SNS antagonists Flashcards
give some actions of the sympathetic nervous system
dilate pupil inhibit salivation relaxes bronchi accelerate HR inhibit digestive activity stimulate glucose release by liver secrete A and NA from kidney relax bladder contracts rectum
give some examples of parasympathetic activity
constrict pupil stimulates salivation inhibit heart constrict bronchi stimulates digestive activity stimulates gallbladder contracts bladder relaxes rectum
where does the sympathetic innervation come from?
sympathetic ganglia
thoraco-lumbar segment
where does the parasympathetic innervation come from?
cervical/ sacral sections
adrenoceptor subtypes: what do they do? alpha 1 alpha 2 beta 1 beta 2 beta 3
a1- Vasoconstriction, Relaxation of GIT.
a2 - Inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions.
b1- Increased cardiac rate and force, relaxation of GIT, renin release from kidney.
b2- Brochodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis
b3- Lipolysis
what is alpha 2 receptor used for in the synapse?
alpha 2 is on the presynaptic neurone so mediates a negative feedback, reducing the release of more NA from the presynaptic neurone
give some examples of drugs as the adrenoceptor antagonists for the following receptors:
Non-selective: (a1+ b1) a1+ a2 : a1: b1 + b2: b1:
Non-selective: (a1+ b1) Carvedilol a1+ a2 : Phentolamine a1: Prazosin b1 + b2: Propranolol b1: Atenolol
What is the physiology behind hypertension?
Blood pressure (BP) = cardiac output (CO) x total peripheral resistance (TPR)
what is the pathophysiology for hypertension?
Hypertension is defined as being consistently above 140/90 mmHg
Single most important risk factor for stroke, causing about 50% of ischaemic strokes
Accounts for ~25% of heart failure (HF) cases, this increases to ~70% in the elderly
Major risk factor for myocardial infarction (MI) & chronic kidney disease (KD)
Ultimate goal of hypertension therapy reduce mortality from cardiovascular or renal events
what are the main contributors in hypertension?
Blood volume
Cardiac output
Vascular tone
(kidney releases renin when leads to angiotensin/aldosterone system stimulation- water reabsorption)
what are the tissue targets for anti-hypertensives?
o SNS-nerves that release vasoconstrictor molecules (NE).
o The kidney and heart.
o Arterioles – control/determine TPR.
o CNS – determine BP set-point and regulate some systems involved in BP control and autonomic NS.
what beta receptors are in: the heart sympathetic nerves the kidney CNs
heart: beta 1
sympathetic nerves: beta 1/2
the kidney: beta 1
CNS: beta1/2
how do adrenoceptor antagonists- beta blockers work?
Competitive Antagonism of b1 adrenoceptors, although b2 antagonism may be important, but what extent is not clear.
Acts in CNS to reduce sympathetic tone.
Heart (b1) to reduce heart rate and force of contraction leading to decreased cardiac output but this effect disappears in chronic treatment.
Kidney (b1) to reduce renin production, which then reduces angiotensin II release (this is a potent vasoconstrictor and increases aldosterone production). Common long-term feature in their anti-hypertensive action is a reduction in peripheral resistance
Also note the b1-receptor on the pre-synaptic membrane and thus blockade of this reduces positive feedback on NE release and may contribute to anti-hypertensive effects.
which receptors do the following drugs have greater affinity for? propranolol atenolol carvedilol nebivolol sotalol
propranolol: non-selective, equal affinity for beta 1 and 2 receptors
atenolol: beta 1 selective (more)
carvedilol: mixed beta and alpha blocker, a1 blockade gives additional vasodilator properties
nebivolol: also potentiates NO
sotalol: also inhibits K+ channels
what can be the negative impacts of beta blockers?
Bronchoconstriction - Little importance in the absence of airway disease. In asthmatics patients this can be dramatic and life-threatening. Also clinical importance in patients with obstructive lung disease e.g. bronchitis.
Cardiac Failure - Patients with heart disease may rely on a degree of sympathetic drive to the heart to maintain an adequate cardiac output, and removal of this by blocking b-receptors will produce a degree of cardiac failure.
Hypoglycemia - The use of b-antagonists mask the symptoms of hypoglycemia (sweating, palpitations, tremor). Use of non-selective b-antagonists are more dangerous in such patients since they will also block the b2- receptors driven breakdown of glycogen . b1- selective agents may have advantages since glucose release from the liver is controlled by b2- receptors.
Fatigue - Due to reduced cardiac output and reduced muscle perfusion.
Cold Extremities - Loss of b-receptor mediated vasodilatation in cutaneous vessels.
Bad Dreams
what is the advantage of atenolol over propranolol?
Atenolol is beta 1 selective - Historically called cardio-selective drugs.
b1-Selective, antagonises the effects of noradrenaline on the heart but will affect any tissue with b1 receptors e.g. Kidney.
Less effect on airways than non-selective drugs (as trachea and bronchioles have beta 2 receptors), but still not safe with asthmatic patients (since there is some slight affinity for beta 2 receptors even though it is considerably less than beta 1). Selectivity is concentration dependent.
what advantage does carvedilol have over atenolol and propranolol?
Dual acting b1 and a1 antagonists, higher ratio of b1 to a1 (4:1).
This drug lowers blood pressure by via a reduction in peripheral resistance.
Blood vessels have alpha 1 receptors.
Like b-blockers, carvedilol, induces a change in heart rate or cardiac output but this effect wanes with chronic use.
what type of receptors are alpha 1 and alpha 2?
1-receptors Gq-linked Postsynaptic on vascular smooth muscle 2-receptors Gi-linked Presynaptic autoreceptors inhibiting NE release
name two alpha blockers and state what they do?
Non-selective -blocker: phentolamine - used to treat phaechromocytoma-induced hypertension
alpha 1 specific blocker: prazosin inhibit the vasoconstrictor activity of NE
Have modest blood pressure lowering effects
Only used as adjunctive treatment
how does phentolamine work?
Non –selective:
Causes vasodilatation and a fall in blood pressure due to blockade of a1-receptors.
However, concomitant blockade of a2-receptors tends to increase noradrenaline release, enhances the reflex tachycardia that occurs with any blood pressure lowering agent.
Increased GIT motility (as the gut also has a/b receptors), diarrhea common problem
No longer clinically used!
why do alpha 2 receptors and baroreceptors reduce the effectiveness of phentolamine?
Simultaneous blockade of a2 receptors tends to increase NE release which enhances the reflex tachycardia that occurs.
how does prazosin work?
Prazosin - Highly selective for a1-receptors.
Vasodilatation and fall in arterial pressure.
Less tachycardia than non-selective antagonists since they do not increase noradrenaline release from nerve terminals (no a2 actions)
Cardiac output decreases, due to fall in venous pressure as a result of dilation of capacitance vessels.
Hypotensive effect is dramatic.
Does not affect cardiac function appreciably, although postural hypotension is troublesome.
Unlike other anti-hypertensive agents a1-antagonists cause a modest decrease in LDL, and an increase in HDL cholesterol. Starting to become more popular again as anti-hypertensive agents.
Identify the actions of the false transmitter methyldopa
Methyldopa is taken up by noradrenergic neurons -> methyldopa is the decarboxylated and hydroxylated to form a false NT, a-methyl-noradrenaline.
Methyldopa is then not broken down within the neuron by MAO -> tends to accumulate in larger quantities than NA and displaces NA from vesicles.
what is the method of action of methyldopa?
o Less active than NA on a1-receptors – less effective in causing vasoconstriction.
o More active on presynaptic a2-receptors – more negative feedback on NE release.
o Some minor effects on CNS – stimulates vasopressor centre.
