SNS antagonists Flashcards
where are alpha 2 receptors located?
presynaptic terminals
what effect do alpha 2 receptors have?
negative feedback on NA release
these can be targetted
normal alpha 1 function
vasoconstriction
relaxation of GIT
normal alpha 2 function
inhibition of NA release
contraction of VSMC
CNS
normal beta 1 function
cardiac stimulation
relaxation of GIT
renin release
normal beta 2 function
bronchodilation
vasodilation
relaxation of VSMC
hepatic glycogenolysis
normal beta 3 function
lipolysis
non selective antagonist example (alpha and beta)
carvediol
labetalol
non selective alpha antagonist
phentolamine
alpha 1 selective antagonist
prazosin
non selective beta antagonist
propanolol
beta 1 selective antagonist
atenolol
what are the main elements that need to be controlled to treat hypertension
blood volume
cardiac output
TPR
what tissues are targeted by anti-hypertensives?
- kidney (renin) beta 1
- heart beta 1
- arterioles (TRP determinant) alpha 1/2
- SNS nerves (vasoconstrictor molecule release e.g. NA) beta 1/2
- CNS (BP set point, system regulation in BP control) beta 1/2
beta blocker suffix
-olol
what is used to treat hypertension
beta blockers
targeting the heart (beta 1)
kidney (beta 1) and CNS
effect of beta blockers on the heart
Beta 1
reduce inotropic and chronotropic effect
(this effect disappears in chronic treatment)
effect of beta blockers on kidney
beta 1
reduced renin production
effect of beta blockers on CNS
beta 1 and 2
reduce sympathetic tone
beta 1 blockade
beta 1 is also located on pre-synaptic membrane
when bound, it reduces positive feedback on NA release
this has anti-hypertensive effects
unwanted effects of beta blockers/antagonists
o Bronchoconstriction – patient has an airway disease e.g. asthmatics
o Cardiac failure – in patients with heart disease sympathetic drive is required
o Hypoglycaemia - beta blockers may mask symptoms (tremors etc.) and non-selective beta blockers will also block hepatic glycogenolysis (beta 2).
o Fatigue – reduced CO and muscular perfusion
o Cold extremities – loss of beta-receptor mediated vasodilation.
o Bad dreams- CNS
non selective beta blocker
propanolol
has equal affinities for beta 1 and 2, therefore can have adverse effects
causes little effect at rest
during exercise it reduced HR, CO and BP
cardiac selective beta blocker
atenolol
beta 1 selective
antagonises the effects of NA on the heart but affects organs with beta 1 like kidneys
atenolol vs propanolol
atenolol (beta 1 selective) is less selective for beta 2, so is less likely to give asthmatic patients an issue compared to non selective propranolol but is not entirely safe
change in atenolol selectivity
with higher concentrations, the drug becomes non-selective
labetalol and carvediol (mixed)
alpha 1 and beta 1 more for beta 1 than alpha 1 vasodilator effect lowers BP via TRP reduction therefore decreased HR or CO effect wanes with chronic use
what is the problem with using alpha antagonists?
postural hypotension
arterioles are affected, decreasing the TPR
this leads to reflexive tachycardia therefore increased HR and CO (beta mediated)
phentolamine
non selective alpha antagonist
causes vasodilation
fall in BP
how does phentolamine enhance reflexive tachycardia?
they bind to alpha 2 receptors presynaptically
blocking the inhibition of NA
When is phentolamine mainly used?
treating phaechromocytoma induced hypertension
increased GIT motility, therefore diarrhoea
prazosin
alpha 1 selective
causes vasodilation by inhibiting the vasoconstrictor activity of NA
fall in BP and CO
also decreased LDL and increases HDL (good effect)
phentolamine vs prazosin
prazosin causes less reflexive tachycardia as it does not bind to alpha 2, so NA release can be inhibited.
phentolamine is non-selective and will bind to alpha 2 too.
example of false transmitter prodrug
methyldopa
what is the false transmitter that methyldopa produced
once taken up by noradrenergic neurones, decarboxylated and hydroxylated, it becomes alpha methyl noradrenaline
alpha methyl NA activity
less affinity/active to alpha 1 than NA
more affinity/active to presynpatic alpha 2 than NA
therefore less vasoconstriction and more inhibition of NA release
why is alpha methyl NA good at its job
it is not degraded by MAO-O so it accumulates in the synaptic cleft in larger quantities than NA, so it displaces NA from the vesicles
clinical use of methydopa
renal disease
cerebrovascular disease
[helps maintain blood flow to these regions]
hypertension, e.g. in pregnant women as it has no adverse effects despite crossing the placenta
adverse effects of methyldopa
dry mouth (reduced salivations) sedation orthostatic hypotension male sexual dysfunction
what is an arrhythmia?
abnormal or irregular heart beat mainly caused by myocardial ischaemia
why do SNS antagonists need to be used to treat arrhythmias?
