Cardiovascular Drugs Part One

Cardiovascular Drugs
Contents
Antihypertensive
Drugs used for Heart Failure
Antiangina
Anti-arrhythmias
Hyperlipidemia drugs
Drugs used for shock managements
1 optimized by EA 07/17/2022
Case study
 A.M. is a 32-year-old woman (height 66 inches, weight 70 kg) with
type 1 diabetes and HTN. Her blood pressure has been difficult to
control, with her SBP over170 mm Hg at times. Her current
medication regimen is as follows: ramipril 10 mg/day,
chlorthalidone 25 mg/day, amlodipine 10 mg/day, ethinyl estradiol
20 mcg/norethindrone 1 mg daily (for the past 5 years),and insulin
as directed. Her vital signs today include blood pressure 146/82 mm
Hg, repeated blood pressure 142/80 mm Hg; heart rate 82
beats/minute; and body mass index (BMI) 24.5 kg/m2. A.M. would
prefer not to take any more drugs, if possible.
A. Which drugs are HTNs drugs and not?
B. Classify each drugs via MOA
C. Which is the best clinical plan for A.M.?
Hypertension
Out-Line
 Introduction
 Classification of antihypertensive drugs
 Mechanism of action of antihypertensive drugs
 Indication of antihypertensive drugs
 Side effect and Contraindication
 Principle of Combination drugs
 Hypertensive crisis management
Hypertension
 Hypertension is the most common cardiovascular disease.
 It is persistently elevated arterial blood pressure (BP).
 Isolated systolic hypertension is DBP values less than 90 mm Hg
and SBP values of 140 mm Hg or more.

 Hypertensive crisis (BP >180/120 mm Hg)
 Hypertensive emergency (extreme BP elevation with acute or progressing
target-organ damage)
 Hypertensive urgency (high BP elevation with out acute or progressing
target organ damage
Classification > =18Y
Category Systolic Diastolic
(mmHg) (mmHg)
Normal <120 <80
High Normal 120-139 80-89

Hypertension
Stage 1 (mild) 140-159 90-99
Stage 2 (moderate) 160-179 100-109
Stage 3 (Severe) 180-209 110-119
Stage 4 (very severe) >210 >120
Types of hypertension
 Essential or primary—poorly understood etiology contributors
include: salt sensitivity, insulin resistance, genetics, sleep apnea,
environmental factors
 Secondary(10-15%)—renal, adrenal, coarctation of the aorta,
steroids, pregnancy
 White coat /office hypertension
Mechanisms for controlling blood pressure
 Arterial BP is directly proportional to the product of the cardiac
output(CO) and the peripheral vascular resistance(PVR)
 CO and PVR are controlled mainly by two overlapping control
mechanisms
 The baroreflexes: responsible for the rapid, moment-to-moment
regulation of blood pressure
 Mediated by autonomic nerves
 E.g. Decreased BP leads to reflex response of increased

sympathetic and decreased parasympathetic output to the heart and
vasculature causing vasoconstriction and increased cardiac output
(rise in BP)
Cont…
 The renin-angiotensin-aldosterone system
 Humoral mechanism: kidney provides for the long-term control of
blood pressure by altering the blood volume

 Kidney releases the enzyme renin when its baroreceptors are
stimulated by reduced arterial pressure (and to sympathetic

stimulation of ß-adrenoceptors)
 Low sodium intake and greater sodium loss also increase renin
release.
Cont…
 Renin converts angiotensinogen to angiotensin I which in turn changed
to angiotensin II in the presence of angiotensin-converting enzyme

(ACE)
 Effects of angiotensin II: on angiotensin II AT1 receptors
 Is potent vasoconstrictor (both arterioles and veins) causing an
increase in BP
 Stimulates aldosterone secretion, leading to increased renal sodium
reabsorption and increased blood volume which contribute to a further

increase in blood pressure
Management of hypertension
Non-Pharmacological therapy Pharmacological therapy

