PHARM 250 - LESSON 5.1

DRUGS THAT AFFECT THE CARDIOVASCULAR SYSTEM

PART 1: ANTIHYPERTENSIVES

PART 1: ANTIHYPERTENSIVES

What values indicate hypertension?

A PERSISTENT systolic above 140mmHg or diastolic over 90mmHg

What risk factors are associated with hypertension?

Stroke and Heart Failure,

CAD, cardiovascular diseases

Kidney failure, peripheral vascular disease

blood pressure is determined by the product of what two values?

(Cardiac output) X (Systemic vascular resistance)

what four factors influence cardiac output?

1. Heart rate
2. Myocardial contractility (force of contraction)
3. blood volume
4. venous return to the heart

What happens to blood pressure and cardiac output when the four factors that influence cardiac output change?

an increase in any will increase CO and BP

a decrease in any will decrease CO and BP

what is systemic vascular resistance?

The resistance to blood flow which is determined by the diameter of the vessel and vascular musculature (smaller hole=higher pressure).

What is MAP and what is the equation to find it?

Mean arterial pressure - indicates tissue perfusion and must be above 60 to maintain this

\
MAP = \[(2diastolic)+(systolic)\] / 3

What is high-normal blood pressure? Values and risks

VALUES: systolic between 130-139 or diastolic 85-89

RISKS: high risk for developing hypertension, higher risk if someone is overweight

What are the three types of hypertension

1. Essential (idiopathic/primary)
2. Secondary
3. Malignant

Causes of essential (idiopathic, primary) hypertension

no known cause

controlled, not cured

90-95% of cases

Causes of secondary hypertension

Usually due to another disease process (ex. thyroid disease, pre-eclampsia)

may result from medications

5-10% of cases

if the cause is eliminated, BP returns to normal

Causes of malignant hypertension

Develops rapidly and usually results in organ damage

is identified by a BP above 180/120, this is a medical emergency.

What 7 drug categories are used to treat hypertension?

1. Diuretics
2. Adrenergics
3. CCBs (calcium channel blockers)
4. vasodilators

renin-angiotensin effectors:


5. ACE (angiotensin converting enzyme) inhibitors
6. ARBs (angiotensin II receptor blockers)
7. Direct renin inhibitors

Diuretics in treating hypertension-

How are they used:

Results:

Overall effects:

Which are most commonly used:

HOW: first line antihypertensive. Decrease blood volume and vascular resistance, resulting in decreased BP

RESULTS: decreased preload, Cardiac output, and total peripheral resistance

OVERALL EFFECTS: decrease the workload of the heart and decrease BP.

MOST USED: thiazide diuretics

How do adrenergics decrease blood pressure?

What are the 5 categories of adrenergics?

HOW: blocking a1, b1, and/or b2 receptors, OR stimulating a2 receptors in the brainstem which block the effects of the SNS. This leads to vasodilation

5 CATEGORIES:


1. adrenergic neuron blockers
2. a1 receptor blockers
3. a2 receptor agonists
4. b receptor blockers
5. combo a1 and b receptor blockers

How do the five categories of adrenergics effect the body?

1. adrenergic neuron blockers- central (brain) and peripheral (heart and blood vessel) effects
2. a1 receptor blockers- peripheral effects when stimulated (vasoconstriction), blocking receptors causes a decrease in BP
3. a2 receptor agonists- central effects, inhibit norepinephrine, decreasing BP
4. b receptor blockers- peripheral effects
5. combo a1 and b receptor blockers- peripheral effects

Centrally acting adrenergics

examples of:

which receptors they act on, and how:

results in:

EXAMPLES: clonidine and methyldopa

RECEPTORS: stimulate a2 adrenergic receptors in the brain

RESULTS: decreased sympathetic signal from the CNS, leading to:

* decreased norepinephrine production
* decreased renin activity in the kidneys

These both cause a decrease in BP

Less renin = decreased BP, why?

recall- renin is a hormone and enzyme that converts angiotensinogen into the protein angiotensin I.

Angiotensin I is the precursor for angiotensin II, which is a vasoconstrictor, which increases BP.