SNS activity exacerbates arrhythmia via beta 1, especially after ischaemia
AV conductance depends on SNS activity
what drug is usually used to treat arrhythmias?
propanolol (non selective beta antagonist, class II)
- reduced mortality of patients with myocardial ischemia
- works particularly well in cases that occur during exercise or mental stress
what is angina?
chest pain due to insufficient O2 supply to myocardium, so it is unable to meet its demands
referred pain of angina
spreads down dermatome T1 in the chest, arm and neck
brought on by exertion of excitement
types of angina
stable
unstable
variable
stable angina
fine at rest, pain on exertion due to fixed narrowing of coronary vessels
unstable angina
pain with less exertion and at rest
thrombus without the complete occlusion of the vessel
variable angina
at rest, caused by coronary artery spasm , associated with atheromatous disease
what are the 3 ways beta blockers ease angina?
reduce myocardial demand by:
- decrease inotropic effect (contractility)
- decrease chronotropic effect (heart rate)
- decrease systolic pressure
at low effects does not affect bronchial smooth muscle
adverse effects of beta adrenoreceptor antagonist
fatigue insomnia dizziness sexual dysfunction bronchospasm bradycardia heart block hypotension
therefore not used in patients where this can be exacerbated e..g congestive heart failure
what is glaucoma?
an increase in intraocular pressure due to the poor drainage of aqueous humour
can permanently damage the optic nerve
how is aqueous humour produced?
by blood vessels in the ciliary body
uses carbonic anhydrase
indirectly related to BP (fluid leakage used)
what is the flow pathway of aqueous humour?
ciliary body posterior chamber pupil anterior chamber trabecular meshwork into veins and canal of Schlemm
examples of beta adr. antagonists used in glaucoma treatment
carteolol hydrochloride
levobunolol hydrochloride
timolol maleate
non selective of beta 1 and 2
betaxolol hydrochloride is beta 1 selective
what is the effect of glaucoma medication?
reduce the rate of which aqueous humour is produced by blocking Beta-1 and stimulating alpha 2 on the ciliary body
what effect does beta 1 blockade have?
vasodilation and fall in total peripheral resistance and BP
antagonises noradrenaline on the heart
also effects on kidney
what are the main mediators of peripheral resistance?
alpha 1 receptors
therefore alpha blockade causes rapid fall in arterial pressure
how does non-selective alpha antagonism lead to drop in peripheral resistance and therefore BP?
- subcutaneous vasodilation
- increased flow through cutaneous and splanchnic vascular beds
which cells of the adrenal medulla is impacted by phaechromocytoma?
chromaffin cells
what is phentolamine used for?
phaechromocytoma induced hypertension
what is the negative consequence of using a non selective alpha antagonist like phentolamine?
- can bind to alpha 2
- less inhibition of NA release
- enhanced reflex tachycardia
what is the benefit of using an alpha 1 selective antagonist over a non-selective alpha antagonist?
e.g. prazosin over phentolamine
less reflex tachycardia as there is no alpha 2 blockade
what is the main effect of methyldopa?
as a false transmitter it is most active on pre-synaptic alpha 2
auto-inhibitor of NA release
stimulates vasopressor centre in brainstem–> reduced sympathetic outflow
what aggravates arrhythmia?
increases sympathetic drive to the heart via beta 1
particularly after MI where there is an increase in sympathetic tone
what does AV conductance depend on ?
sympathetic activity via beta 1
what effect do beta antagonists have on the refractory period?
increases the refractory period to slow ventricular rate by interfering with AV conductance
what effect do beta antagonists have in glaucoma?
reduces aqueous humour production
how is aqueous humour production indirectly linked to blood pressure?
increased blood flow to ciliary body means more production of aqueous humour