Reduction of weight Diuretics
Salt restriction Sympatholytic
Alcohol restriction ACEIs
Physical exercise ARB
Relaxation Ca++channel blockers
Stop smoking Vasodilators
Group Discussion on Patient Case
 A 46-year-old white woman is new to your clinic. While shopping
recently, she took her blood pressure at an automatic blood pressure
station, which informed her that her blood pressure is “too high.”
Today, her blood pressure is 144/90 mm Hg, with similar repeat. She
takes no prescription medications, though over the counter, she takes
an appetite suppressant, St. John’s wort, and ibuprofen 400 mg twice
daily. For the past week, she has also taken pseudoephedrine 30 mg
twice daily for a cold. She drinks “at least” 4 cups of coffee daily, 2
diet sodas/day, and 2 or 3 alcoholic drinks every evening. Although
she has no symptoms of illness or of feeling bad, she has difficulty
falling asleep at night. Her laboratory test results today are normal.
Her BMI is 30.2 kg/m2.
A. Which is the best intervention for this patient’s HTN and list the
risk factors?
Cont…
 The sensitivity of patients differs to non-pharmacological

approaches, but, on the average, only modest reductions (5 to 10
mmHg) in blood pressure can be achieved.
 This may be sufficient for the treatment of some mild hypertensive
cases.
 The major advantage of non-pharmacological approaches is their
relative safety and freedom from side effects, compared with

pharmacology therapy
Diuretics
 Used as first-line drug therapy for hypertension unless there are
compelling reasons to choose another agent

 Thiazides have found the most widely used among diuretics
 Thiazide diuretics: hydrochlorothiazide
 Initially the BP is lowered by increasing sodium and water
excretion which causes a decrease in extracellular volume,

resulting in a decrease in cardiac output.
 With long-term treatment, plasma volume approaches a normal
15
value and so does CO, but peripheral resistance decreases. 07/17/2022
optimized by EA
Cont…
 Used in mild to moderate HTN for patients with proper renal and
cardiac function
 evoke a compensatory increase in renin secretion, which is one
reason why using the drug in combination with an angiotensin
inhibitor is effective.
 They are orally active
Loop diuretics: furosemide
 It act promptly, even in patients with poor renal function or who
have not responded to thiazides (severe HTN) or other diuretics
 Potassium-sparing diuretics are often used combined with
thiazides and loop diuretics
Sympatholytic agents
 ß-adrenoceptor blocking agents
 Primarily by decreasing cardiac output (through reducing rate
and force of myocardium contraction)
 May also decrease sympathetic outflow from CNS and inhibit
the release of renin from the kidneys(blockade of ß receptors on
the kidney)
 Resulting in a decrease in total peripheral resistance and blood
volume
 Are orally active, but propranolol undergoes extensive and
highly variable first-pass metabolism
Cont…
 Pharmacological differences
 Non selective -blockers: - Propranolol, Sotalol, Timolol,

