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LCRS Year 2 - Pharmacology and Therapeutics > Lecture 8 - SNS Antagonists > Flashcards

Lecture 8 - SNS Antagonists Flashcards

1
Q

What are the neurotransmitter molecules at peripheral (rather than ganglionic) synapses in the sympathetic nervous system?

A
  • Noradrenaline
  • Adrenaline
  • Acetylcholine (sweat glands only)
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2
Q

Describe the release of noradrenaline into a sympathetic synapse and how it acts on a1 and a2 adrenoceptors as well as what these receptors cause.

A
  • Noradrenaline packed into vesicles
  • Vesicles move to and fuse with presynaptic membrane
  • Noradrenaline is released into and diffuses across the synapse
  • Binds to a1 adrenoceptors on postsynaptic membrane
  • Also then bind to a2 adrenoceptors on the PRESYNAPTIC membrane

A1 adrenoceptors initiate a sympathetic effect when bound to e.g. vasoconstriction

A2 adrenoceptors have a negative effect on the synthesis and release of noradrenaline from presynaptic terminal when bound to, reduces NA in synapse and thus stimulation of a1 adrenoceptors

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3
Q

What are the 5 types of adrenoceptor?

A 
Alpha 1
Alpha 2
Beta 1
Beta 2
Beta 3
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4
Q

What effects do the 2 alpha adrenoceptors cause?

A

Alpha 1 - vasoconstriction, relaxation of GI tract

Alpha 2 - inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions

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5
Q

What effects to the 3 beta adrenoceptors cause?

A

Beta 1 - increased cardiac rate/force, relaxation of GI tract, increased renin release from kidney

Beta 2 - Bronchodilation, vasodilation, relaxation of visceral smooth muscle

Beta 3 - Lipolysis

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6
Q

What are 5 examples of adrenoceptor antagonist drugs and what is their selectivity?

A 
Labetalol - a1 + b1
Phentolamine - a1 + a2
Prazosin - a1
Propranolol - b1 + b2
Atenolol - b1
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7
Q

What are the main clinical uses of SNS antagonists and false transmitters?

A

There are 4 main areas of use

  • Hypertension
  • Cardiac arrhythmias
  • Angina
  • Glaucoma
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8
Q

What is hypertension and why is it important?

A

“Sustained diastolic blood pressure greater than 90mmHg”
BP >140/90mmHg
Ambulatory or home monitoring average >135/85mmHg

Important as it is strongly associated with increased risk of other diseases.

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9
Q

What are the main elements that contribute to hypertension?

A

There are 3 main elements

  • Blood volume, influenced by the kidney
  • Cardiac output
  • Peripheral vascular tone (total peripheral resistance)
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10
Q

How does the sympathetic NS affect blood pressure and what are its effects on organs influencing blood pressure?

A

Sympathetic control of the heart via b1 receptors increases cardiac output

Major control of BP is sympathetic drive to kidneys

  • B1 receptors stimulate renin release
  • Renin release stimulates production of angiotensin II (powerful vasoconstrictor)
  • Angiotensin II also leads to production of aldosterone which further increases BP
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11
Q

What are the tissue targets for anti-hypertensives from primary to last target?

A

Kidneys
Heart
CNS

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12
Q

Were the first anti-hypertensive beta antagonists non-selective or selective, why was this important and what were they succeeded by?

A
  • Non-selective, targeted both b1 and b2 adrenoceptors
  • B1 blockade is what produced the majority of the desired effects, b2 blockade produces most of the side effects
  • Non-selective antagonists were then succeeded by b1 selective antagonists due to their fewer side effects
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13
Q

What is another term to describe beta-1 selective antagonists?

A

Cardioselective drugs

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14
Q

What are the 3 ways beta adrenoceptor antagonists act to reduce blood pressure?

A
  • Act in CNS to reduce sympathetic tone/output
  • Act on b1 receptors in the heart reducing HR and cardiac output
  • Acts on b1 receptors in kidneys to reduce renin production and indirectly reduce total peripheral resistance
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15
Q

What effect do PRESYNAPTIC beta 1 receptors have and what happens if they are blocked?

A
  • Positive facilitation effect on synthesis and release of neurotransmitter
  • If blocked, facilitation effect is remove and amount of noradrenaline being released is reduced
  • One of the contributing factors to the anti-hypertensive effect of b1 antagonists
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16
Q

What are the unwanted effects of beta antagonists?

