Therapeutics: Cardiology I-II COMBINED

Describe "primary" hypertension

No identifiable cause (idiopathic)

Describe "secondary" hypertension

Hypertension which develops secondary to diabetes, obesity, stressful lifestyle, high dietary intake of sodium, and smoking

Chronic hypertension is the major risk factor for CVDs including...? (six)

1. Heart failure

2. Coronary artery disease

3. Stroke

4. Renal failure

5. Rheumatic heart disease

6. Arrythmias

Potential causes of primary hypertension? (six)

1. Smoking

2. Family history

3. Sedentary lifestyle

4. Being overweight or obese

5. Having a poor diet

6. Not managing stress

Potential causes of secondary hypertension? (six)

1. Kidney disease

2. Adrenal disease

3. Hyperparathyroidism

4. Thyroid disease

5. Tightening of the aorta

6. Obstructive sleep apnea

(DISEASES)

Physiologic factors controlling BP can be impacted by malfunctions of... (five systems)

1. The renin-angiotensin-aldosterone system (RAAS)

2. Vasodepressor mechanisms

3. Abnormal neuronal mechanisms

4. Defects in peripheral autoregulation

5. Disturbances in sodium, calcium, and natriuretic hormones

Activation and regulation of the RAAS system are primarily governed by which organ?

Kidney

T/F: The RAAS system regulates sodium, potassium, and blood volume.

True

Which of the following activities does the RAAS system significantly influence? (select all that apply)

A. Vascular tone

B. Sympathetic nervous system activity

C. Homeostatic regulation of BP

D. Vascular permeability

A. Vascular tone

B. Sympathetic nervous system activity

C. Homeostatic regulation of BP

Describe the role of natriuretic hormone

Inhibits sodium and potassium-ATPase and thus interferes with sodium transport across cell membranes

Where do B1 receptors predominate? (organ)

Heart

Where do B2 receptors predominate (organ)

Lungs

Given on slides = bronchioles

T/F: Stimulation of B1 receptors in the heart decreases heart rate and force of contraction.

False; stimulation of B1 receptors in the heart increases heart rate and force of contraction.

T/F: Stimulation of B2-receptors causes vasodilation in arteries and veins.

True

Explain they kidneys' "volume-pressure adaptive mechanism"

Kidney maintains normal BP through a volume-pressure adaptive mechanism; abnormalities in renal or tissue autoregulatory systems can cause HTN.

Given on slide = renal defects in sodium excretion may result in higher BP

Explain the role of vascular endothelial mechanisms in the maintenance of normal BP?

Local synthesis of vasodilators (prostacyclin, bradykinin)

Excess vasoconstricting substances (angiotensin II, endothelin I) contribute to essential HTN.

T/F: High-sodium diets are not empirically associated with a high prevalence of stroke and HTN.

False; high-sodium diets = high risk of stroke and HTN.

Describe how diuretics act to treat HTN (like you would give it to a patient almost)

Lower blood pressure by depleting the body of sodium and reducing blood volume

(and perhaps by other mechanisms)

How do agents that block production or action of angiotensin act to treat HTN?

Reduction of peripheral vascular resistance and (potentially) blood volume

How do direct vasodilators act to treat HTN?

Reduce pressure by relaxing vascular smooth muscle; dilate resistance vessels and increase capacitance

How do sympathoplegic agents work to treat HTN?

Lower BP by reducing peripheral vascular resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels

Propranolol and other B-blockers act where? (as given on slide)

B-receptors of the heart

Hydralazine, minoxidil, verapamil and other CCBs act where? (as given on slide)

Vascular smooth muscle

Thiazides etc. act where? (as given on slide)

Kidney tubules

Clonidine, guanfacine, methyldopa, and guanabenz act where? (as given on slide)

Vasomotor center

Losartan and other ARBs act where? (as given on slide)

Angiotensin receptors of vessels

Prazosin and other a1 blockers act where? (as given on slide)

a-receptors of vessels

Diuretics are indicated specifically for what? (two)

Hypertension

Congestive heart failure (with edema)

The amount of electrolytes excreted following administration of a diuretic is determined by what? (four)

1. Chemical structure of the diuretic

2. The site or sites of action of the agent

3. The salt intake of the patient

4. The amount of extracellular fluid present

Two mechanisms of action of diuretics?

