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Therapeutic Pharmacology 2 > Cardiovascular Pharmacology > Flashcards

Cardiovascular Pharmacology Flashcards

1
Q

What are the risk factors for CV disease?

A

Smoking: Free radicals, atherogenic, prothrombotic, COHb, causes HR to increase so increases BP

Obesity: Fat stores have to be supplied with blood

Diet: Excess cholesterol, salt

Stress: Prolonged increases BP

Lack of exercise

Genetics

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2
Q

Define Cardiovascular disease

A

A variety of cardiac and/or vascular diseases that usually stem from atherosclerosis

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3
Q

How many deaths does CVD account for?

A

1: 6 males before the age of 75
1: 12 females before the age of 75

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4
Q

Define atheroma

A

Arterial disease in which atherosclerotic plaques slowly develop in the luminal walls

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5
Q

Define hyperlipidaemia

A

Either raised cholesterol or triglyceride levels or both in the blood

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6
Q

Define hypercholesterolaemia

A

High blood cholesterol

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7
Q

How is hypercholesterolaemia treated?

A

Initially with dietary control, followed by drug treatments

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8
Q

What is ideal blood cholesteral levels?

A

Less than 5mM

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9
Q

What is the UK average blood cholesterol level?

A

5.7mM

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10
Q

What is considered to be high cholesterol levels?

A

Above 6.5mM

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11
Q

How do statins reduce blood cholesterol levels?

A

HMG CoA inhibitors reversibly inhibit hepatic HMG CoA reductase, so reducing
cholesterol production.

To compensate, the liver expresses more HMG CoA
reductase, so cholesterol synthesis is restored, however,
statins also induces an increased expression of hepatic LDL receptors.

This increases the liver’s uptake of LDL, so increases the
clearance of cholesterol from the plasma

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12
Q

What are the side effects of statins?

A 
Constipation or diarrhoea
Flatulence
Nausea
Rash
Muscle pain
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13
Q

What are contraindications for statins, and why?

A

Pregnancy and breastfeeding
- Cholesterol is required during development

Liver disease
- Statins are extensively metabolized by hepatic cytochrome P450s

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14
Q

Why are the contraindications of statins of importance?

A

Because simvastin is now available ‘over the counter’, although at a low dose

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15
Q

How are statins administered, and why?

A

Statins are orally administered, mostly at night.

This is to try and reduce the body’s peak cholesterol synthesis, which occurs early in the morning.

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16
Q

Give two examples of statins

A

Simvastatin

Pravastatin

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17
Q

Give two examples of Fibrates

A

Bezafibrate

Gemfibrozil

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18
Q

How do fibrates reduce blood cholesterol?

A

Thought to work by stimulating lipoprotein lipase, so reducing triglyceride content of VLDLs and chylomicrons, and also stimulates hepatic LDL receptor expression

Reduce plasma triglycerides (~30%) and LDL (~10%), and increase HDL (~10%)

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19
Q

What are the side effects of fibrates?

A

Intestinal disturbances

Myositis-like syndrome (inflammatory muscular degeneration)

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20
Q

How are fibrates administered?

A

Orally

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21
Q

How are Bile Acid Binding Resins administered?

A

Orally

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22
Q

How do bile acid binding resins reduce blood cholesterol?

A

Bind to intestinal bile acids, so preventing their reabsorption.

This promotes the conversion of cholesterol into bile acids.

This increases hepatic cholesterol demand, so increases
hepatic LDL receptor expression and activity.

This increases plasma LDL cholesterol clearance

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23
Q

What are the side effects of bile acid binding resins?

A

Mostly confined to the intestines

  • Bloating,
  • Abdominal discomfort
  • Diarrhoea

They can interfere with the absorption of fat soluble vitamins (A, D, E and K).

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24
Q

What are the contraindications of bile acid binding resins?

A

Complete biliary obstruction

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25
Q

How does nicotinic acid reduce blood cholesterol?

A

Inhibits hepatic VLDL formation, so lowers plasma triglyceride levels by ~30-50%.

Reducing VLDL levels will reduce LDL production and so lowers cholesterol levels by ~10-20%.