Peripherally acting a1 blockers

examples of:

which receptors they act on, and how:

results in:

EXAMPLES: tend to end in “zosin” ex. doxazosin

RECEPTORS: block a1 adrenergic receptors

RESULTS: vasodilation

* Also increase urinary outflow and decrease obstruction by preventing smooth muscle contraction in the bladder
* This is useful in the treatment of benign prostatic hyperplasia (BPH)

Doxazosin - used as, effects, and route

USED AS: the most common a1 blocker

EFFECTS: decrease peripheral vascular resistance and BP by vasodilation

* beneficial in treating hypertension and BPH

ROUTE: oral

Beta blockers

examples of:

which receptors they act on, and how:

results in:

EXAMPLES: tend to end in “olol”, ex. propranolol

RECEPTORS: block b1 receptors

RESULTS: decreased heart rate and decreased secretion of renin

* Long term use causes reduced peripheral vascular resistance

Combination a1 and b receptor blockers

examples of:

effects:

EXAMPLE: labetalol

EFFECTS:

* (through b1 receptor blockade) - decrease heart rate
* (through a1 receptor blockade) - vasodilation

indications for the use of adrenergic drugs

hypertension, glaucoma, BPH (benign prostatic hypertrophy), heart failure, prophylactically for migraines, withdrawal symptoms from opioids and alcohol.

Contraindications for the use of adrenergic drugs

known allergy, acute heart failure, use of MAOIs, depression, peptic ulcer ,liver/kidney disease, asthma, use of vasodilator drugs.

adverse effects of adrenergic drugs

High incidence for orthostatic hypotension - especially with a-blockers - expect first dose syncope.

also: bradycardia with reflex tachycardia, postural and post exercise hypotension

also: dry mouth, edema, sexual dysfunction, drowsiness, constipation.

Adrenergic drug interactions

additive CNS depression (avoid alcohol, benzos, opioids)

additive hypotension (diuretics, nitrates, etc)

decreased hypotensive effects

Agents that affect renin-angiotensin -

what do they do?:

What system do they affect?

what are the three types?

WHAT THEY DO: increase urine volume by preventing the renin-angiotensin system. this causes a decrease in blood volume and BP. Some also decrease heart rate.

EFFECT: the sympathetic nervous system

THREE TYPES:

* ACE (angiotensin converting enzyme) inhibitors
* ARBs (angiotensin II receptor blockers)
* Direct renin inhibitors

ACE inhibitors - mechanism of action. Why is this important?

they block ACE (this is the enzyme responsible for converting angiotensin I to angiotensin II).

IMPORTANCE: recall - angiotensin II is a vasoconstrictor, and it stimulates aldosterone secretion from adrenal glands.

* Aldosterone stimulates Na+ and H2O reabsorption, which can increase BP

This prevention therefore decreases BP

ACE inhibitors -

Examples:

When are they used:

Safety:

EXAMPLES: tend to end in “pril”, ex. captopril

WHEN: as first line drugs for heart failure and hypertension. Also in diabetes to protect the kidneys.

SAFETY: safe, and effective, may be combined with both diuretics or CCBs.

primary effects of ACE inhibitors

cardiovascular and renal effects. It is the drug of choice for people with hypertension and heart failure.

Antihypertensive effects - decrease BP by decreasing SVR

In heart failure - prevent sodium and water reabsorption, increasing urine production, decreasing preload, and decreasing the hearts workload

what are ACE inhibitors renal protective effects?

decrease glomerular filtration pressure,

decrease proteinuria

* Standard drug for diabetic patients to prevent the progression of diabetic neuropathy

indications for ACE inhibitors

hypertension, heart failure, left ventricular hypertrophy after an MI (cardioprotective), and renal protective effects in diabetes

contraindications for ACE inhibitors

known allergy, hyperkalemia, pregnancy/lactation, children, decline in kidney function.

Management of ACE inhibitor toxicity

presents as hypotension,

treatment is symptomatic and supportive,

* usually IV fluids to expand volume.

ACE inhibitors interactions

NSAIDS - decrease antihypertensive effects, may develop acute kidney failure

antihypertensives, or diuretics - hypotensive effects

Lithium - lithium toxicity

Potassium sparing diuretics - hyperkalemia

Captopril vs Enalapril

CAPTOPRIL: short half life, must be taken 3/4 times per day. Used to reduce the risk of heart failure after an MI by preventing ventricular remodeling

ENALAPRIL: oral or parenteral, IV does not need cardiac monitoring. Improves survival after an MI by decreasing the incidence of heart failure.

ARBs mechanism of action - why is this important?

affect the vascular smooth muscle and adrenal glands.

Selectively block angiotensin II from binding with type one angiotensin II receptors in tissues.

* Block vasoconstriction and the secretion of aldosterone, resulting in decreased BP.

