SNS antagonists Flashcards
1
Q
Adrenoceptor subtypes
A
- Alpha 1: vasoconstriction of the vasculature, relaxation of gastrointestinal tract (inhibitory effect on the gut so blood can be diverted to more important systems for immediate survival)
- Alpha 2: inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions (tends to diminish sympathetic activity)
- Beta 1: HEART=increased cardiac rate and force of contraction, relaxation of gastrointestinal tract, renin release from kidney
- Beta 2: bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis (liberate glucose when in demand from increased cell activity in multiple tissues)
- Beta 3: lipolysis (fat breakdown)
2
Q
Adrenoceptor antagonists
A
- Alpha 1 and beta 1 (non-selective adrenoceptors): Carvedilol
- Alpha 1 and alpha 2 (non-selective for alpha adrenoceptors): Phentolamine
- Alpha 1 (selective adrenoceptor): Prazosin
- Beta 1 and beta 2 (non-selective for beta adrenoceptors): Propranolol
- Beta 1 (selective adrenoceptor): Atenolol
- Non-selective: Carvedilol
3
Q
Clinical uses of adrenoceptor antagonists
A
- Hypertension
- Cardiac arrhythmias
- Angina
- Glaucoma
4
Q
Main contributors to hypertension
A
- Blood volume
- Cardiac output
- Vascular tone
5
Q
Tissue targets for anti-hypertensives
A
- Heart (to influence cardiac output)
- Sympathetic nerves that release noradrenaline (vasoconstrictor)
- Kidneys (regulates blood volume/vasoconstriction=effect on renin and aldosterone)
- Arterioles (determine peripheral resistance)
- CNS (determine blood pressure set point and regulates some systems involved in blood pressure control and the autonomic nervous system)
6
Q
Unwanted effects of beta adrenoceptor antagonists (beta blockers)
A
- Bronchoconstriction: life-threatening in asthmatics and clinically important for patients with obstructive lung disease
- Cardiac failure: patients with heart failure may rely on some sympathetic drive to the heart to maintain an adequate cardiac output->removal by beta-1 receptors produces a degree of heart failure
- Hypoglycaemia: beta antagonists mask hypoglycaemic symptoms which is dangerous in diabetic patients (typical warning sign of urgent need for carbohydrates). Non-selective beta antagonists are more dangerous in diabetics as block glycogen breakdown driven by beta-2 receptors. Beta-1 selective agents may be advantageous since glucose release from the liver is controlled by beta-2 receptors
- Fatigue: results from reduced cardiac output and reduced muscle perfusion
- Cold extremities: loss of beta receptor mediated vasodilation in cutaneous vessels
- Bad dreams
7
Q
Alpha-1 receptors
A
- Gq-linked (coupled to stimulatory G protein)
- linked to PLC and calcium influx
- Postsynaptic adrenoceptors on vascular smooth muscle
8
Q
Alpha-2 receptors
A
OPPOSITE TO BETA RECEPTORS
- Gi-linked (coupled to adenylate cyclase via inhibitory G protein
- decreases cAMP to decrease cell activity
- Presynaptic autoreceptors which inhibit noradrenaline release (decrease neuron ability to stimulate noradrenaline release)
9
Q
Non-selective alpha blocker
A
PHENTOLAMINE
-used to treat phaechromocytoma-induced hypertension
10
Q
Alpha-1 specific blocker
A
PRAZOSIN
-inhibits the vasoconstrictor activity of noradrenaline
11
Q
Methyldopa
A
ANTIHYPERTENSIVE AGENT
- FALSE TRANSMITTER REPLACING NORADRENALINE IN SYNAPTIC VESICLES
- taken up by noradrenergic neurons
- less active at beta/alpha 1 receptor
- decarboxylated and hydroxylated to form the false transmitter, alpha-methylnoradrenaline
- not de-aminated within neuron by MAO (Mono Amine Oxidase)->tends to accumulate in larger quantities than noradrenaline and displaces noradrenaline from synaptic vesicles
12
Q
Sides effects of Methyldopa
A
PROFOUND SIDE EFFECTS INTERFERING WITH SYMPATHETIC NERVOUS SYSTEM ACTIVITY EVERYWHERE
- dry mouth (dries up sympathetic driven saliva production)
- sedation
- orthostatic hypotension (fall in blood pressure when you stand up quickly, particularly found in the elderly=major issue)
- male sexual dysfunction
13
Q
Clinical uses of Methyldopa
A
IMPROVES BLOOD FLOW
- Powerful antihypertensive, especially used where hypertension contributes to kidney disease (renal) and cerebrovascular disease (CNS)
- some CNS effects->stimulates the vasomotor/vasopressor centre in the brainstem to inhibit sympathetic outflow
14
Q
Arrhythmias
A
- abnormal or irregular heartbeats
- any deviation from the normal (sinus) rhythm of the heart
- Main cause is myocardial ischaemia but various causes but often linked to dysfunction or damage within heart tissue itself (nodal tissue, valves, muscle etc)