A 
Bronchoconstriction 
Cardiac failure 
Hypoglycaemia 
Fatigue
Cold extremities
Bad dreams
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17
Q

Why is it dangerous to give non-selective beta antagonists to asthmatics and those with cardiac failure/heart disease?

A
  • beta 2 receptors on bronchial smooth muscle allow for bronchodilation
  • during an asthma attack or in those with COPD, if bronchodilation is not possible, due to b2 blockade, patient can suffocate and die
  • patients with cardiac failure rely on a degree of sympathetic drive to the heart to maintain adequate cardiac output which is removed if a non-selective beta antagonist is taken = cardiac failure
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18
Q

Why is it a bad idea to give beta antagonists to diabetics?

A
  • Blockade of beta receptors masks the symptoms of hypoglycaemia so the patient doesn’t know they’re having a hypo episode so they won’t get something to boost their blood glucose
  • Beta 2 receptors drive glucose release from the liver so when blocked it further worsens the hypoglycaemia
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19
Q

Why do non-selective beta antagonists cause fatigue and cold extremities?

A

Fatigue - reduced cardiac output and reduced muscle perfusion

Cold extremities - loss of beta receptor-mediated vasodilation of cutaneous vessels

20
Q

What are the four main conditions in which you wouldn’t give a non-selective beta antagonist?

A

Asthma
COPD
Cardiac failure/disease
Diabetes

21
Q

What is the selectivity, what does the effects, and what are the side effects of PROPRANOLOL?

A
  • Non-selective (b1+b2)
  • Very little change in HR, CO or BP at rest but reduces all of these during exercise (compared with the normal response to exercise)
  • Produces all typical adverse effects due to its non-selectivity and b2 antagonism
22
Q

What is the selectivity, what does the effects, and what are the side effects of ATENOLOL?

A
  • Beta-1 selective
  • Mainly antagonises effects of NA in the heart but acts in any tissue with b1 receptors (kidneys)
  • Fewer side effects due to selectivity but still NOT safe for asthmatics
23
Q

What is the selectivity, what does the effects, and what are the side effects of LABETALOL?

A
  • Alpha-1 and beta-1 selective
  • Acts more on beta-1 (4:1 ratio)
  • Lowers BP by reducing TPR, reduces HR/CO
  • Even fewer side effects of atenolol
24
Q

How do alpha antagonists cause postural hypotension, what with be the cardiac response and what is this response called?

A
  • Alpha-1 is the main mediator of TPR so when blocked, TPR decreases and BP drops
  • When you stand up, SNS kicks in and gives a boost to the blood pressure. This is blocked with an alpha antagonist resulting in postural hypotension
  • Cardiac output and heart rate are increased as a response to the hypotension
  • This is called “baroreceptor mediated tachycardia” or “reflex tachycardia”
25
Q

What is the selectivity, what does the effects, and what are the side effects of PHENTOLAMINE?

A
  • Non-selective (a1+a2)
  • Vasodilation and fall in BP (a1 blockade)
  • However, also blocks a2 receptors which removes inhibitory effect on NA release resulting in an ENHANCED reflex tachycardia to the BP drop
  • Other side effects are increased GIT motility and diarrhoea

Phentolamine is NO LONGER in clinical use

26
Q

What is the selectivity, what does the effects, and what are the side effects of PRAZOSIN?

A
  • Highly alpha-1 selective
  • Vasodilation and dramatic BP drop
  • Some reflex tachycardia but much less than phentolamine, cardiac output decreases due to fall in venous pressure
  • Can cause problematic postural hypotension
  • Cause decrease in LDL and increase in HDL cholesterol which has made it regain popularity as an anti-hypertensive agent
27
Q

What is methyldopa and what does it do in presynaptic noradrenergic neurons?

A
  • Anti-hypertensive false transmitter
  • It is taken up by the neurone, decarboxylated and hydroxylated to form alpha-methyl noradrenaline, the false transmitter
  • Alpha-methyl NA is not deaminated by MAO in the neuron and thus accumulates in larger quantities than NA.
  • It also displaces NA from synaptic vesicles before being released in the same way
28
Q

What is the activity of alpha-methyl NA on a1 and a2 receptors compared with NA and what does this mean it causes?