Differences between ACE inhibitors and ARBs

They are very similar!, but:

ACE INHIBITORS: may cause a cough, more effective cardioprotective and renal protective effects

ARBs: do not cause a cough, better tolerated and have a lower mortality associated with them after an MI than are ACE inhibitors.

ARBs: AKA,

examples of:

AKA: angiotensin II blockers

EXAMPLES: tend to end in “sartan”, ex. losartan, valsartan, candesartan, etc.

Indications for ARBs

hypertension, adjunct to treat heart failure, can be used alone or in conjunction with other drugs- like diuretics.

contraindications of ARBs

known allergy, pregnancy/lactation, caution in older adults and kidney dysfunction.

management of ARBs toxicity

presents with hypotension and tachycardia

Treatment is symptomatic and supportive

* IV fluids to expand volume.

ARBs drug interactions

NSAIDS: decrease antihypertensive effects

Lithium: lithium toxicity

Phenobarbital: increase metabolism which decrease the effects of ARBs

Potassium sparing diuretics: hyperkalemia

direct renin inhibitors

How new are they:

MOA:

Used for:

NEW: most recent drug class used to treat hypertension,

* Only 1 drug in this classification

MOA: bind directly to renin enzyme, and block the conversion of angiotensinogen to angiotensin I and II

USED FOR: mild to moderate hypertension.

calcium channel blockers: (CCBs)

Treat (3 things):

Examples:

How they tx hypertension:

TREAT: hypertension, angina, and dysrhythmias

EXAMPLES: tend to end in “dipine”, ex. amlodipine

TX OF HTN: block the binding of calcium to its receptors, preventing contraction (or allowing relaxation) of smooth muscles.

Vasodilators -

What do they do:

Examples:

WHAT THEY DO: directly relax arteriole and/or venous smooth muscle, causing peripheral vasodilation, resulting in decreased SVR (systemic vascular resistance).

EXAMPLES: diazoxide (arteriole), hydralazine (arteriole), sodium nitroprusside (arteriole/venous).

indications for vasodilators

hypertension

* may be used in combination with other drugs
* sodium nitroprusside and IV diazoxide are reserved for hypertensive emergencies.

contraindications for vasodilators

known allergy, hypotension, cerebral edema, head injury, acute MI, CAD (coronary artery disease), heart failure .

PART 2: ANTIANGINALS

PART 2: ANTIANGINALS

Coronary artery disease -

includes:

causes:

INCLUDES: angina and myocardial infarction (MI)

CAUSES: the narrowing or occlusion of a coronary artery due to an atherosclerotic plaque.

* causes decreased blood supply
* can lead to MI by blocking an artery to the myocardium

What is ischemia:

What is ischemic heart disease:

What is myocardial infarction:

ISCHEMIA: poor blood supply to an organ

ISCHEMIC HEART DISEASE: poor blood supply to the heart,

* atherosclerosis, or coronary artery disease

MYOCARDIAL INFARCTION: necrosis of cardiac tissue due to ischemia to the heart.

What is angina pectoris?:

How does it present?:

IT IS: reduced oxygen supply to a portion of the heart.

* “aching” heart muscle

PRESENTS: steady, intense pain

* substernal region
* radiates to mid-epigastric or abdominal area, or left shoulder and arm
* feeling of “doom”

Pallor, dyspnea, diaphoresis, tachycardia, hypertension

3 types of angina

1. classic/chronic, or exertional
2. unstable
3. variant/vasospastic

classic/chronic (exertional) angina -

Why:

Triggered by:

Presents as:

Treatment:

WHY: the O2 demand increases suddenly

TRIGGERS: exertion or stress (cold, alcohol, emotions, nicotine, etc)

PRESENTS: intense pain subsiding within 15 minutes of rest or medications

TX: nitrates

unstable angina -

Triggered by:

Presents as:

Treatment:

TRIGGERS: occurs at rest, has a recent onset

PRESENTS: much more serious, may lead to an MI

TX: nitrates/nitroglycerine

variant/vasospastic angina -

Why:

Triggered by:

Presents as:

Treatment:

WHY: vasospasm of the smooth muscle layer surrounding the atherosclerotic artery at rest. Less common.

