autonomic nervous system pharmacology Flashcards
describe the effect of drugs that target the parasympathetic nervous system
- mimic acetylcholine = cholinergic = muscarinic agonists= parasympathomimetic
- block acetylcholine= anticholinergic= muscarinic antagonist= parasympatholytic
describe the effect of drugs that target sympathetic nervous system
- mimic norepinephrine= adrenergic = adrenergic agonist= sympathomimetic
- block norepinephrine= antiadrenergic = adrenergic antagonist= sympatholytic
what are the classifications of adrenoreceptors?
alpha (1,2)
beta (1,2,3)
what do the D1 and D2 type of adenoreceptors do?
D1= works on smooth muscle, and dilates renal blood vessels
D2= works on nerve endings, modulates trasmitter release
describe the process of signalling through adrenoreceptors
- tyrosine is transported into the noradrenergic ending or varicosity by sodium-dependent carrier
- Tyrosine is converted to dopamine and transported into the vesicle by the vesicular monoaine transporter
- this carrier also transports norepinephrine and other amines into these granules
- dopamine is converted to NE in vesicle by dopamine beta hydroxylase
- physiological release of transmitter occurs when an action potential opens voltage-sensitive calcium channesl and increases intracellular calcium
- fusion of vesicals with the surface membrane result sin expulsion of norepinephrine, cotransmitters, and dopamine beta hydroxylase
- after release norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter
what drugs block the physiological release of transmitters?
guanethidine and bretylium
what drugs can block the diffusion of norepinephrine into the cytoplasm of the terminal?
cocaine and tricyclic antidepressants
what are the 5 targets for pharmacological intervention of adrenergic transmission?
- receptor ligands
- neurotransmitter synthesis
- re-uptake into neuron
- re-uptake into post-synaptic tissue
- feedback pathway
describe the biosynthesis of neurotransmitters
- L-tyrosine is converted to dopa
- dopa is converted to dopamine
- dopamine is converted to noradrenaline in synaptic vesicles
- in the adrenal medulla, noradrenaline is converted to adrenaline
- dopamine and noradrenaline and adrenaline are referred to as catacholamines or monoamines
what are the two types of endogenous catecholamines?
epinephrine (adrenaline)= agonist at both alpha and beta receptors-functionas as vasoconstrictor and cardiac stimulant - rise in systolic blood pressure mediated through beta 1 receptors, activation of beta 2 especially in skeletal muscle blood vessels leads to vessel dilation
norepinephrine (noradrenaline) = agonist at alpha1 and alpha 2 receptors -also activates beta 1 receptors with similar potency as epinephrine - increases peripheral resistance anb oth systolic and diastolic pressure
what is the term for adrenoreceptor agonists?
sympathomimetics
including
- endogenous catecholamines
- direct sympatho
- indirect sympatho
these drugs have a preference for which they bind
describe how phenylephrine maintains blood pressure
selective alpha1 -agonist (symphatomimetic amines)
these cause vasoconstriction and increase in blood pressure, hence used vasopressors, nasal decongestants, dilation of pupils….
selective alpha 2 agonist includes clonidine
describe the effect of midrodrine
it is a prodrug cleaved to produce desgylmidrodrien ( a selective alpha1 receptor agonist)
used to treat orthostatic hypotension
describe the effects of methoxamine
pharmacologically similar to midodrine - direct acting alpha1 agonist, may lead to increase in blood pressure as a result of vasoconstriction
describe the effects of alph2 selective agonists
they have the ability to reduce blood pressure - drugs including clonidine, methyldopa used in treatment of hypertension
describe the effect of beta-selective agonists
important to separate beta 1 and beta 2 mediated effects
dobutamine- beta1 selective agonist, has a positive inotropic effect (mediating voltage gated channel)
describe the effect of ephedrine
plant derived, mild stimulant and activates beta receptors, early use in asthma
(aka = sudafed - common side effect is drowsiness due to muscle relaxant activity)
describe the effect of phenylpropanolamine
common component in over-the-counter appetite suppressants - can lead to increase in blood pressure in patients with impaired autonomic reflexes
describe the two mechanism of action of the indirect acting sympathomimetics
1) enter the sympathetic nerve and displace stored catecholamine transmitter (amphetamine-like)
2) may inhibit the reuptake of released transmitter by interfering with action of norepinephrine transporter
how do ‘drugs of abuse’ like cocaine and amphetamines work?