A
  • Less active than NA at a1 = less effective at causing vasoconstriction
  • MORE active than NA at a2 = more effective at inhibiting NA release
29
Q

What is the effect of methyldopa on the CNS?

A

Stimulates the vasopressor centre in the brainstem and inhibits sympathetic outflow so general sympathetic effect is reduced

30
Q

What are other benefits of methyldopa?

A
  • Renal and CNS blood flow maintained well so widely used in patients with renal insufficiency or cerebrovascular disease
  • Recommended anti-hypertensive agent in pregnant women as it has no adverse effects on the foetus
31
Q

What are the adverse effects of methyldopa and how much is it used?

A

Dry mouth
Sedation
Orthostatic hypotension
Male sexual dysfunction

Rarely used

32
Q

What is arrhythmia and what is its main cause?

A

Abnormal or irregular heart beats

  • main cause is myocardial ischaemia
  • damage to the heart muscle can result in re-entry of impulses which interrupts the heart rhythm
33
Q

There are different classes of anti-arrhythmic drugs. Which class are beta-blockers and how do they help treat arrhythmia?

A

Class II

  • AV conductance is critically dependent on sympathetic activity
  • When beta-blockers are given, they increase the AV node refractory period and this interferes with AV conduction in atrial tachycardias which all slows down ventricular rate
  • So even if you have re-entry of impulses into cardiac muscle, it won’t stimulate another heart beat as it is now still in the refractory period
34
Q

Which beta-blocker is given as an anti-arrhythmic and how does it affect mortality?

A

Propranolol

  • Reduces mortality of patients with myocardial infarction
  • Particularly successful in arrhythmias occurring during exercise or mental stress
35
Q

What is angina, what is its pain distribution and what is it brought on by?

A

“Pain that occurs when the oxygen supply to the myocardium is insufficient for its needs”

  • Chest, arm, neck
  • Brought on by exertion or excitement
36
Q

What are the 3 types of angina?

A

Stable
Unstable
Variable

37
Q

When does pain present in stable angina and why is this?

A

Pain on exertion

  • Due to fixed (stable) narrowing of coronary vessels
  • Increased demand on the heart
38
Q

When does pain present in unstable angina and why is this?

A

Pain with less and less exertion as it develops culminating in pain at rest

  • Atheromatous plaque is starting to rupture
  • Platelet-fibrin thrombus associated with the plaque but not complete occlusion of the coronary vessel
  • High risk of infarction
39
Q

When does pain present in variable angina and why is this/

A

Pain at rest

  • Caused by coronary artery spasm
  • Associated with atheromatous disease
40
Q

What effect do beta antagonists have on angina, which beta blocker particularly, and how does this occur?

A

Decrease the chance of having an angina attack

  • Decrease HR, systolic BP, cardiac contractility WITHOUT affecting bronchial smooth muscle
  • Overall reduce oxygen demand whilst maintaining the same degree of effort
  • METOPROLOL (beta-1 selective at low dose)
41
Q

What are the adverse effects of beta antagonists being used to treat angina?

A 
Fatigue
Insomnia
Dizziness
Sexual dysfunction
Bronchospasm
Bradycardia
Heart block
Hypotension
Decreased myocardial contractility
42
Q

Which groups of patients are b-1 selective agents, such as metoprolol, not used in?

A

Bradycardic (HR<55bpm)
Patients with bronchospasm
Hypotensives (SBP<90mmHg)
AV block or severe congestive heart failure - beta blockers could increase risk of MI

43
Q

How do beta blockers treat glaucoma? (how also does alpha blockade treat it?)

A

Carbonic anhydrase produces aqueous humour in ciliary body

  • B1-receptors facilitate carbonic anhydrase so when BLOCKED = reduced activity of carbonic anhydrase and reduced production of aqueous humour
  • A1-receptor blockade causes vasoconstriction of blood vessels in ciliary body so reduces fluid volume in aqueous humour

Overall reduction in intraocular pressure as less AH produced

44
Q

What are 3 examples of non-selective beta antagonists used to treat glaucoma?

A

Carteolol hydrochloride
Levobunolol hydrochloride
Timolol maleate

45
Q

What is the word ending affixed to beta-blocker names?

A

-olol (sometimes -alol)

LCRS Year 2 - Pharmacology and Therapeutics (14 decks)

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