TRIGGERS: usually at rest with no precipitating cause, however there is usually a pattern (time of day)

PRESENTS: severe and prolonged

TX: calcium channel blockers (CCBs)

3 antianginal agents used to reduce angina pain:

How do they reduce angina pain?:

1. nitrates/nitrites
2. beta-blockers
3. calcium channel blockers

HOW: They slow HR, cause vasodilation (reducing preload \[veins\] and afterload \[arterioles), reduce contractility

therapeutic goals of antianginals (4 things)

1. minimize the frequency of attacks, and decrease the duration and intensity of the pain
2. improve the persons functional capacity with few adverse effects
3. prevent or delay MI
4. improve blood supply to the heart during acute angina

nitrates -

what they do:

result in:

indications:

WHAT THEY DO: vasodilate coronary arteries

RESULTS IN: relaxation of arterial and venous smooth muscle,

* decrease preload and afterload
* decrease workload and O2 demand
* Alleviate chest pain

INDICATIONS: all types of angina

* for acute relief, or prophylactically in situations that may provoke angina.

available forms of nitrates and nitrites

* Chew tabs, oral capsules, ointments

The following bypass the liver and first-pass effect:

* sublingual, IV, transdermal patch, translingual spray

rapid forms of nitrates and nitrites -

examples:

forms:

used for:

EXAMPLES: nitroglycerine, isosorbide dinitrate

FORMS: SL tabs or spray, IV, oral, ointment

USED FOR: acute anginal attacks

long-acting forms of nitrates and nitrites -

examples:

forms:

used for:

EXAMPLES: isosorbide mononitrate

FORMS: transdermal patches, extended release oral

USED FOR: preventing anginal episodes

contraindications for nitrates

known allergy, severe anemia, closed-angle glaucoma, hypotension, severe head injury, alcohol, use of erectile dysfunction meds

when does nitrate tolerance occur, and how can it be prevented

WHEN: in people taking them around the clock or with long-acting forms

PREVENTION: allow a regular nitrate free period to allow the enzyme pathways to replenish

nitrate drug interactions

increase hypotension with:

* alcohol, beta blockers, CCBs, phenothiazines, erectile dysfunction meds

Nitroglycerine -

used for:

IV form specifically used for:

routes:

* prototypical nitrate, has a large first-pass effect with oral forms.

USED FOR: symptomatic treatment of angina

IV: to control BP in perioperative hypertension, heart failure, ischemic pain, pulmonary edema, and hypertensive emergencies

ROUTES: oral, SL, IV, topical.

beta blockers -

when are they used:

effects:

indicated by:

WHEN: 1st line of choice for chronic, stable angina

* does not develop tolerance

EFFECTS: cardioprotective (increases O2 supply), antihypertensive

INDICATED BY: ending of “olol”

beta blockers - mechanism of action

block b1 receptors on the heart

* Decrease HR, resulting in decreased O2 demand and increased O2 delivery
* decrease myocardial contractility, conserving energy and decreasing demand
* decrease conduction through the AV node

Block the harmful effects of catecholamines

* This improves survival after an MI

indications for beta blockers

exertional angina, MI, hypertension, dysrhythmias, some uses for migraines, essential tremors, and stage fright

contraindications for Beta blockers

systolic heart failure, conduction disturbances

* caution: asthma
* relative contraindications: diabetes mellitus, peripheral vascular disease

beta blockers interactions

diuretics and antihypertensives: increased hypotension

CCBs: increase AV node suppression, increase hypotension, bradycardia, heart block.

Insulin and oral antihyperglycemics: masks hypoglycemic effects, can caused unrecognized hypoglycemia.

Atenolol -

What is it:

How does it help:

WHAT: (oral) cardioselective b1 adrenergic receptor blocker

HOW: prophylactic treatment of angina pectoris

3 groups of calcium channel blockers:

1. phenylalkylamines (Ex. verapamil)
2. benzothiazepines (Ex. diltiazem)
3. dihydropyridines (Ex. amlodipine)

What do calcium channel blockers do? (6 things)

1. cause coronary artery vasodilation
2. cause peripheral arterial vasodilation, which decreases systemic vascular resistance
3. INCREASE blood flow/O2 to the heart
4. DECREASE workload/contractility
5. DECREASE myocardial O2 demand
6. DECREASE heart rate

What inotropic and chronotropic effects do calcium channel blockers have?

Negative inotropic effect

* decrease myocardial contractility, resulting in a decreased O2 demand.

