Sympathetic nervous system drugs Flashcards
what is the structure of adrenoreceptors?
what are alpha and beta adrenoreceptors coupled to?
G coupled protein receptors, with 7 transmembrane domains
alpha receptors:
- coupled to phospholipase C
- alpha 2 negatively coupled to adenylate cyclase
beta receptors:
- coupled positively to adenylate cyclase
- protein kinase A
what is the general effect of alpha adrenoreceptors? what is the exception?
what has higher affinity for noradrenaline? for adrenaline?
alpha adrenoreceptors are generally excitatory, except in the gut - they’re inhibitory there
noradrenaline has a higher affinity for A1 adrenoreceptors
adrenaline higher affinity for beta adrenoreceptors in general
what are the characterstics of B1 adrenoreceptors? where are they found?
stimulatory and innervated
found in heart - increase heart rate and force of contraction
found in kidney - juxtaglomerular apparatus - causing increased renin secretion
what are the characterstics of B2 adrenoreceptors? where are they found?
inhibitory and non-innervated
found in lungs - cause bronchodilation
found in uterus - cause uterine muscle relaxation (can be used in premature labour)
most metabolic effects of cateloamines are mediated through B2 receptors what are those effects?
in liver: due to adenylate cyclase activation
- glycogen –> glucose
in muscle:
- glucose –> lactic acid (hyperlactic acidaemia)
increased Na+/K+ activation - causes increased risk of hypokalaemia. although increased activation of K+ channels in the liver due to A1 receptors causes hyperkalemia
what are the effects of B3 adrenoreceptors?
lipolysis in brown adipose tissue
detrusor bladder relaxation
what is the difference between alpha 2 and alpha 1 adrenoreceptors
what is the exception for the A2 receptors?
alpha 2 receptors: are autoreceptors. they’re prejunctional receptors
EXCEPT in platelets, they’re post-junctional and they cause platelet aggregation
alpha 1 receptors: are heteroreceptors: they’re post-junctional
how does auto inhibition in A2 adrenoreceptors work?
released NA acts on A2 receptors, this causes inhibition of adenylate cyclase
the inhibition of enzyme leads to reduction in cAMP, which leads to less calcium channel opening
without calcium channels opening, the vesicles containing noradrenaline cannot bind with membrane to release NA
what are the effects mediated through A1 receptors?
BV constrict GI motility decreases bladder sphincter contraction contraction of pupillae dilator muscle minor glycogenolysis in liver
what are the effects mediated through A2 receptors?
BV vasoconstriction
reduced GI motility
platelet aggregation
inhibition of NA release at adrenergic nerves
what are the effects of B1 receptors?
increase in Heart rate and FORCE of contraction
causes renin release in juxtaglomerular apparatus
what are the effects of B2 receptors?
BV dilation
dilation of bronchi smooth muscle
reduction in GI motility
relaxation of uterine muscle
causes tremor in skeletal muscle
causes glycogenolysis in liver
causes inhibition of histamine release from mast cells
list some of the clinical uses of A1 agonists
nasal decongestion - phenylephrine
what are the clinical uses of adrenaline?
anaphylactic shock
open angle glaucoma
cardiac arrest
prolongation of LA
explain the mechanism of action of adrenaline in anaphylactic shock
displays physiological antagonism
anaphylactic shock characterised by:
- low blood pressure
- laryngo-oedema
- bronchospasm
drug causes:
- vasoconstriction through A1 receptors to increase BP
- bronchodilation through B2 receptors
explain how open angle glaucoma can be treated?
A2 agonist - e.g. brimonidine - causes vasoconstriction of ciliary afferent arterioles, this reduces aqueous fluid production
contra-indicated in closed angle glaucoma because of its mydriatic action
beta adrenoreceptor antagonist: timolol
- reduces the production of aqueous humour production, because of vasoconstrictive effects
what can B2 agonists be used for?
what can be some of their unwanted side -effects?
premature labour (by relaxing uterine muscle) asthma (by causing bronchodilation)
side-effects:
- skeletal muscle tremor
- peripheral vasodilation, leading to reflex tachycardia
- hypokalaemia
- hyperlactic acidaemia
what is a sympathomimetic drug?
give examples?
a drug that mimics the effects of sympathetic neurotransmitters at their receptors - drugs that directly act on adrenoreceptors
salbutomal
what is an indirect acting sympathomimetic?
give examples
those do not directly act on adrenoreceptors, but they cause the release of neurotransmitter to act on the adrenoreceptors. basically they can cause NA release in the absence of nerve stimulation
examples:
- tyramine
- amphetamine
- ephedrine
what is the mechanism of action of indirect acting sympathomimetics?