HDL levels are stimulated.

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26
Q

What are the side effects of nicotinic acid?

A 
Flushing
Dizzyness
Headaches
Palpitations
Nausea
Vomiting

Use is limited

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27
Q

Define hypertension

A

Elevated arterial blood pressure above the expected range (140/90 to 160/95 mmHg boardline)

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28
Q

What causes primary (essential) hypertension?

A

Small increases in cardiac output ( sympathetic activity)
Peripheral resistance
Genetics
Environmental factors

Cause may be unknown

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29
Q

What is the distribution of hypertension?

A

Primary hypertension ~90% of cases

Secondary hypertension ~10% of cases

30
Q

What causes secondary hypertension?

A

Secondary hypertension has a known cause such as kidney, endocrine or diseases

31
Q

What is hypertension associated with?

A

Hypertension is associated with reduced life expectancy, left ventrical wall thickening, atheroma, coronary heart disease, stroke, peripheral vascular disease, etc

32
Q

What are hypertension treatments aimed at?

A

Lowering BP

33
Q

What are the various treatments for hypertension?

A

Initially:

  • Reduction in weight, and salt and alcohol consumption
  • Smoking cessation

Types of drugs:

  • Vasodilators
  • Beta-blockers
  • Centrally acting drugs
  • Diuretics
34
Q

Name the types of vasodilators used for treating hypertension

A
  1. Angiotensin converting enzyme (ACE) inhibitors
  2. Angiotensin Receptor Antagonists (sartans)
  3. Calcium channel antagonists/entry blockers
  4. Alpha1-Adrenoceptor Antagonists
  5. Hydralazine
  6. Minoxidil
35
Q

How do ACE inhibitors treat hypertension?

A

Angiotensin II is a potent vasoconstricting octapeptide and a stimulus for aldosterone release, so is involved with regulating BP by controlling Na+ ion excretion and vascular tone.

Renin, an enzyme, is released from the juxtaglomerular
apparatus in response to a reduction [Na+] in distal tubules and a reduction renal perfusion pressure.

So, if angiotensin II production is inhibited, BP will then fall

36
Q

Name three examples of ACE inhibitors

A

Enalapril

Lisinopril

Ramipril

37
Q

What effect do ACE inhibitors have in normotensives?

A

Little effect

38
Q

What effect do ACE inhibitors have in hypertensives?

A

A large drop in BP

39
Q

ACE inhibitors affect resistance vessels, so decrease BP as well as cardiac workload.

Do they affect cardiovascular reflexes?

A

No, they do not effect cardiovascular reflexes

40
Q

What are the main side effects of ACE inihibitors?

A

First dose hypotension

Dry cough due to bradykinin accumulation

41
Q

What are the contraindications for ACE inihibitors?

A
  • Potassium sparing diuretics.
  • Bilateral renovascular disease - renal failure may occur due to a lowered afferent arteriolar reducing glomerular filtration.
  • Pregnancy.
42
Q

How are Angiotensin Receptor Antagonists used to treat hypertension?

A

The Renin-Angiotensin System can be affected by antagonizing AT1 receptors

Since ACE is still active, bradykinin can still be
metabolized, so the sartans do not produce a dry cough.

43
Q

Give examples of angiotensin receptor antagonists

A
  • losartan
  • valsartan
  • candesartan
44
Q

How are Calcium Channel Antagonists used to treat hypertension?

A

These cause a generalized arterial vasodilatation.

Vascular smooth muscle tone is determined by free intracellular [Ca2+]:
• Increased sympathetic tone results in vascular a1- adrenoceptor activation.
• This results in inositol trisphosphate (IP3) production, which triggers Ca2+ release from sarcoplasmic reticulum stores.
• Ca2+ binds to calmodulin, which activates a kinase to phosphorylate myosin light chain (MLC).
• This triggers myosin and actin interactions, resulting in smooth muscle contraction

In addition to this, voltage operated L type Ca2+ channels on vascular smooth muscle membranes open, causing more Ca2+ to enter.

