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Pharmacology and therapeutics > Drugs and the vasculature > Flashcards

Drugs and the vasculature Flashcards

1
Q

Summarise the regulation of vascular tone

A

The contractile state of vascular smooth muscle regulates the diameter of arteries and veins and influences blood flow, blood pressure and venous return. The contractile state of vascular
smooth muscle is controlled by a variety of neural, circulating and local factors
Some agents cause relaxation, some cause contraction.

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2
Q

Describe the influence of the sympathetic nervous system on the vasculature

A

The sympathetic nerve has varicosities along its length and these primarily release NA to stimulate vasoconstriction.
Can also release ATP and NPY

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3
Q

What mediators can cause vascular smooth muscle contraction

A

§ VSM mediators that can increase [Ca2+] in the vascular smooth muscle cell and stimulate a VSM contraction include:

o AngII à AT1r

o PGG2, PGH2 à TP (T-prostanoid receptor).

o ET1 à ETA/B (various thrombin, IL-1 and endotoxin can stimulate this receptor)

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4
Q

What mediators can cause vascular smooth muscle relaxation

A

§ Endothelial cell agonists that can stimulate a relaxation from an increase in [Ca2+] in the endothelial cell include:

o NO. (cGMP)

o CNP – C-Type Naturietic Peptide.cGMP)

o PGI2.

IP (cAMP)

o EDHF – Endothelial Hypopolarising Factor.

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5
Q

What is important to remember about prostaglandins and their influence on the vasculature

A

Some cause contraction, others cause relaxation.

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6
Q

What is blood pressure mediated by

A

§ BP is generally mediated by CO and TPR (BP =CO x TPR).

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7
Q

What is the effect of shear stress on the vasculature

A

Causes VSMC relaxation by inhibiting ET1 whilst increasing the conc of Ca2+ in the endothelial cell.

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8
Q

What happens when our arterial blood pressure falls

A

The fall in arterial blood pressure is detected by a reduced firing of arterial baroreceptors.
The baroreceptor reflex mediated via medullary centres then takes place:
Increased sympathetic discharge to arterioles (excluding the brain and the heart)- increasing arteriolar constriction and peripheral resistance.
Increased sympathetic discharge to veins- increasing venous tone, venous pressure, venous return, ventricular filling and EDV- increasing SV
Increased sympathetic discharge to heart- increasing HR and contractility- increased Q
Decreased PSNS discharge to heart- increasing heart rate- increased Q

All of these will increase arterial pressure.

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9
Q

What is important to remember about arterioles

A

§ Arterioles contribute the greatest to blood pressure regulation.

o These vessels exhibit “vascular tone” and so always display a partial state of constriction.

o Hypertensive patients tend to have a raised base vascular tone à more TPR à more BP.

Sum of resistance in arterioles is TPR
More resistance- the harder it is for blood to move from the arteries to the arterioles- thus increasing the pressure of blood in the arteries- hypertension.

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10
Q

Describe the effects of contraction and relaxation of the arteriole

A

Contraction:
decreased radius, increased resistance, decreased flow

Relaxation:
Increased radius, decreased resistance, increased flow/.

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11
Q

What is the normal blood pressure range

A

120/80 mmHg
Depends on factors such as size, height and gender
Someone who is tall and skinny may have a lower BP

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12
Q

What is hypertension defined as

A

Hypertension is defined as being consistently above 140/90 mmHg

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13
Q

Describe the morbidity and mortality associated with hypertension

A

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 (failing heart has to work harder to pump blood against an increased afterload)
Major risk factor for myocardial infarction (MI) & chronic kidney disease (KD)- blood flow to the kidneys needs to be tightly regulated.

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14
Q

What is the ultimately goal in management of hypertension

A

Ultimate goal of hypertension therapy  reduce mortality from cardiovascular or renal events

However, as anti-hypertensive drugs are often given when the patient isn’t experiencing any symptoms, there is an issue with adherence as if that drug produces a side-effect, the patient will stop taking the drug due to them seeing no percieved benefit

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15
Q

What is step 1 in the treatment for hypertension

A

o Step 1 – Single Therapy:

§ Under 55 – ACEi or ARB (Angiotensin Receptor Blocker).

§ Over 55, Afro-Caribbean – CCB or Thiazide diuretic.

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16
Q

What is step 2 in the treatment for hypertension

A

§ ACEi and CCB.

