parasympathomimetic activity.
Stimulation of adrenal chromaffin cells to discharge catecholamines into the circulation.
Initial stimulation and subsequent depolarization block of nicotinic receptors of autonomic ganglia and skeletal muscle fibers.
examples of Reversible cholinesterase-inhibitors (5)
Physostigmine
Neostigmine
Edrophonium – synthetic
Pyridostigmine bromide
Ambenonium chloride
Last three agents are used in management of myasthenia gravis and curare overdose (a muscle relaxant of plant origin, arrow poison).
Mechanism of action of Indirect-acting cholinomimetics
Reversible inhibitors combine with cholinesterase and prevent the enzyme from hydrolyzing Ach.
The interaction with cholinesterase is reversible, as the inhibitor-enzyme complex breaks down, the enzyme is reactivated.
Neostigmine/a cholinesterase inhibitor is believed to directly stimulate
nicotinic receptors of skeletal muscle fibers.
Contraindications, side effects of Indirect-acting cholinomimetics
gestation, obstruction of the intestine contra.
Side effects: Diarrhoea, colic, vomiting, Muscle tremors, weakness, Shortness of breath,
Bradycardia, decrease in blood pressure
etc.
Antidote to Indirect-acting cholinomimetics
atropine, a cholinoblocker
Physostigmine can be used to produce what in the eye
is a a reversible cholinesterase inhibitor.
so miosis of the pupil and reduces intraocular pressure in the treatment of glaucoma;
(also to stimulate ruminal activity in cattle)
massive doses of Indirect-acting cholinomimetics can cause
Large doses first stimulate and then depress CNS, massive doses can produce convulsions.
Toxic doses produse skeletal muscle weakness, nausea, vomiting, colic, diarrhea, dyspnea, bradycardia, lowered blood pressure.
example of a phos containing Indirect-acting cholinomimetic
organophosphorus substances Primarily used as pesticides, insecticides, have also been used as peroral anthelmintics and for extermination of ectoparasites.
Mechanism of action of Organophosphorus substances
Binding cholinesterase irreversibly. Enzyme must be synthesised again in order to restore the normal function of the synapse. This takes weeks.
how does atropine act as an antidote to organophosphates
competitive antagonist to acetylcholine
Blocks muscarinic receptors, lessens severity of parasympathomimetic effects.
Blocks muscarinic receptors, lessens severity of parasympathomimetic effects, increases the quantity of organophosphate required to produce death.
what is pralidoxime
a Cholinesterase reactivator used as an antidote to toxic doses of indirect-acting parasympathomimetics.
If atropine is given in conjunction with pralidoxime, the lethal dose is increased many more times.
Clinical uses of organophosphates
Highly toxic to a wide variety of internal and external parasites.
what type of mediator is acetylcholine?
its a mixed nicotinic-muscarinic cholinergic agonist.
required to maintain the homeostasis of the body.