1. Diuretics lower blood pressure by depleting body sodium stores

2. Diuretics reduce blood pressure by reducing blood volume and cardiac output and decrease peripheral vascular resistance

What is the most common adverse effects of diuretics (excluding K sparing diuretics)?

Potassium depletion

T/F: Chlorthalidone is more effective than hydrochlorothiazide due to its longer duration of action.

True

Thiazide diuretics are appropriate for most patients with what hypertension severities?

Mild or moderate HTN

Require normal renal and cardiac function

Aliskerin inhibits what?

Renin

Potassium-sparing diuretics are useful for what reasons? (two)

1. Avoid excessive potassium depletion

2. Enhance natriuretic effects of other diuretics

The release of renin from the juxtaglomerular cells (JG) cells in the kidney is... (three, straight from the slide)

1. Stimulated by reduced renal arterial pressure

2. Sympathetic neural stimulation

3. Reduced sodium delivery at the distal renal tubule

Mechanism of action of aliskiren?

Directly inhibits renin thereby preventing the formation of angiotensin I and II.

What is the rate-limiting step in the renin-angiotensin pathway?

Renin mediated formation of angiotensin I and II

Which enzyme metabolizes aliskiren?

CYP3A4

What side effects are associated with aliskiren therapy? (two big ones)

1. Cardiovascular failure

2. Renal failure

What are the three chemical classes of ACE inhibitors?

1. Sulfhydryl

2. Dicarboxylate

3. Phosphonate

Which of the three ACE chemical classes shows superiority in binding to zinc?

Sulfhydryl group

Captopril is an example of which of the three ACE chemical classes?

Sulfhydryl

The mercapto (-SH) group of captopril is responsible for what two side effects (that are not present in other ACE inhibitors)?

1. Rashes

2. Loss of taste

T/F: Sulfhydryl (mercapto (-SH)) group abolishes the conversion of angiotensin I to angiotensin II but does not block angiotensin II receptors.

True

Lisinopril is an example of which of the three ACE chemical classes?

Dicarboxylate

T/F: Enalapril is a prodrug sulfhydryl ACE inhibitor.

False; enalapril is a prodrug dicarboxylate ACE inhibitor.

Enalapril is activated by what metabolic process?

Hydrolysis

Is enalapril's absorption affected by food?

nah

Fosinopril is an example of which of the three ACE chemical classes?

Phosphate

T/F: Fosinopril is a prodrug; its active form is known as fosinoprilat.

True

MOA of ACE inhibitors?

Block ACE, which cleaves angiotensin I to form the potent vasoconstrictor angiotensin II.

T/F: ACE is responsible for the breakdown of bradykinin and prostacyclin.

True

T/F: All ACE inhibitors undergo hepatic conversion to active metabolite, save for captopril and lisinopril.

True

T/F: Fosinopril is the only ACE inhibitor that is not eliminated primarily by the kidneys.

True

T/F: Enalaprilat cannot be administered intravenously.

False

ARBs are also known as __________

peptidomimetics

ARBs are ________ (basic, acidic) drugs with __________ (adequate, excellent) lipid solubility

ARBS are acidic drugs with adequate lipid solubility

T/F: Losartan is a prodrug.

True

By which enzymes is losartan oxidized in order to be activated as EXP-3174?

CYP2C9, CYP3A4

MOA of CCBs?

Inhibit calcium influx into arterial smooth muscle cells

What are the two main classes of CCBs?

1. Non-dihydropyridines

2. Dihydropyridines

Amlodipine, nifedipine are examples of which class of CCB?

Dihydropyridines

Verapamil, Diltiazem are examples of which class of CCB?

Non-dihydropyridines

T/F: Clevidipine is a newer CCB available both PO and IV.

False; only IV

What are some of the side effects associated with excessive vasodilation? (five)

1. Flushing

2. Hypotension

3. Nasal congestion

4. Headache

5. Dizziness

T/F: Most effective drug regimens for HTN include an agent that inhibits function of the sympathetic nervous system.

True

What side effects are commonly associated with drugs which lower BP by actions on the central nervous system? (three)

1. Sedation

2. Mental depression

3. Nightmares

Drugs that act chiefly by reducing release of norepinephrine from sympathetic nerve endings cause... (three)

1. Inhibition of ejaculation

2. Hypotension increased by upright posture and after exercise

T/F: Sympathoplegic antihypertensives are most effective when used concomitantly with a diuretic.

True

MOA of methyldopa?