§ ACEi and thiazide diuretic.

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17
Q

What is step 3 in the treatment for hypertension

A

Step 3 – Triple Therapy:

§ ACEi, CCB and thiazide diuretic

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18
Q

What is step 4 in the treatment for hypertension

A

Now classified as resistant hypertension.

Symptomatic Relief:

§ Low-dose spironolactone (diuretic therapy).

§ b-blockade or a-blockade.

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19
Q

What is important to remember about RAAS

A

Not necessarily the cause of hypertension- but it will exacerbate its progression- therefore we want to control it in hypertension.

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20
Q

Name 3 drug classes that can interfere with RAAS

A

Renin inhibitors

ACE inhibitors

Angiotensin receptor blockers

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21
Q

What is RAAS stimulated by

A

o LOW renal Na+ reabsorption.

o LOW renal perfusion pressure.

o HIGH SNS activation.

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22
Q

Outline the RAAS

A 
RAAS stimulated (i.e SNS activation)
Renin converts angiotensinogen to angiotensin I

ACE then converts angiotensin I — angiotensin II

Ang II (effector hormone)
Ang II exerts various effects (through the AT1 receptor) to increase BP:
Increased SNS activation and thirst – brain
Vasoconstriction
Salt and water retention
Aldosterone secretion.

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23
Q

Describe the effects of aldosterone in the collecting duct tubule cells

A

Aldosterone passes through the plasma membrane and binds to mineralocorticoid receptors intracellularly and increases the synthesis of Na+ channels and Na+/K+ pumps

This causes an increase in sodium reabsorption

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24
Q

What is important to remember about aldosterone

A

Aldosterone increases sodium retention by the kidney and may exert pro-fibrotic effects on the heart and vasculature.

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25
Q

Describe the actions of ACEi and their uses

A

Inhibit the somatic form of angiotensin converting enzyme (ACE)
Prevent the conversion of angiotensin I to angiotensin II by ACE

Uses:• hypertension• heart failure• post-myocardial infarction• diabetic nephropathy• progressive renal insufficiency• patients at high risk of cardiovascular disease

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26
Q

Give an example of an ACEi

A

Enalapril

27
Q

What are the anti-hypertensive effects of ACEi

A

o Reduce TPR – more bradykinin & less AngII à reduces TPR via less AT1R-mediated vasoconstriction so less BP and more bradykinin vasodilation.

o Sodium retention – less Na+ retention in the kidneys via blocked actions of AngII on the AT1R in the kidneys AND less aldosterone secretion as blocked AT1R in the adrenal medulla.

o Thirst drive – less SNS activation of thirst in the brain via AT1R.
Also decreases venous return (less salt and water retention)- therefore- less preload- reduced contractility- reduced Q

28
Q

What law links venous return to contractility

A

Starling’s Law

29
Q

Describe the beneficial effects of ACEi for HF

A

Heart failure: Increased vasoconstriction increases the afterload and increases cardiac work. Increased venous return leads to long term fluid retention and congestion, leading to oedema.

ACEi will lead to vasodilation- reduced afterload.
Bradykinin- venodilation- reduced venous return
ACEi and aldosterone- reduced Na+ retention.

30
Q

What is diabetic nephropathy caused by

A

It is due to significant damage to the kidney glomerulus because of toxic products

NOTE: hyperglycaemia increases the risk of exposure to oxygen free radicals

31
Q

Why are ACEi used in diabetic nephropathy

A

ACE inhibitors reduce the angiotensin II-mediated vasoconstriction of the efferent arteriole

This reduces the blood pressure at the glomerulus and hence reduces the accumulation of toxic products at the glomerulus

32
Q

What are angiotensin receptor blockers

A

Example: losartan

Antagonists of type 1 (AT1) receptors for Ang II, preventing the renal and vascular actions (will also reduce aldosterone secretion) of Ang II.
Uses: hypertension, heart failure

33
Q

What is important to remember about ACEi and ARBs

A

Generally well tolerated – particularly ARB

34
Q

State the side effects associated with ACEi and ARBs

A

§ Cough – ACEi.

§ Urticaria/angioedema – ACEi rarely.

§ Hypotension – ACEi, ARBs.

§ Hyperkalaemia – ACEi, ARBs – care with K+ supplements or K+-sparing diuretics.

o Aldosterone promotes K+ loss so aldosterone inhibitors (ACEi, ARBs) produce a hyperkalaemia.

