What are the SNS adrenoceptor subtypes and what do they cause to happen?
alpha 1- vasoconstriction, relaxation of GIT
alpha 2 - inhibition of transmitter release, contraction of vascular smooth muscle and CNS actions
beta 1 - increased cardiac rate and force, relaxation of GIT and renin release from kidney
beta 2 - bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis
beta 3 - lipolysis
What can neurotransmitters also act as?
-auto receptors on the presynaptic membrane that influence the synthesis and release of neurotransmitter
What adrenoceptors does carvedilol favour?
- totally non-selective
- alpha 1 and beta 2
what adrenoceptor does phentolamine favour?
- alpha 1 and -alpha 2
- non-selective
what adrenoceptor does prazosin favour?
-alpha 1
what adrenoceptor does propranolol favour?
- beta 1 and beta 2
- non-selective
what adrenoceptor does atenolol favour?
-beta 1
what is hypertension defined as?
-BP consistently over 140/90 mmHg
what is the most important risk factor for stroke?
-hypertension
what is hypertension a high risk factor for?
- chronic kidney disease
- myocardial infarction
what is the equation for blood pressure?
BP=CO x TPR
What are the main contributors towards blood pressure?
- cardiac output
- blood volume
- vascular tone
What effect do beta blockers have on adrenoceptors?
- block beta 1 receptors on the heart leading to a reduction in HR and force of contraction, leading to reduced BP
- blocks beta 1 receptors on the kidney, reducing renin production, reducing angiotensinogen II - decreasing peripheral resistance
- blockade of beta 1 and beta 2 may block noradrenaline release from sympathetic nerves
- reduces sympathetic tone in the CNS
What are the side effects of beta blockers?
- bronchoconstriction
- cardiac failure
- hypoglycaemia
- fatigue
- cold extremities
- bad dreams
what extra property does carvedilol have?
-alpha 1 blockade give additional vasodilator properties
what does nebivolol effect?
- it is a beta 1 blocker
- stimulates NO release
what does sotalol effect?
- blocks both beta1 and beta 2
- inhibits K+ channels, interferes with cell hyperpolarisation
what type of patients do you not want to give beta blockers to?
- asthmatic/COPD
- cardiac failure (these patients rely on a degree of sympathetic drive to maintain adequate CO)
- diabetic (beta blockers can mask the symptoms of hypoglycaemia e.g. sweating)
Why do you experience fatigue?
-reduced CO and reduced muscle perfusion
Why do you suffer from cold extremities?
-loss of beta receptor mediated vasodilation of cutaneous vessels
What are the advantages of propranolol vs atenolol
- atenolol has a reduction of B2side effects
- asthmetics and diabetics are lesslikely tp respond badly to the drug but it is STILL NOT SAFE
What advantage does carvedilol have over atenolol and propranolol?
-more powerful hypotensive effect - decreases FOC on the heart through B1, blocked renin release on the kidney through B2 and blocks vasoconstriction on vessels through A1
What is the mechanism for A1 receptors and where are they found?
- Gq linked
- PIP2 - IP3 - Ca2+
- PIP2 - DAG - PKC
- postsynaptic on vascular smooth muscle
What is the mechanism for A2 receptors and where are they found?
- Gi linked
- ATP - CAMP -PKA
- presynaptic autoreceptors inhibiting NA release
What is phentolamine used for?
-pheochromocytoma- induced hypertension
What is prazosin used for?
- inhibits vasoconstrictor activity of NA
- modest BP lowering effects
- adjunctive treatment
How does phentolamine work?
- blocks alpha 1 and alpha 2 (non-selective)
- reduced negative feedback from alpha 2 leads to increased release of NA
- this competes with the alpha 1 blockade
- baroceptors detect dilated blood vessels through decreased vagal activity, sympathetic activity is increased
What is an advantage of prazosin over phentolamine?
- less tachycardia occurs as NA release is not increased from the end of nerve terminals
- CO decreases due to fall in venous pressure and from dilation of capacitance vessels
- hypotensive effect is dramatic
- also causes a modest decrease in LDL, increase in HDL
Describe how methyldopa works?
- it is taken up by noradrenergic neurons, it is then decarboxylated and hydroxylated to form a false transmitter (a-methyl-noradrenaline) so it cannot be modified by MAO
- it accumulates in larger quantities than noradrenaline, displacing it from synaptic vessels
How is A-methyl-noradrenaline release?
the same way as noradrenaline
what adrenoceptors does AMN act on?
- less effective than NA on alpha 1 so they are less effective causing vasoconstriction
- more active on presynaptic alpha 2, reduces NA release below normal
- stimulates vasopressor centre in the brain to inhibit sympathetic outflow
What other benefits are there of methyldopa?
- used in renal insufficiency or cerebrovascular disease
- advised for an antihypertensive in pregnant women as it has no adverse side effects on the foetus
What are the side effects of methyldopa?
-dry mouth
-sedation
-orthostatic hypotension
male sexual dysfunction
What is an arrhythmia and what is its main cause?
- abnormal or irregular heartbeat
- myocardial ischemia
What increases the chance of an arrhythmia?
exercise
What are used for treatment of arrhythmia and why?
- beta blockers
- -increase the refractory time of AV node, slowing down ventricular rate- beneficial in the case of atrial tachycardia
- this controls sympathetic drive
-propranolol, particularly successful in ones that occur during exercise or mental stress
What is angina?
-pain when the oxygen supply to the myocardium is insufficient for its needs
What causes angina?
-exertion or excitement, mostly by atherosclerosis
What are the 3 types of angina?
- stable (pain on exertion)
- unstable (pain with less and less exertion)
- variable (at rest)
What are used to treat anginas and why?
- beta adrenoceptor antagonists
- decrease HR, systolic BP and cardiac contractile activity
- they will reduce oxygen demand whilst maintaining the same degree of effort
-at low dose metoprolol reduces HR and myocardial contractile activity without affecting bronchial smooth muscle
What patients are beta blockers not used in to treat angina?
- bradycardic (<55 bpm)
- Bronchospasm
- Hypotensive
- AV block or severe congestive heart failure
What is glaucoma?
-increase in intraocular pressure
How does fluid normal pass through the eye?
- aqueous humour is produced by blood vessels in the ciliary body via carbonic anhydrase
- the amount of humour produced is directly related to the blood flow in the ciliary body
- the aqueous humour flows through the posterior chamber, through the pupil and into the anterior chamber
- drains into the trabecular meshwork in the canal of schlemm
What can adrenaline act on in the eye?
-alpha 1 receptors to cause vasoconstriction and reduce blood flow through the ciliary body
What are used to treat glaucoma?
- non selective or selective antagonists
- they reduce the rate of aqueous humour formation by blocking receptors on the ciliary body
- non selective that work: carteolol hydrochloride, levobunolol hydrochloride, timolol maleate
- selective that work: betaxolol hydrochloride
WHat other uses of beta antagonists are there?
- anxiety states e..g palpitations and tremor
- migraine prophylaxis, maintains a good supply to the CNS
- benign essential tumour