Pindolol, Penbutolol
 Cardioselective -blokers: - Acebutolol, Atenolol, Betaxolol,
Metoprolol, Esmolol
 Intrinsic Sympathomimetic activity: - Pindolol, Acebutolol,
Penbutolol
 Lipid solubility (lipophylics): Propranolol, metoprolol, timolol,
penbutolol
Cont…
They are useful in treating conditions that may coexist with
hypertension, such as myocardial infarction, tachyarrhythmia,
angina pectoris, chronic heart failure, and migraine headache
 Most common side effects of beta blockers are fatigue,
drowsiness, dizziness, bronchospasm, nausea and vomiting.
 Sudden withdrawal can lead to exacerbation of angina and MI or
even death in patients with underlying cardiovascular disease.
 Dose should be tapered gradually over two weeks to prevent
withdrawal symptoms.
Cont…
 Peripheral a-1 adrenergic antagonists- Prazosin, terazosin and
doxazosin
 Effect on arteriolar resistance predominates
 Unlike non-selective α blockers, these drugs do not produce
reflex sympathetic stimulation and tachycardia does not
compensate for fall in BP.
 Selectivity allows NE to exert unopposed negative feed back
(through α2 receptors) on its own release.
 Retention of salt and water occurs when these drugs are
administered without a diuretic.
 May be particularly beneficial in patients with coexisting benign
prostatic hypertrophy.
Cont…
 More effective when used in combination with β blocker and a diuretic,
than when used alone.
 The difference between α1 antagonist is mainly in their
pharmacokinetics
 Terazosin ( t ½ = 12hrs) and doxazosin (t ½ = 22hrs) are long acting
congeners of prazosin(t ½ = 3-4hrs).
 Prazosin is well absorbed, undergoes substantial metabolism, and is
eliminated entirely by metabolism.
 Most common side effect is postural hypotension and syncope when
administered for the first time (“first- dose phenomenon”).
 This disappears with continued therapy, tolerance develops and
cardiovascular reflexes are not impaired appreciably by chronic
therapy.
Cont…
  and ß adrenoceptor blocking agents
o Labetalol and carvedilol
block both 1- as well as ß 1- and ß 2- receptors
Reduce BP without reflex tachycardia
Given PO/IM/IV
Fatigue, impotence, orthostatic hypotension may occur
Labetalol is used in the management of gestational hypertension
and hypertensive emergencies.

Cont…
 Centrally acting 2 adrenergic/
Clonidine
Used for mild to moderate hypertension
Used primarily for the treatment of hypertension unresponsive
to treatment with two or more drugs
Because it may cause sodium and water retention, clonidine
may be administered in combination with a diuretic
Can produce sedation and dry mouth, ejaculation problem,
rebound hypertension occurs following abrupt withdrawal of
clonidine
Cont…
 Methyldopa
 It is a pro drug, in CNS α – methylnorepinephrine to exert
effect
 Most common side effects are sedation and drowsiness.
 Dry mouth, nausea, vomiting, diarrhea, postural hypotension,
impotence, haemolytic anemia, hepatotoxicity, weight gain may

also occur
 It has been used in hypertensive pregnant patients.
Cont…
 Adrenergic neuron – blocking agents
 Guanethidine and reserpine
Depletes NE storage
Lowers blood pressure by reducing both cardiac out put and total
peripheral resistance
Recommended for treatment of severe forms of hypertension
when others fail but it is rarely used

Has significant adverse effects
Calcium-channel blockers
They block the inward movement of calcium by binding to L-
type calcium channels in the heart and in smooth muscle of the
coronary and peripheral vasculature.
This causes vascular smooth muscle to relax, dilating mainly
arterioles.
Based on structure or selectivity to smooth muscle or cardiac
muscle they are divided into three:
 Diphenylalkylamines: e.g. verapamil
 Benzothiazepines: eg. diltiazem
 Dihydropyridines: e.g. nifidipine
Mechanism of muscle contraction and relaxation.
Diphenylalkylamines: e.g. verapamil
It has significant effects on both cardiac and vascular smooth
muscle cells
Benzothiazepines: eg. diltiazem
It affects both cardiac and vascular smooth muscle cells, but has
a less pronounced negative inotropic effect on the heart
compared to that of verapamil
Dihydropyridines e.g. Nifedipine, Amlodipine..
They have a much greater affinity for vascular calcium channels
than for calcium channels in the heart
Cont…
Dihydropyridines are useful in the treatment of hypertensive patients


who also have asthma, diabetes
Dihydropyridines use is usually accompanied by a reflex increase in

heart rate and sympathetic activation.
Non- dihydropyridines are used to treat patients with hypertension and

angina and arrhythmia
Non- dihydropyridines have been shown to reduce proteinurea and may

be used as second line agents in diabetic hypertensive patients with
proteinurea.
They have an intrinsic natriuretic effect ,do not usually require the

addition of a diuretic
Adverse
 effects:-bradycardia, cardiac arrest, constipation are
more frequent with non-dihydropyridines
Dizziness,
 headache, and a feeling of fatigue caused by a
decrease in BP are more frequent with dihydropyridines
No adverse fetal affects can be used during pregnancy.