Negative chronotropic effect

* Decrease heart rate, resulting in decreased O2 demand.

why is arterial vasodilation important in calcium channel blockers?

arterial vasodilation = decreased SVR

decreased SVR = increased O2 to the myocardium

\
treats coronary artery spasm

indications for calcium channel blockers

* angina
* hypertension
* SVT
* short term, for AFib, Aflutter
* migraines and coronary artery spasm

contraindications for calcium channel blockers

* allergy
* acute MI
* second or third degree AV block (unless a pacemaker is present)
* hypotension

Adverse effects of calcium channel blockers

mainly due to overexpression of their therapeutic effects

* hypotension, palpitations, tachy/bradycardia, constipation, nausea, dyspnea, peripheral edema

Calcium channel blockers - interactions

with beta blockers: bradycardia and AV block

with digoxin: elimination problems, can increase DIG levels

with amiodarone: decreased metabolism & cardiac output, bradycardia

with statins: increased risk of statin toxicity

Diltiazem

classification:

effective for:

route:

CLASS: antianginal, antihypertensive, antiarrhythmic

EFFECTIVE: tx of angina from coronary insufficiency and hypertension

ROUTE: oral and parenteral

PART 3: DRUGS FOR HEART FAILURE

PART 3: DRUGS FOR HEART FAILURE

TERMS:

Contractility, inotropic, dromotropic, chronotropic

CONTRACTILITY: strength of heart contracting

INOTROPIC: affect contractility

DROMOTROPIC: affects the AV conduction

CHRONOTROPIC: affect heart rate

What is heart failure?

What are the types of heart failure?

HEART FAILURE is when the failing heart cannot meet the demands on it. The ventricles cannot efficiently eject blood, and it can be caused by MI or defects from the outside.

TYPES: right sided/left sided

Left sided heart failure: manifestations and the problem it causes with circulation

MANIFESTATIONS: pulmonary edema, coughing, SOB, dyspnea

PROBLEM: difficult to get blood from the lungs, out to the body, resulting in cyanosis.

Right sided heart failure: manifestations and the problem it causes with circulation

MANIFESTATIONS: systemic venous congestion, pedal edema, JVD, ascites, hepatic congestion.

PROBLEM: difficult to get the blood back to the heart, results in venous pooling/swelling

4 classes of heart failure according to the New York Association

I: no physical activity limitations

II: ordinary physical activity results in fatigue/dyspnea

III: marked limitation in physical activity

IV: symptoms at rest.

Causes of heart failure (4 things)

1. inadequate contractility - MI, CAD
2. inadequate filling - AFib, infection, ischemia
3. pressure overload - hypertension, outflow obstruction
4. volume overload - hypervolemia, infection, diabetes, thyroid disease

What are the three drugs used to treat heart failure?

1. Positive inotropics: increase the force of contraction
2. Positive chronotropics: increase heart rate
3. Positive dromotropics: accelerate cardiac conduction

what are the six classes of drugs used to treat heart failure?

1. ACE (angiotensin converting enzyme) inhibitors
2. ARBs (angiotensin II receptor blockers)
3. Beta Blockers
4. Diuretics
5. Phosphodiesterase inhibitors
6. cardiac glycosides

ACE inhibitors - what do they do?

This results in?

WHAT THEY DO: prevent sodium and water reabsorption, and inhibit aldosterone.

RESULTS: decreased blood volume (decreasing preload), decreased work load, and decreased peripheral edema

ARBs - what they do?

This results in?

WHAT THEY DO: potent vasodilators

RESULTS: decrease systemic vascular resistance

beta blockers - what they do?

This results in?

WHAT THEY DO: decrease or block SNS stimulation

RESULTS: decreased BP and HR

diuretics - what they do?

Types, and what they do?

WHAT THEY DO: decrease peripheral edema and pulmonary congestion

TYPES:

* Loop diuretics (Lasix) - reduce fluid overload
* potassium sparing (spironolactone) - inhibit aldosterone

phosphodiesterase inhibitors - what they do?

This results in?

What is the only drug currently available?

WHAT THEY DO: inhibit the phosphodiesterase enzyme, resulting in vasodilation and an increase in calcium for myocardial contraction

RESULTS: positive inotropic effect

ONLY DRUG: milrinone

Milrinone - route, effects, and adverse effects

ROUTE: only in injectable form

EFFECTS: positive inotropic response and vasodilation

ADVERSE EFFECTS: dysrhythmias, hypotension, angina, hypokalemia

cardiac glycosides - effects

EFFECTS: negative chronotropic, positive inotropic, improves cardiac output, slows the rate of conduction.

Promotes tissue perfusion and diuresis.

Digoxin (cardiac glycoside) - mechanism of action

inhibits the Na+/K+/ATPase pump to increase myocardial contraction.

Prolongs the refractory period, which slows the HR

Digoxin indications

heart failure, pulmonary congestion, peripheral edema, AFib