Lowers blood pressure chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output

MOA of clonidine?

Reduction of cardiac output due to decreased heart rate and relaxation of capacitance vessels, as well as a reduction in peripheral vascular resistance

Clonidine, methyldopa are examples of what class of hypertensive?

Centrally acting a-2 agonists

Methyldopa is used primarily for HTN during ___________

pregnancy

T/F: Clonidine produces a sharp drop in blood pressure followed by a more prolonged hypotension.

False; produces a brief rise, followed by a more prolonged hypotension

Adverse effects of centrally acting a-2 agonist? (two categories and their constituents)

1. Sympathoplegia (sex bad, excessive orthostatic hypotension)

2. Parasympathoplegia (constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth)

MOA of reserpine?

Blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines, probably by interfering with the vesicular membrane-associated transporter (VMAT). Effect appears irreversible

Reserpine can cause a depletion of which neurotransmitters? (three)

1. Norepinephrine

2. Dopamine

3. Serotonin

Adverse effects (affecting the brain) of reserpine (and adrenergic neuron blocking agents in general) include? (four)

1. Sedation

2. Lassitude

3. Nightmares

4. Severe mental depression

Adverse effects (affecting the GIT) of reserpine (and adrenergic neuron blocking agents in general) include? (three)

1. Mild diarrhea

2. GI cramps

3. Increased gastric acid secretion

MOA of B-adrenergic receptor blockers?

Bind to and block the binding of norepinephrine and epinephrine to these receptors, causing inhibition of normal sympathetic effects

BBs are very effective in patients whose hypertension is caused by... ?

Emotional stress, pheochromocytoma; results in elevated circulating catecholamines

1st generation B-adrenergic receptor blockers are _______

A. Nonselective

B. B1-selective

C. B2-selective

A. Nonselective

2nd generation B-adrenergic receptor blockers are _______

A. Nonselective

B. B1-selective

C. B2-selective

B. B1-selective

Atenolol, metoprolol are examples of ______ generation B-adrenergic receptor blockers

A. 1st

B. 2nd

C. 3rd

B. 2nd

Pindolol, propanolol, timolol are examples of ______ generation B-adrenergic receptor blockers

A. 1st

B. 2nd

C. 3rd

A. 1st

Labetalol, carvedilol are examples of _______ generation B-adrenergic receptor blockers

A. 1st

B. 2nd

C. 3rd

C. 3rd

T/F: 3rd generation B-adrenergic receptor blockers also possess vasodilator actions via blockade of vascular a-adrenoceptors and are therefor also known as mixed a1-/b1-adrenergic blockers.

True

Common adverse effects of beta-blockers (BBs) include? (five)

1. Decreased exercise tolerance

2. Cold extremities

3. Depression

4. Sleep disturbance

5. Impotence

T/F: 2nd generation BBs have less side effects than do 1st generation BBs.

True

Lipid-soluble side effects have been associated with more side effects of what nature?

CNS side effects

i.e. dizziness, confusion, depression

A1-adrenergic receptor blockers are chemically classified as ___________

Quinoxalines

What is the role of the quinoxaline ring in the structure of a1-adrenergic receptor blockers?

Important for a1-receptor affinity

MOA of a1-adrenergic receptor blockers?

Cause vasodilation, decreased blood pressure, and decreased peripheral resistance

T/F: A-blockers have been established as helpful in both heart failure and angina.

False; not shown to be beneficial in HF or angina.

Clonidine, methyldopa are __________ acting sympatholytics

A. Centrally

B. Peripherally

A. Centrally

Prazosin, terazosin, doxazosin are examples of which of the following sympatholytic classes?

A. a2-adrenergic receptor agonists

B. B-adrenergic receptor blockers

C. a1-adrenergic blockers

D. B and a- adrenergic receptor blockers

C. a1-adrenergic blockers

Arterial dilator drugs are used to treat which of the following? (select all that apply)

A. Systemic HTN

B. Pulmonary HTN

C. HF

D. Angina

A. Systemic HTN

B. Pulmonary HTN

C. HF

D. Angina

Hydralazine, minoxidil are examples of ______ vasodilators

A. Oral

B. Parenteral

C. CCBs

D. Nitrates

A. Oral

Nitroprusside, fenoldopam are examples of _________ vasodilators

A. Oral

B. Parenteral

C. CCBs

D. Nitrates

B. Parenteral