PHARM 9: SNS Antagonists Flashcards
What are the main subtypes of adrenoceptor subtypes?
a1
a2
B1
B2
stimulation of a1 adrenoceptor subtype causes –>
a1
- vasoconstriction
- relaxation of GIT
stimulation of a2 adrenoceptor subtype causes –>
a2
- causes inhibition of transmitter release
- causes contraction of vascular smooth muscle
- causes CNS actions
stimulation of B1 adrenoceptor subtype causes –>
B1
- causes increase in cardiac rate + force
- causes relaxation of GIT
- causes renin release from kidney
stimulation of B2 adrenoceptor subtype causes –>
B2
- causes bronchodilator
- causes vasodilation
- causes relaxation of visceral smooth muscle
What are the 5 main adrenoceptor antagonists?
- Labetalol –> a1 + B1
- Phentolamine –> a1 + a2
- Prazosin –> a1
- Propranolol –> B1 + B2
- Atenolol –> B1
What are the main clinical uses of SNS antagonists + false transmitters?
- hypertension
- cardiac arrhythmias
- angina
- glaucoma
What is considered as hypertension?
NICE guideline = 140/90 mmHg or higher
What are 3 main elements that contribute to hypertension?
- blood volume
- cardiac output
- vascular tone
Where are the tissue targets for anti-hypertensives ?
a) Heart (B1)
b) sympathetic nerves (B1/2)
c) Kidney (B1)
d) arterioles (B1)
Describe the mechanism of how beta adrenoceptors antagonists act as anti hypertensives
- they act on the CNS –> to reduce sympathetic tone
- they act on B1 receptors on the heart
- -> reduces HR + CO
- they act on B1 receptors on the kidney
- -> reduces Renin production
- -> reducing ATII
- -> which causes reduction in TPR
What are the 4 different categories/ types of beta blockers?
- non selective
- B1 - selective
- Mixed blockers
- other
give examples of each type of beta blockers
- non selective
- B1 - selective
- Mixed blockers
- other
- non selective
e. g propranolol - B1 - selective
e. g atenolol - Mixed blockers
e. g carvedilol - other
e. g nebivolol, sotalol
How do the 4 types of beta blockers differ?
- non selective
- B1 - selective
- Mixed blockers
- other
- non selective
- -> has equal affinity for B1 + B2 receptors - B1 - selective
- -> more selective for B1 receptors - Mixed B-a blockers
- -> a1 blockade give additional vasodilator properties - other
- -> Nebivolol potentiates NO
- -> Sotalol Inhibits K+ channels
List some unwanted effects of beta antagonists
- beta blockers can mask symptoms of hypoglycemia
- dangerous for diabetics –> because it also blocks B2 mediated glycogen breakdown.
- fatigue
- cold extremities
- bad dreams
If you have what condition - would you not give a non selective beta blocker?
- asthma
- COPD
- Cardiac Failure
- Diabetes
What is Propranolol?
- it is a non selective beta antagonist.
- at rest: little effect on HR/CO
- exercise: has effect
What is atenolol
- it is a B1 selective beta blocker
- mainly antagonists effect of NA on the heart
- but also acts on other tissues with B1 receptors
- not safe with asthmatic patients
note: selectivity depends on conc
-
What is the advantage of atenolol over propranolol?
Atenolol = B1 selective
- so effects are predominantly on the heart
- so there is for e.g less effects on the lung such as bronchoconstrction
What is Carvedilol?
- mixed B-a blocker
- has dual acting b1 + a1 antagonists
- at ratio 4:1
- lower BP through reduction in TPR
What advantage does carvedilol have over atenolol + propranolol ?
carvedilol also acts on alpha 1 receptor –> which causes vasodilation of blood vessels
- which would decrease TPR and causes decrease in BP
What is the difference between a1 vs a2 adrenoceptor?
a1
- Gq linked
- postsynaptic on vascular smooth muscle
a2
- Gi linked
- presynaptic autoreceptors inhibiting NE release
Give an example of a non selective a-blocker
phentolamine
give an example of an a1 specific blocker
prazosin
what is phentolamine used for?
- used to treat phhaechromocytoma-induced hypertension
–> has dramatic hypotensive effect
what is prazosin used for?
- used to inhibit vasoconstrictor activity of NE
- -> leads to vasodilation + decrease in BP
What is the effect of a1 antagonists on cholesterol?
- causes a decrease in LDL
- causes an increase in HDL cholesterol
Why do a2 receptors + baroreceptors reduce the effectiveness of phentolamine?
with phentolamine, you would be blocking a1 + a2 receptors.