§ Foetal injury – ACEi, ARBs.

§ Renal failure (in patients with renal artery stenosis) – ACEi, ARBs.

o Glomerular filtration is maintained by AngII so you need to be careful in renal failure patients.

35
Q

How can drugs that interfere with AngII cause renal failure

A

AngII is the main determinant of efferent arteriole vasoconstriction, and helps to maintain GFR (by increasing the pressure gradient across the afferent to the efferent arterioles) when renal perfusion pressure is low (bilateral renal artery stenosis, elderly patients with CHF and volume depletion).
Blocking the effect of Ang II will therefore prevent the patient from maintaining their GFR, and thus can cause acute renal failure.

36
Q

What type of agents are ARBs

A

These agents act as insurmountable (i.e. non-competitive) antagonists at AT1

37
Q

What are aldosterone antagonists

A

Spironolactone is an antagonist of the mineralocorticoid, aldosterone. It inhibits the sodium retaining effects of aldosterone. Spironolactone has limited diuretic effects, but is useful in heart failure and resistant cases of hypertension. Spironolactone can cause hyperkalaemia as a result of its aldosterone antagonism and also exerts unwanted steroid-like effects such as gynaecomastia, menstrual disorders and testicular atrophy.

38
Q

Outline the mechanism for vascular smooth muscle contraction

A

o Membrane depolarisation opens VGCC.

o Ca2+ enters and binds calmodulin (CaM).

o Ca2+-CaM complex activates MLCK.

o MLCK mediated phosphorylation à VSM contraction.

39
Q

What are the rate-limiting CCBs

A

Dihydropyridines (DHPs)
More selective for blood vessels
Amlodipine -does not cause any negative inotropy
Also licensed for prophylaxis of angina

Nicardipine

Nitrendipine

Amlodipine

Nisoldipine

40
Q

What are the non-rate limiting CCBs

A

Non-DHPs (aka rate-limiting)

Verapamil - large negative inotropic effect

41
Q

What part of the calcium channel do the different CCBs bind to.

A

Dihydropyridines bind to the extracellularly component of the calcium channel

Diltiazem and verapamil binds to the intracellular component so for a CCB to have an effect on the heart it needs to be able to penetrate the membrane and act on the receptor inside the cell

42
Q

Which of the CCBs would you use to treat hypertension

A

§ Amlodipine is used to treat hypertension as it does not have an ionotropic effect on the heart.

o DHPs inhibit Ca2+ entry into the VSMCs so less contraction of the cells à less TPR à less BP.

o NOTE: powerful vasodilation can lead to a reflex tachycardia and increased ionotropy thus increased myocardial oxygen demand.

43
Q

Why are ACEi and ARBs given as first line treatment for hypertension

A

o The reason those drugs are the first line drugs is due to the good patient adherence as seen in studies (left figure).

o Higher adherence = less side effects.

o Not much difference between ACEi and ARB in reducing BP.

44
Q

Why is the first line therapy for afro-carribeans different

A

o This group of people have a different drug schedule due to low plasma renin activity and so ACEi doesn’t work as well – the studies into this are not confirmed.

45
Q

Why is the first line therapy for elderly patients different

A

Hypertension most likely to be due to atherosclerosis.
Therefore the drugs that control vascular tone are less effective- because the receptors are de-sensitised- can’t do much against the atheroscleorsis- hence diuretics are a better option.

46
Q

Compare RAS inhibitors to CCBs

A

CCBs  SBP more than RAS inhibitors
RAS inhibitors  heart failure
RAS inhibitors  stroke
No difference for all-cause death

47
Q

Compare RAS inhibitors to thiazide diuretics

A

Thiazides  SBP more than RAS inhibitors
RAS inhibitors  heart failure
RAS inhibitors  stroke
No difference for all-cause death

48
Q

Compare RAS inhibitors to beta blockers

A

No difference in SBP reduction
RAS inhibitors  CV events
RAS inhibitors  stroke
No difference for all-cause death

49
Q

Summarise alpha blockers

A

Alpha blockers (competitive antagonists of α1-adrenoceptors), such as doxazosin, act as arterial vasodilators by inhibiting the vasoconstrictor effects of the sympathetic nervous system acting via α1‑adrenoceptors on vascular smooth muscle. They can induce postural hypotension and are only used as third or forth line agents in the treatment of hypertension. An irreversible nonselective alpha antagonist, phenoxybenzamine, is used to provide long-lasting alpha-blockade in pheochromocytoma (combined with a beta blocker).