they work by elevating CNS levels of catecholamines - have predictable side effects on the autonomic nervous system
amphetamine is a stimulant, it releases catecholamines (dopamine and norepinephrine in brain)- also used to treat attention deficit hyperactivity disorder
describe the respiratory application of Salbutamol (or other adrenergic agonists)
- beta-adrenoceptor agonist
- causes smooth muscle relaxation - vasodilation and reduction of blood pressure
- usually inhaled
- therapeutic use in asthma - bronchodilation
- not used clinically as a anti-hypertensive as drop in blood pressure causes strong sympathetic reflex (tachycardia)
*
describe the use of phenoxybanzamide
binds covalently to alpha receptors- leading to irreversible blockage
- also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve terminals, lowers blood pressure, may lead to an increase in cardiac output
- b/c arteriolar and venous tone are determined by alpha1 receptors in vascular smooth muscle, alpha1- antagonists cause a lowering of peripheral resistance and a fall in blood pressure
describe the use of selective/non-selective alpha receptor antagonists
drugs that block alpha 1 and 2 adrenoreceptors non-selectively - were once used to produce vasodilation in treatement of peripheral vascular disease but are now largely obsolete
- non-elective alpha blocking drugs are unsatisfactory as they induce tachycardia, dysrhythmias, and increased GIT activity
what is postural hypotension?
a pronounced sympathetic reflex is initiated when a person stands up from a sitting or lying position- mediated by an alpha1 adrenoreceptor
- this reflex increases sympathetic tone to vasculature causing an immediate vasoconstriction - this facilitates cardiac return of blood
- failure of this reflex to occur causes postural hypotension ultimately resulting in fainting
describe the non-vascular usage of alpha-receptor antagonists
- urinary obstruction - internal urethral sphincter controlled by alpha receptors
- erectile dysfunction - yohimbine is an alpha2 antagonist - enhances the amount of noradrenaline released
what is phaeochromocytoma?
a neuroendorcrine tumour of the adrenal medulla resulting in excessive secretion of catecholamines especially noradrenaline or adrenaline -
patients present with notable nervousness, excessive sweating, rapid heart rate, severe hypertension, gastrointestinal pain and an irregularly increased breathing pattern
- alpha receptor antagonists are used in the preoperative management of patients
- phenoxybenzamine is the antagonist of choice - equipotent on both alpha1 and alph2 receptors, beta-antagonists may be required to reverse cardiac effects of excessive catecholamines - alphamethyl tyrosine can sometimes be used to prevent the synthesis of catecholamines
drescribe the use of propanolol
the first clinically useful beta adrenergic receptor antagonists non-selective between beta 1 or 2
describe the use of atenolol
a beta1 selective (cardioselective) primarily used in cardio cases - used to treate cardiac dysrhythmias, angina, myocardial infaction, also anxiety
- important hazards are bronchoconstriction, bradycardia, and cardiac failure -
is there any clinical use for beta 2 or beta 3 antagonists?
NO clinical use for these
describe the cardiovascular applicaiton of beta blockers
- beta blocker slows the sinoatrial node which initates heartbeat
- slow heart rate allows left ventricle to fill completely and lowers the heart workload
describe the mechanism of action for propanolol
induction of peripheral vasoconstriction by propranolol can be attributed to three main actions
- inhibition of beta 1 receptors in the heard decreases cadiac output- therefore induce reflexive peripheral vasoconstriction via stiulation of alph1 receptors in smooth muscle
- direct inhibition of beta 2 receptors incites peripheral vasoconstriciton
- by blocking beta-adrenergic effects of circulating catecholamines (epinephrine and norepinephrine),
describe the treatment of glaucoma
primary manifestation of this disease involves increased intraocular pressure
- 5 general groups of drug= cholinomimetics, alpha agonists, beta blockers, prostaglandin F2 alpha analogs, and diuretics
*prostaglandin analogs and beta blockers most popular due to convenient dosing and lack of side effects
(beta blockers decrease aqueous humor production)
what are the broad disadvantages of adrenergic agonists and antagonisst?
- mimetics potentiate both alpha and beta effects
- lytics result in loss of alpha and beta effects and unopposed parasympathetic tone
specifically
- amphetamines: stimulate release of NA and dopamine, causing euphoria and alertness
- cocaine: prevents NA metabolism also causing euphoria and alertness