- if you block a2 receptors, then you lose the negative feedback effect –> and you get an increase in NA release
- so NA outcompetes phentolamine so there is reduced effect of the drugs
- also when you block a1 –> it causes dilation
- which reduces arteriole pressure
- -> but it is also associated with a decrease in baroreceptors firing
- so there is increases in sympathy effect
- HR goes up
- therefore reducing effect of phentolamine
How does Methyldopa act as an anti hypertensive? describe its mechanism of action.
methyldopa = taken up by noradrenergic neurons
- then it is converted to a false transmitter (a-methyl-NA)
- which is less active on b1 + a1 receptors
- it is also more active on presynaptic a2 receptors
which causes less release of NA
- ALSO –> it is not metabolized by MAO so displaces NA from vesicles
What processes does Methyldopa undergo to form the final false transmitter?
Methyldopa –> decarboxylated –> hydroxylated –> to form alpha-methyl noradrenaline
How does the false transmitter alpha-methyl NA work?
- false transmitter = not metabolized by MAO
- accumulates in larger quantities than NA
- then it displaces NA from synaptic vesicles
- false transmitter = less active than NA on a1 receptors
- so has less effect on vasoconstriction
(it is more active on a2 receptors)
- has -ve feedback mechanism
- and reduces NA release –> to below normal levels
What effect does the false transmitter alpha-methyl NA have on the CNS?
- stimulates vasomotor centre in the brainstem –> to inhibit sypathetic outflow
What re some benefits of methyldopa?
renal/CNS blood flow = well maintained
–> widely used in patients with renal insufficiency / cerebrovascular disease
- recommended for pregnant women
What are some negative side effects of methyl dopa?
- causes dry mouth
- sedation
- orthostatic hypotension
- causes male sexual dysfunction
What is an arrhythmia?
arrhythmia = abnormal or irregular heart beats
What is the main cause of an arrhythmia?
- main cause = myocardial ischemia
damage to heart muscle –> causes re-entry of impulses, which messes up heart rhythm
an increase in sympathetic drive to the heart via the ____ receptor can aggravate arrhythmias.
an increase in sympathetic drive to the heart via the B1 receptor can aggravate arrhythmias.
AV conductance = also dependent on _______ _______
AV conductance = also dependent on sympathetic activity.
Give an example of an antagonist which works to avoid / reduce arrhythmia
Propranolol
–> reduces mortality of patients with MI
Define angina
angina = pain that occurs whe the oxygen supply to the myocardium is insufficient for its needs.
–> which tends to be brought on by exertion/excitement
pain distribution of angina = usually :
pain distribution of angina = usually : chest, arm , neck
What are the 3 different types of angina?
- stable angina
- unstable angina
- variable angina
How do the 3 different types of angina vary?
- Stable angina
- -> pain on exertion
- -> due to fixed narrowing of coronary vessel
- -> increased demand on heart - Unstable angina
- -> pain w less + less exertion culminates with pain at rest
- -> atheromatous plaque = starting to rupture
- -> but it isn’t a complete occlusion of vessel - Variable angina
- -> occurs at rest
- -> due to coronary artery spasm
- -> linked with atheromatous disease
How do B1 selective agents such as metoprolol help with angina?
- at low does
- they reduce HR + myocardial contractile activity
- -> but doesn’t affect the bronchial smooth muscle
so it reduced o2 demand, whilst maintaining same degree of effort
What is glaucoma characterized by?
increased in intraocular pressure
what is glaucoma caused by?
- caused by poor drainage of aq humour
what happens if glaucoma is left untreated?
- it permanently damaged the optic nerve
- -> results in blindness
The amount of humour produced - directly related to the ________
The amount of humour produced - directly related to the BLOOD FLOW IN THE CILIARY BODY
What effect might adrenaline have on blood flow through the ciliary body ?
- A can act on a1 receptors
- to cause vasoconstriction
- which causes reduction in blood flow through the ciliary body
How can Beta antagonists help in glaucoma?
give examples
- beta antagonists (selective + non selective)
- -> reduce formation of aq humour formation by blocking the receptors on the ciliary body
ciliary body B1 receptors are coupled with carbonic anhydrase which forms bicarbonate ions
–> blockage of this causes reduction in formation of aq humour
non selective e.g: carteolol hydrochloride / levobunolol hydrochloride / timolol hydrochloride
selective e.g betaxolol hydrochloride