- Results in 350,000 deaths in the US alone
15
Q
Propranolol
A
- Non-selective beta adrenoceptor antagonist
- Class II drug with effects mainly attributed to beta-1 antagonism
- reduces mortality of patients with myocardial infarction
- particularly successful in arrhythmias occurring during exercise or mental stress
16
Q
Stable angina
A
- pain on exertion
- increased demand on the heart, due to fixed narrowing of coronary vessels (eg: atheroma)
17
Q
Unstable angina
A
- pain with less and less exertion, culminating with pain at rest
- platelet-fibrin thrombus associated with ruptured atheromatous plaque, but without complete vessel occlusion
- risk of infarction
18
Q
Variable angina
A
- occurs at rest
- caused by coronary artery spasm, associated with atheromatous disease
19
Q
Non-selective beta blocker
A
-equal affinity for beta-1 and beta-2 receptors
EG: PROPRANOLOL
20
Q
Beta-1 selective blocker
A
-more selective for beta-1 receptors
EG: ATENOLOL
21
Q
Mixed beta-alpha blocker
A
- alpha-1 blockade gives additional vasodilator properties
- EG: CARVEDILOL
22
Q
Other beta blockers
A
- Nebivolol: also potentiates NO
- Sotalol: also inhibits potassium ion channels
23
Q
Angina
A
- Chest pain that occurs when the oxygen supply to the myocardium is insufficient for its needs (blood flow does not match tissue demand)
- Pain distributed to the chest, arm and neck
- bought on by exertion or excitement
24
Q
Hypertension physiology
A
Blood pressure= cardiac output x total peripheral resistance
- heart drives cardiac output, with the heart being under the control of the brain
- blood vessels directly influence total peripheral resistance but also, the actions of the blood vessels influence the kidney’s ability to produce renin and aldosterone (renin-angiotensin system stimulated by reduced renal BP)
25
Hypertension pathophysiology
- Defined as being consistently above 140/90 mmHg (reference measurement deviates slightly depending on size=smaller height means less pressure required in system to get blood around the body so hypertensive at lower value to what is stated)
- Single most important risk factor for stroke, causing about 50% of ischaemic strokes
- Accounts for ~25% of heart failure cases, this increases to ~70% in the elderly
- Major risk factor for myocardial infarction and chronic kidney disease (end organ dysfunction)
- Silent disease in which many patients are not aware of their hypertension but problematic as contributes to a lot of end organ dysfunction
- Low compliance with antihypertensive medication->side effects etc
- The ultimate goal of hypertension therapy is reduce to morbidity (to a certain degree) and mortality from cardiovascular or renal events
26
Mechanism of action of beta blockers
- Beta blockers do not target alpha adrenoceptors so arterioles are not impacted by beta blocker administration
- Acts on beta 1 adrenoceptors of the heart to reduce heart rate and force of contraction->ultimately reduces cardiac output (effect disappears in chronic treatment)
- Acts on beta 1 adrenoceptors of the kidneys to reduce renin production (and hence reduce angiotensin II and aldosterone synthesis and release)->blocking beta adrenoceptors stops the sympathetic activity directly stimulating renin production, resulting in reduced angiotensin II production (loss of vasoconstrictive effect which has a positive effect on the total peripheral resistance=angiotensin II is a potent vasoconstrictor so will impact on vascular tone directly)->ultimately leads to reduced aldosterone production (aldosterone drives sodium reabsorption into the body by apical sodium channel expression on the collecting duct, causing reuptake of water by osmosis=lack of aldosterone reduces blood volume)
- Acts in CNS to reduce sympathetic tone
27
Comparison of pharmacology between Propranolol (non-selective adrenoceptor antagonist) and Atenolol (selective adrenoceptor antagonist)
- Atenolol is a cardio-selective drug (beta 1 selective adrenoceptor antagonist)=selectively antagonises the effects of noradrenaline on the heart and any tissue with beta 1 receptors (eg: kidneys)
- less effect on the airways and liver compared to non-selective drugs as these have beta 2 adrenoceptors
- used by asthmatics and diabetics as less likely to respond negatively to the beta adrenoceptor antagonist->selective drugs do not have pure selectivity so some b2 adrenoceptor blockade still remains (on airways and liver) so still not safe with asthmatics and diabetics