- they have weak actions on adrenoreceptors
- but they resemble NA so they’re up taken through uptake mechanism one into the nerve terminal
- in the nerve terminal they displace a vesicular NA, through VMAT
- the NA is released into the cytosol, some degraded into metabolites via MAO or mostly released into synapse via Uptake mechanism 1 in exchange for tyramine
this mechanism does not require calcium, because no vesicle fusion
explain adrenaline reversal?
and how is the dosage of adrenaline related to its effect?
adrenaline reversal is when adrenaline is fused at a high concentration, so that the effects produced by alpha adrenoreceptors mask the effect of B adrenoreceptors
phentolamine is used, an A adrenoreceptor antagonist, this means the effects mediated by Badrenoreceptors are unmasked those are:
- reduction in BP due to vasodilation
adrenaline at low concentration activates B adrenoreceptors
adrenaline at high concentration activates A adrenoreceptors
what are the effects of IV infusion of noradrenaline?
activation of A adrenoreceptors causing:
- vasoconstriction - which leads to increase in mean BP
- this causes bradycardia, in response to reflex
- this bradycardia still ensues, despite of B1 trying to increase heart rate
what are the effects of the IV infusion of adrenaline
activation of B adrenoreceptors causing:
- vasodilation
- mean BP does not change, because HR increases due to B1 action
what are the effects of the IV infusion of isoprenaline?
isoprenaline is beta adrenoreceptor specific:
- causes massive vasodilation effect
this causes massive drop of mean BP
- this causes a massive reflex tachycardia
what are ergot alkaloids?
they’re no specific 5HT agonists
they’re partial adrenoreceptor agonists or antagonists
give an example of beta adrenoreceptor partial agonists, and when they’re used?
oxprenalol and pindolol:
- they’re full antagonists to the beta adrenoreceptor agonist adrenaline
- but they have their own weak agonist activity
- used in cases of severe bradycardia due to prolonged beta blocker use
- the increase the heart rate, whilst maintaing the depression of the sympathetic nervous system
Give examples of non selective of A antagonists?
what can they be used?
why are the disadvantageous?
phenoxybenzamine - long acting
phentolamine - short acting
they can be used in cases of hypertension, they cause vasodilation and thereby decrease BP
non-selective are bad:
- because their reflex tachycardia is greater than with selective antagonists
give examples of selective A adrenoreceptor antagonists
prazosin and doxazosin
what are the consequences of using alpha adrenoreceptor antagonists?
- failure of ejaculation
- postural hypotension
- fall in BP
- nasal stuffiness
- miosis
reflex tachycardia and increases renin secretion - because B1 receptors are not blocked
renin secretion causes: oedema, because of increased water retention and gain of weight
why is reflex tachycardia greater with non-selective A adrenoreceptor antagonists than selective ones?
because A1 and A2 both cause venoconstriction
A2 are inhibitory in the periphery
A1 are excitatory
what are the therapeutic uses of alpha adrenoreceptor antagonists?
hypertension - e.g. in cases of phaeochromocytoma
bengin prostatic hyperplasia:
- the hyperplasia constricts bladder sphincter
- an alpha antagonist causes increase in flow rate, by relaxing the sphincter
give an example of a cardio-selective b1 antagonist
an example of a non selective beta adrenoreceptor antagonist
cardio-selective - atenolol
non selective - propanolol - lipid soluble - can enter brain
stalol - acts on Na+ channels and can be used as an LA
what are the therapeutic uses of beta adrenoreceptor antagonists
angina hypertension glaucoma Chronic heart failure anxiety migraine prophaylaxis MI arrhytmias thryotoxicosis
what are the contraindication of beta adrenoreceptor antagonists?
asthma
peripheral vascular disease
diabetes
AV block
what are the side effects of using B adrenoreceptor blockers?
fatigue bradycardia cold extremeties breathlesness sleep distubrance and nightmares
how does alpha methyltyrosine interfere with NT synthesis?
it REDUCES NA release
the drug inhibits the rate limiting enzyme in NA synthesis
this enzyme is tyrosine hydroxylase
drug is used in phaechromocytoma - to reduce NA release and therefore reduce hypertension
dopamine release can be increased, by passing the rate limiting step and administering L -dopa - used in Parkinson released
list some of the drugs the work on the dopa decarboxylase enzyme
what is so special about this enzyme
this enzyme lacks substrate specificity
can convert the drug alpha methyl dopa –> alpha methyldopamine
this then can be converted to alpha methyl noradrenaline- this is a false NT - therefore, does not have any actions - but it is also not degraded - drug used in hypertension treatment
carbidopa: inhibits the enzyme
this is a polar drug, does not cross into brain, used to inhibit peripherial metabolism of levodopa, this means more levodopa can cross into brain
drug used in Parkinson’s treatment
what is the drug disulfiram used for?
alters alcohol metabolism, it inhibits dopamine B hydroxylase
leading to dopamine build up: excess dopamine leads to anxiety, restlessness
this drug is used to create an acute sensitivity to alcohol
how does reserpine alter neurotransmitter storage?
what was it used for? why was it stopped?
how does tetrabenazine work? what is it used for?
