SNS antagonists

Question 1

give some actions of the sympathetic nervous system

Answer 1

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

Question 2

give some examples of parasympathetic activity

Answer 2

constrict pupil 
stimulates salivation 
inhibit heart 
constrict bronchi 
stimulates digestive activity 
stimulates gallbladder 
contracts bladder 
relaxes rectum

Question 3

where does the sympathetic innervation come from?

Answer 3

sympathetic ganglia

thoraco-lumbar segment

Question 4

where does the parasympathetic innervation come from?

Answer 4

cervical/ sacral sections

Question 5

adrenoceptor subtypes: 
what do they do? 
alpha 1
alpha 2
beta 1
beta 2
beta 3

Answer 5

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

Question 6

what is alpha 2 receptor used for in the synapse?

Answer 6

alpha 2 is on the presynaptic neurone so mediates a negative feedback, reducing the release of more NA from the presynaptic neurone

Question 7

give some examples of drugs as the adrenoceptor antagonists for the following receptors:

Non-selective: (a1+ b1) 
a1+ a2 : 
a1: 
b1 + b2: 
b1:

Answer 7

Non-selective: (a1+ b1) Carvedilol
a1+ a2 : Phentolamine
a1: Prazosin
b1 + b2: Propranolol
b1: Atenolol

Question 8

What is the physiology behind hypertension?

Answer 8

Blood pressure (BP) = cardiac output (CO) x total peripheral resistance (TPR)

Question 9

what is the pathophysiology for hypertension?

Answer 9

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

Question 10

what are the main contributors in hypertension?

Answer 10

Blood volume
Cardiac output
Vascular tone
(kidney releases renin when leads to angiotensin/aldosterone system stimulation- water reabsorption)

Question 11

what are the tissue targets for anti-hypertensives?

Answer 11

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.

Question 12

what beta receptors are in:
the heart 
sympathetic nerves 
the kidney 
CNs

Answer 12

heart: beta 1
sympathetic nerves: beta 1/2
the kidney: beta 1
CNS: beta1/2

Question 13

how do adrenoceptor antagonists- beta blockers work?

Answer 13

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.

Question 14

which receptors do the following drugs have greater affinity for? 
propranolol 
atenolol 
carvedilol 
nebivolol 
sotalol

Answer 14

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

Question 15

what can be the negative impacts of beta blockers?

Answer 15

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

Question 16

what is the advantage of atenolol over propranolol?

Answer 16

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.

Question 17

what advantage does carvedilol have over atenolol and propranolol?

Answer 17

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.

Question 18

what type of receptors are alpha 1 and alpha 2?

Answer 18

1-receptors
Gq-linked
Postsynaptic on vascular smooth muscle
2-receptors
Gi-linked
Presynaptic autoreceptors inhibiting NE release

Question 19

name two alpha blockers and state what they do?

Answer 19

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

Question 20

how does phentolamine work?

Answer 20

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!

Question 21

why do alpha 2 receptors and baroreceptors reduce the effectiveness of phentolamine?

Answer 21

Simultaneous blockade of a2 receptors tends to increase NE release which enhances the reflex tachycardia that occurs.

Question 22

how does prazosin work?

Answer 22

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.

Question 23

Identify the actions of the false transmitter methyldopa

Answer 23

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.

Question 24

what is the method of action of methyldopa?

Answer 24

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.

Question 25

what are the side effects of methyldopa?

Answer 25

Adverse effects:

o Dry mouth, sedation, orthostatic hypotension, male sexual dysfunction.

Question 26

what are the benefits of methyldopa?

Answer 26

Benefits:
o Renal and CNS blood flow well maintained so used in patients with renal insufficiency or CNS disease.
o Recommended in hypertensive pregnant women as no adverse effects on foetus (but DOES cross placenta).

Question 27

what is an arrhythmia?

+main cause

Answer 27

abnormal or irregular heart beats

main cause is myocardial ischemia

Question 28

what can precipitate or aggravate arrhythmias?

Answer 28

An increase in SNS drive to the heart via b1 can precipitate or aggravate arrhythmias, particularly after MI. AV conductance is also dependant on SNS activity as the refractory period is increased by b-adrenoceptor antagonists.

Question 29

how does propranolol work?

Answer 29

Propranolol - non-selective b-antagonist Class II drug, effects mainly attributed to b1-antagonism.
Reduce mortality of patients with myocardial infarction.
Particularly successful in arrhythmias that occur during exercise or mental stress.

Question 30

what is angina?

Answer 30

Pain, that occurs when the oxygen supply to the myocardium is insufficient for its needs.
Pain distribution - chest, arm , neck.
Brought on by exertion or excitement.

Question 31

what are the three types of angina?

Answer 31

Stable-pain on exertion. Increased demand on the heart and is due to fixed narrowing of the coronary vessels e.g. atheroma.
Unstable-pain with less and less exertion, culminating with pain at rest. Platelet-fibrin thrombus associated with a ruptured atheromatous plaque, but without complete occlusion of the vessel. Risk of infarction.
Variable-occurs at rest, caused by coronary artery spasm, associated with atheromatous disease.

Question 32

what drugs can be given for angina?

Answer 32

At low doses, b1-selective agents, metoprolol, reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle.
Reduce the oxygen demand whilst maintaining the same degree of effort

Question 33

what is glaucoma and what is it caused by?

Answer 33

Characterized by:
Increase in intraocular pressure.
Caused by: poor drainage of the aqueous humour.
If untreated, it permanently damages the optic nerve, blindness.

Question 34

where is the aqueous humour produced and where does it go?

Answer 34

Produced by blood vessels in ciliary body via the actions of carbonic anhydrase.
Flows into posterior chamber, through the pupil to anterior chamber.
Drains into trabecular network and into the veins and canal of Schlemm.
Production indirectly related to blood pressure and blood flow in ciliary body

Question 35

what drugs can be given for glaucoma?

Answer 35

b-adrenoceptor antagonists (non selective block of beta1 and 2) – carteolol hydrochloride, levobunolol hydrochloride, timolol maleate.
o These reduce the rate of aqueous humour formation by blocking receptors on the ciliary body.

b-adrenoceptor antagonists (selective block of beta1) – betaxolol hydrochloride.
o Been shown to be effective.