They should be avoided in patients with CHF or with AV block


due to its negative inotropic (contraction) and chronotropic
effects
Don’t use with beta blockers

Angiotensin converting enzyme inhibitors (ACEIs)
 Captopril, Enalapril, Fosinopril, Lisinopril, Ramipril etc…
 They block the ACE that cleaves angiotensin I to form the
potent vasoconstrictor angiotensin II
 ACE is also responsible for the breakdown of bradykinin
 Vasodilation occurs as a result of the combined effects of
diminished levels of angiotensin II and the potent vasodilating
effect of increased bradykinin
 They also decrease the secretion of aldosterone by reducing the
angiotensin II level which stimulates adrenal gland.
MOA
Cont…
 Important differences between captopril and other ACEIs is that
captopril is less potent, has fast onset and short duration of action
and less absorption in presence of food in GIT.
 Because of short and fast action, it can cause postural hypotension
which is not seen with other ACEI.
 All ACEI are prodrugs except captopril and lisinopril.
 Other drugs are slow acting.
 Enalaprilat is available as a separate drug meant for use in
hypertensive emergencies by i.v. route.
Comparative features of some ACE inhibitors
Cont…
 Additional use of ACEIs are CHF, evolving MI, diabetic
nephropathy, diabetic retinopathy and non-diabetic renal
disease.
 Most frequent adverse effect is dry cough.
 It can be reduced by iron supplements and asprin.
 ACEI can also cause angioedema.
 Both cough and angioedema is due to elevated levels of bradykinin.
 Hyperkalemia if used along with other agents causing elevation
of serum potassium.
 Other adverse effects include rashes, dysguesia and acute renal
failure.
Cont…
 An increase in serum creatinine upto 30% within 2-5 days can be
expected in most patients started on ACE inhibitors.
 It stabilizes in 2-3 weeks and is reversible on stopping drug
therapy.
 C/I
 pregnancy (teratogenic in second half of pregnancy)
 ARF when serum creatinine is more than 3.5mg/dl .
 bilateral Renal artery stenosis
Angiotensin receptor blockers (ARBs)
 Losartan, valsartan, irbesartan, candesartan, telmisartan and
eprosartan.
 Act by antagonizing the action of angiotensin II at AT1 receptors.
 Produce arteriolar and venous dilation and block aldosterone
secretion.
 Not increase bradykinin and thus have less chances of causing
cough and angioedema.
 Inhibit the activity of RAAS even when angiotensin II is generated
by non-ACE pathway due to acting at a distal site.
 Losartan is also a competitive antagonist of TA2 and attenuates
platelet aggregation.
Cont…
 ARB can be combined with ACEI for various indications.
 All indications, adverse effects and C/I of ACEI also apply to
ARB except that incidence of cough and angioedema is less with
ARB.
 Used as an alternative to ACE inhibitors for patients who can not
tolerate adverse effects of ACE inhibitors.
 Other possible indications for their use would be coexisting heart
failure
 They decrease the nephrotoxicity of diabetes, making them an
attractive therapy in hypertensive diabetics.
Direct vasodilators
They act primarily on arterioles ,but some act primarily on veins,
and some act on both types of vessel.
Sodium nitroprusside (mixed dilators)
Hydralazine (arteriolar dilators)
Minoxidil (arteriolar dilators)
Nitrates (venodilators)
The vasodilators have common side effects due to increased plasma
renin concentration, resulting in sodium and water retention and
reflex tachycardia
To solve this concomitant use of a diuretic and a ß-blocker is
advisable
Sodium nitroprusside
 Dilates both arteriolar and venular vessels with reflex tachycardia.
 It is a prodrug
 Activates guanylyl cyclase via release of NO
 Has rapid onset (30s) and brief duration of effect (3 min)
 Poisonous if given orally because of its hydrolysis to cyanide, so is
administered parentally
Cont…
 Metabolically degraded by the liver to thiocyanate, which are