Ca2+ channel antagonists can block these channels, so
limiting the amount of free cytoplasmic Ca2+. This then causes arteriolar smooth muscle relaxation and peripheral resistance and BP to fall

45
Q

Give examples of Ca2+ channel antagonists

A

Verapamil

Diltiazem

Nifedipine

Although Ca2+ channels are widely distributed, nifedipine selectively affects vascular channels and has no cardiac actions, whereas verapamil and diltiazem are more cardioselective.

46
Q

What are the side effects of Ca2+ channel antagonists?

A

Nifedipine can cause hypotension, peripheral oedema, tachycardia, flushing and dizziness.

Verapamil and diltiazem can cause hypotension, bradycardia, heart block and congestive heart failure.

47
Q

How do a1-Adrenoceptor antagonists work to treat hypertension?

A

These inhibit a1-adrenoceptor mediated vasoconstriction by antagonizing vascular a1-adrenoceptors, which results in a vasodilatation, reduced peripheral resistance and a fall in BP.

48
Q

Give examples of a1-adrenoceptor antagonists

A

Prazosin and Doxazosin (the latter being longer acting).

These drugs are administered orally

49
Q

What are the side effects of a1-adrenoceptor antagonists?

A

Main side effect is postural hypotension, due to an impaired arteriolar vasoconstriction reflex upon standing up.

Therefore blood could temporally pool in the lower portion of the body.

50
Q

What are the additional effects of a1-adrenoceptor antagonists?

A

They improve symptoms of prostatism by reducing bladder and prostate resistance.

Doxazosin slightly improves blood lipid profile by lowing LDL cholesterol, VLDL and triglyceride levels, but raises HDL levels.

51
Q

How does hydralazine work to treat hypertension?

A

Works by an unknown mechanism, but may interfere with vascular smooth muscle IP3, so reducing vascular
resistance and BP.

52
Q

How is hydralazine administered?

A

Orally or intravenous administration

53
Q

What are the side effects of hydrazaline?

A

Reflex tachycardia

Angina provocation

Headaches

Fluid retention

Idiopathic systemic lupus erythematosus

54
Q

How is minoxidil used to treat hypertension?

A

It is a potent vasodilator, which is only used for HT that is resistant to other drugs.

Minoxidil opens vascular smooth muscle K+ATP channels, causing hyperpolarization

This reduces Ca2+ entry through L-type channels,
so causing relaxation and a vasodilatation.

55
Q

What are the side effects of minoxidil?

A

Na+ and H2O retention

Tachycardia

Hirsutism (Excessive hair growth)

Cardiotoxicity

56
Q

What is the benefit of topical minoxidil?

A

Topical minoxidil creams are available for treating baldness.

57
Q

When are beta-adrenoceptor antagonists used in the treatment of hypertension?

A

‘Beta-blockers’ are used in resistant hypertension, when ACE inhibitors or calcium channel blockers in combination with diuretics have been ineffective

58
Q

What is the mechanism of action for beta-blockers?

A

Beta-Blockers have different acute and chronic mechanisms.

Acute mechanism:
Cardiac output (CO) is determined by heart rate (HR) and stroke volume (SV): CO = HR x SV

So, since the SNS activates cardiac beta-adrenoceptors to increase HR etc., antagonizing these receptors will cause HR and hence CO to fall. So, BP will be lowered.

Chronic mechanism:
With time, CO begins to return to normal in beta-blocked
patients.

BP still remains low, however, because there is a (currently unknown) mechanism that causes peripheral vascular resistance to be ‘reset’ at a lower level

59
Q

What does stimulation to the beta-adrenoceptors do?

A

There are three b-adrenoceptors currently known about:

b1-stimulatory cardiac actions,
b2-wide distribution, e.g. dilatation of skeletal muscle blood vessels, bronchodilatation, stimulatory cardiac actions, etc.
b3-lipolysis, thermogenesis

60
Q

What is meant by ‘cardioselective’ Beta-adrenoceptor antagonists?

A

Beta-blockers vary in their receptor selectivity and lipid solubility.

Therefore non-selective b-blockers, such as propranolol, are capable of producing wide spread b1- and b2-blockade.