- selectivity is concentration dependent
28
Comparison of pharmacology between Carvedilol (mixed adrenoceptor antagonist) and Atenolol (selective adrenoceptor antagonist) and Propranolol (non-selective adrenoceptor antagonist)
-Carevedilol use (mixed adrenoceptor antagonist) results in a more powerful hypotensive effect->typically used in instances with very high hypertension
29
Comparison of pharmacology between Phentolamine (non-selective adrenoceptor antagonist) and Prazosin (selective adrenoceptor antagonist)
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30
Glaucoma
- Characterised by raised intraocular pressure
- Caused by poor drainage of the aqueous humour (impaired venous drainage channels result in pressure build up)
- If untreated, it permanently damages the optic nerve, resulting in potential blindness
31
Beta blocker treatment of Glaucoma
- decreases aqueous humour production
- beta 1 adrenoceptors on the ciliary body are coupled to carbonic anhydrase so binding to and blocking these adrenoceptors stops the ciliary body epithelial cells producing aqueous humour via carbonic anhydrase (stops bicarbonate ion production which contributes to aqueous humour formation)
32
Aqueous humour production
- produced by blood vessels in ciliary body via carbonic anhydrase actions
- aqueous humour flows into posterior chamber and through the pupil to the anterior chamber
- aqueous humour drains into trabecular meshwork and into veins and then Canal of Schlemm
- production indirectly related to blood pressure and flow in the ciliary body
- interference with the venous drainage channels results in impaired drainage->leads to pressure build-up
33
Unwanted effects of Phentolamine (non-selective alpha blocker)
- Overactive GI function-> increased GI motility and tone resulting in diarrhoea (common problem)
- Causes vasodilation and hence fall in blood pressure due to alpha 1 receptor blockade but associated (concomitant) alpha 2 receptor blockade tends to increase noradrenaline release->enhances reflex tachycardia (decrease in blood pressure causes heart to beat faster in attempt to raise it) that occurs with any blood pressure lowering agent
34
How do alpha 2 receptors reduce phentolamine effectiveness?
- Phentolamine blocks alpha 1 and alpha 2 receptors
- Blocking the alpha 2 receptor inhibits the negative feedback system in place so more noradrenaline is released into the synapse (instead of undergoing reuptake)
- This sets up competition between Phentolamine and noradrenaline in the synapse for the postsynaptic alpha 1 receptors->with more noradrenaline in the synapse, the ability of phentolamine to effectively block the alpha 1 receptors is reduced
- results in more alpha 1 receptor stimulation (reduced alpha 1 blockade) than what would occur in theory with an selective alpha 1 agent
35
Treatment of angina
- Either increase myocardial oxygen supply (by increasing coronary blood flow and arterial oxygen content) or reduce the work the heart is doing (reduces myocardial oxygen demand)
- Beta blockers work to decrease myocardial oxygen demand (better match of blood flow to the tissue demand)-> beta 1 adrenoceptor antagonists slow the heart rate and decrease contractility
- problem with beta 1 adrenoceptor antagonists reducing the myocardial oxygen demand (from heart working too hard) is that it impairs the ability to exercise (heart cannot beat as fast and as powerfully)
36
Beta blocker action on the main contributors to hypertension
- Blood volume: reduced aldosterone production decreases blood volume
- Cardiac output: actions on the heart (heart rate)
- Vascular tone: vasodilation->directly affected by angiotensin II reduction (due to reduced renin production)
37
Beta blocker action on the main contributors to hypertension
-Blood volume: reduced aldosterone production decreases blood volume
-Cardiac output:
decreased due to actions of the blockade on the heart (heart rate)
-Vascular tone: reduced angiotensin II production (due to reduced renin production) directly acts on vessels to cause vasodilation
38
The sympathetic nervous system
SNS antagonists act on alpha/beta adrenoceptors to block these effects (reverse the sympathetic response)
- Dilates pupils
- Inhibits salivation
- Relaxes bronchi
- Accelerates heart (to get blood round the body more effectively)
- Inhibits digestive activity
- Stimulates glucose release by liver
- Secretion of adrenaline and noradrenaline from kidney
- Relaxes bladder
- Contracts rectum