the drug competes with NA for the VMAT into the vesicles
it binds to vesicular monoamine transporters, irreversibly
this depletes the nerve from its NA storage
because the NA is not stored, it is released into cytosol, where it is degraded by MAO
used previously to treat hypertension, but subjects developed hypertension
similar action - but short lasting - because it is reversible - this can be used to treat hyperkinetic disorders e.g. hunnington’s disease
how does guanethidine inhibit NT release? which mechanism does it use?
how can its affects be reversed?
competes with NA for uptake mechanism 1
- accumulates inside nerve terminal, inhibiting physical conduction of nervous impulse
- accumulates inside vesicles leading to long term depleteion of the nerves NT
anti-tricyclic inhibitors that inhibit uptake 1, can be used to reverse the actions of guanethidine
how does blocking uptake 1 mechanism alter neurotransmitter release?
it potentiates sympathetic effects of the NT, it also reverses the effects of adrengeric blocking drugs
blocking this mechanism increases synaptic levels of neurotransmitter thus enhance sympathetic effect, and circulating noradrenaline increases
the carrier is blocked by tricyclic anti-depressants and cocaine
UPTAKE MECHANISM ONE MUCH HIGHER AFFINITY FOR NORADRENALINE
what is the function of uptake mechanism 2?
this extra-neruonal
specific for taking up adrenaline from blood circulation
this carrier is not affected by the drugs that block uptake 1
blocked by phenoxybenzamine and certain glucocorticoids
what is the mechanism of action of clonidine? what is the danger of it
used for hypertension
it is an A2 agonist
causes reduction in NA release, central sympathoinhibition
but also direct vasoconstriction (peripherally)
problem with rebound hypertension if stopped
what are MAO inhibitors used for?
what is their mechanism of action with regards to transmitter release?
they’re used as anti-depressants
they increase availability of NT, because MAO usually breakdown cytosolic NT
what is the ‘‘cheese reaction’’?
what causes it?
a hypertensive crisis caused by the ingestion of tyramine rich food
MAO - A main one in GI tract, preventing tyramine from food from entering blood stream
when inhibitors used, tryamine is used, and excess NA is released because tryamine is an indirect sympathomimetic
this reaction is only with MAO-A not seen with MAO - B
hence more specific anti-depressants to MAO-B used
where is MAO - B found? what can it be used for?
found within the brain
inhibition of this enzyme, can lead to increased dopamine levels in the brain and can be used to treat parkinson’s
selgiline - is the inhibitor used in Parkinson’s
how can we diganose phaechromocytoma?
increases concentration of VMA in urine (methoxyhydroxymandelic acid)
this is the breakdown metabolite of COMT and MAO
where is MAO found?
why are non specific MAO not used?
MAO has two isozymes A and B A- cheese reaction B - no cheese reaction enzyme found in symapthetic nerve terminals, liver and intestinal epithelium
COMT: in neuronal and non-neuronal tissue
breaksdown cateloamines and catechols
selective MAO inhibitors - selgiline
non-selective - danger of cheese reaction: phenelzine
how would you treat open angle glaucoma?
dipiverfrine:
- this is an adrenaline pro-drug (esterified adrenaline)
- it is lipid soluble - so can cross into the cornea much easier
- probably acts on A2 receptors to reduce aqueous humour production
brimonidine:
- this is a selective A2 receptor agonist
- this causes reduction of aqueous humour production
- causes vasoconstriction on cilliary artery afferents?
timolol:
- this is a non-seletive B adrenegric receptor antagonist
- reduces ocular blood flow - reduces aqueous production
when are alpha agonists contra-indicated in glaucoma? and why?
in closed angle glaucoma because of their mydraitic action
name a selective a1 agonist
phenylephrine
what is phenylephrine
a selective a1 agonist
what is isoprenaline?
a non-selective B-receptor agonist?
give an example of a non-selective B-receptor agonist
isoprenaline
what is clonidine
a selective A2 agonist
what is alpha - methyl
a selective A2 agonist
give examples of selective A2 agonists
alpha methyl and clonidine
What is salbutamol?
a B2 agonist (selective)
give an example of a selective b2 agonist
salbutamol
what can selective B2 agonists be used for?
asthma and premature labour to cause uterine muscle relaxation
what is phentolamine?
a non-selective A antagonist
give an example of a non-selective alpha receptor antagonist
phentolamine and phenoxybenzamine (irreversible)
what is phenoxybenzamine
a non-selective, irreversible Alpha receptor antagonist
what is prazosin
this is a selective A1 receptor antagonist
give an example of a selective A1 receptor antagonist
prazosin
what is propanolol
a non-selective B receptor antagonist
give an example of a non-selective B receptor antagonist
propanolol
what is atenolol
a selective B1 receptor antagonist
what is satolol?
this is a non-selective beta adrenorceptor antagonist?
what is satolol used for?
with LOCAL ANAESTHESIA, it is also a class III dysrhtymic - because acts on potassium channels