50
Q

Which alpha blockers is used in the treatment of hypertension

A

§ a-blockers block a1-mediated vasoconstriction.

§ Prazosin is an a1-antagonist.

§ Phentolamine is an a1/a2 antagonist.

o Action against a2 blocks the –ve feedback of NA release and so there is an enhanced NA release and SNS response.

o This can lead to increased HR (not reflex).

51
Q

Describe the centrally acting anti-hypertensive agents (Sympatholytics)

A

Centrally acting antihypertensive agents include clonidine and -methyldopa (α2-adrenoceptor agonists), moxonidine (imidazoline agonist) and reserpine (depletes neuronal noradrenaline). These agents act by reducing sympathetic activity. They are generally not much used as many have a comparatively poor side effect profile. Adrenergic neuron blockers, such as guanethidine, are or only historical interest in terms of blood pressure lowering. Short acting ganglion blockers, such as trimethaphan, are occasionally used in anaesthesia to lower blood pressure.

52
Q

Describe some other vasodilating agents

A

Hydralazine is a direct vasodilator that acts mainly on arteries and arterioles. In the absence of beta-blockade it causes a reflex tachycardia as a result of its vasodilator effects. It is not much used except in hypertension in pregnancy, as long term use can be associated with a lupus-like disorder.

Organic nitrates and nicorandil are discussed in Drugs and the Heart. Other KATP channel openers (which lack NO donor activity) such as diazoxide cromokalim, or minoxidil are potent vasodilators, but are not much used in clinical practice.

53
Q

Give examples of some drugs used to treat migraines

A

Sumatriptan is an agonist at 5HT1D receptors and causes vasoconstriction of some large arteries and inhibits trigeminal nerve transmission. It is used to treat migraine attacks, but is contraindicated in patients with coronary disease as it also causes coronary vasoconstriction. Other ergot alkaloids are also used in migraine and probably act as 5HT1 receptor partial agonists but their usefulness is limited by side effects.
NOTE: painful stimuli is transferred by the trigeminal nerve and profound vasodilation is also associated with migraine

54
Q

List some of the other side effects of sumatriptan

A

Dizziness, drowsiness, asthenia/fatigue

55
Q

Describe some sympathomimetic agents

A

Adrenaline, the endogenous catecholamine, produced by the adrenal gland is used in cardiac arrest and anaphylactic shock.

56
Q

Summarise the use of beta blockers in the treatment of hypertension

A

The effect of beta blockers on blood pressure is complex and not fully understood. In addition to reducing cardiac output and inhibiting activity of the sympathetic nervous system via a pre-junctional effect, these agents also inhibit renin release by the kidney by inhibiting the effect of the sympathetic nervous system on renin release (which is mediated by β1-adrenoceptors).

57
Q

Name a cardioselective beta blocker

A

Atenolol

58
Q

What type of protein is B-adrenoreceptor

A

Gs- thus linked to AC and cAMP

59
Q

How can NA increase BP

A

Increase in heart rate and cardiac contractility (leads to increase in CO) via beta-1 receptors in the heart

Stimulation of beta-1 receptors in the kidneys promotes renin release à increase in angiotensin II

60
Q

How can NA, Ang ii and ET-1 cause vasoconstriction

A

Receptors linked to Gq
GTP – GDP
PLC converts PIP2 to IP3 + DAG

PKC release.
Release of Ca2+ from SR.

61
Q

What regulates SERCA2A

A

Phospholamban (PLN)

Phospholamban phosphorylation is stimulated by beta-adrenergic activity

It is a target for phosphorylation by protein kinase A

When dephosphorylated it is an inhibitor of SERCA2a (PROTEIN PHOSPHOTASE 1)

When phosphorylated it dissociates from SERCA2a and activates the Ca2+ pump

As a result, the rate of cardiac relaxation is increased and, on subsequent beats, contractility is in proportion to the elevation in the size of the SR calcium store

62
Q

What intracellular pathway is the A1 RECEPTOR linked to

A

Gq
Production of IP3— Ca2+
DAG –PKC

63
Q

What intracellular pathway is the A2 receptor linked to

A

Gs

Pharmacology and therapeutics (30 decks)

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