Antagonists such as atenolol, bisoprolol and metoprolol are more selective for b1-adrenoceptors and are termed
‘cardioselective’

61
Q

What is carvedilol?

A

Carvedilol is a recent drug producing both non-selective beta-and a1-blockade

62
Q

When is carvedilol administered?

A

Carvedilol is a beta-blocker. Beta-blockers affect the heart and circulation (blood flow through arteries and veins).

Carvedilol is used to treat heart failure and hypertension. It is also used after a heart attack that has caused the heart not to pump as well.

63
Q

What are the contraindications for Beta-blockers?

A

Non-selective b-blockers should not be given to asthmatics, as this can trigger severe bronchoconstriction and interfere with the actions of drugs such as salbutamol, and caution is still required with cardioselective b-blockers, as they lose selectivity at higher doses.

64
Q

What are the side effects for Beta-blockers?

A

Bronchospasm: insignificant increases in airway resistance may occur for normal subjects, but can be serious for asthmatics and patients with obstructive lung diseases.

Fatigue: likely to be caused by reduced CO and reduced muscle perfusion.

Cold extremities: loss of b-adrenoceptor mediated vasodilatation, but still occurs with cardioselective blockers.

Sleep disturbances: more lipid-soluble b-blockers can pass through the blood-brain barrier, causing bad dreams.

Bradycardia and cardiac depression: signs of heart failure may develop in elderly patients, whilst heart block can occur in patients being treated with antiarrhythmic drugs that impair cardiac conduction.

Hypoglycaemia: glucose is released in response to
adrenaline and the symptom of tachycardia gives diabetic
patients an urgent warning to intake carbohydrate. Since b-blockers will blunt this response, hypoglycaemia is likely to go unnoticed. Cardioselective b-blockers maybe be better, as hepatic glucose release is mediated by b2-adrenoceptors.

65
Q

How are centrally acting drugs used to treat hypertension?

A

Stimulating presynaptic a2-adrenoceptors in the vasomotor centre of the medulla oblongata reduces noradrenaline release, so reduces sympathetic outflow and causing a vasodilatation

These drugs also reduce HR and CO.

66
Q

Give examples if centrally acting drugs used to treat hypertension

A

Methyldopa (oral), clonidine (oral and intravenous) and moxonidine (oral) are centrally acting a2-adrenoceptor agonists.

Methyldopa can be used to treat HT during pregnancy (unlike ACE inhibitors, sartans and b-blockers).

67
Q

What are the side effects of centrally acting drugs?

A

Orthostatic hypotension

68
Q

Why should non-selective a-adrenoceptor antagonists, such as phentolamine, not be administered in hypertension?

A

They antagonise a2-adrenoceptors, so negative feedback is lost, which results in more noradrenaline being released, which causes tachycardia

69
Q

Describe two ways in which heart rate can be increased and two ways in which heart rate can be decreased using drugs that affect the autonomic nervous system.

A

Increase: a sympathetic agonist or parasympathetic antagonist (e.g. beta-agonists or phosphodiesterase inhibitors)

Decrease: a parasympathetic agonist or sympathetic antagonist (e.g. a1-adrenoceptor antagonist)

70
Q

Why is it likely that bile acid binding/anion exchange resins reduce the absorption of vitamins A, D, E and K?

A

These are fat soluble vitamins and so preventing the absorption of lipids, such as cholesterol, means that more fat soluble vitamins will remain in the GI tract, and so absorption will be reduced

71
Q

Describe how a calcium channel blocker, such as nifedipine, reduces blood pressure

A

Nifepidine binds to L-type calcium channels and blocks the entry of calcium ions into vascular smooth muscle cells.

Therefore extracellular calcium cannot enter into these cells and interact with calmodulin, so a reduced amount of intracellular calcium/calmodulin complex will be formed from only intracellular calcium stores.

So, reduced amounts of MLCK will be activated, leading to a reduced amount of MCL being phosphorylated. This interferes with actin and myosin interactions, and so vascular smooth muscle cells will not generate their usual tone, which causes arteriolar vasodilatation. This will therefore reduce blood pressure

Therapeutic Pharmacology 2 (7 decks)

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