excreted by the kidney (patients with impaired renal function
likely to develop toxicities)
 It is used for treatment of hypertensive emergencies (continuous
IV infusion)
 Adverse effects
 Excessive lowering of BP causing hypotension.
 Accumulation of thiocyanate
 Metabolic acidosis, and arrhythmias
 Hypothyroidism (thiocyanate inhibits uptake of iodine)
Hydralazine
It relaxes arteriolar smooth muscle
Given PO/IM/IV
It is used to treat moderately severe hypertension
Headache, tachycardia, nausea, sweating, arrhythmia,
and precipitation of angina some side effect of

hydralazine
Minoxidil
 It is a prodrug
 It causes dilation of resistance vessels (arterioles)
 Metabolized by hepatic sulfotransferase to the active molecule
 Administered orally for treatment of severe to malignant
hypertension that is refractory to other drugs

 It causes hypertrichosis (the growth of body hair)
 It is now used topically to treat male pattern baldness.
PHARMACOLOGIC THERAPY
 Initial drug selection depends on the degree of BP elevation and
presence of compelling indications for selected drugs.
 ACE inhibitors, ARBs, CCBs, and thiazide diuretics are acceptable
first-line options.
 β-Blockers are used to either treat a specific compelling indication
or as combination therapy with a first-line antihypertensive agent
for patients without a compelling indication.
 Most patients with stage 1 hypertension should be treated initially
with a first-line antihypertensive drug or a two-drug combination.
 Combination therapy is recommended for patients with stage 2
hypertension, preferably with two first-line agents.
Cont…
 Other antihypertensive drug classes (α1-blockers, direct renin
inhibitors, central α2-agonists, peripheral adrenergic antagonists,
and direct arterial vasodilators) are alternatives that may be used
for select patients after first-line agents
 There are six compelling indications where specific
antihypertensive drug classes provide unique benefits.
Patients case
 A 50-year-old African American woman with dyslipidemia presents to your
clinic for blood pressure assessment.When she participated in a health fair the
past week, she was told her blood pressure was “too high.”She has smoked
for the past 35 years but has recently considered quitting. Her blood pressure
today an average of 154/94 mm Hg and heart rate is 72 beats/minute. She
takes vitamin D supplementation daily, fish oil, and acetaminophen as
needed. Laboratory tests show TC 230 mg/dL, HDL 35 mg/dL, LDL 155
mg/dL, SCr 0.9 mg/dL, K 4.0 mEq/L, and Na 141 mEq/L. Her BMI is 26.0
kg/m2. Her 10-year ASCVD risk is 15.2%. Which is the next best action?
A. Treat with education on diet and exercise only
B. Treat with education on diet and exercise, and initiate metoprolol succinate 25
mg/day.
C. Treat with education on diet and exercise, and initiate chlorthalidone 12.5 mg/day.
D. Treat with education on diet and exercise, and initiate chlorthalidone 12.5 mg/day
and amlodipine 5 mg/day.
HYPERTENSIVE URGENCIES AND EMERGENCIES
 Hypertensive urgencies are ideally managed by adjusting
maintenance therapy by adding a new antihypertensive and/or
increasing the dose of a present medication.
 Acute administration of a short-acting oral drug (captopril,
clonidine, or labetalol)
 Followed by careful observation for several hours to ensure a
gradual BP reduction is an option.
 Oral captopril doses of 25 to 50 mg may be given at 1- to 2-hour intervals.
The onset of action is 15 to 30 minutes.
 For treatment of hypertensive rebound after withdrawal of clonidine, 0.2 mg
is given initially, followed by 0.2 mg hourly until the DBP falls below 110
mm Hg or a total of 0.7 mg has been administered; a single dose may be
sufficient.
 Labetalol can be given in a dose of 200 to 400 mg, followed by additional
doses every 2 to 3 hours.
Cont…
 Hypertensive emergencies require immediate BP reduction to limit
new or progressing target-organ damage.
 The goal is not to lower BP to normal; instead, the initial target is a
reduction in mean arterial pressure of up to 25% within minutes to
hours.
 If BP is then stable, it can be reduced toward 160/100 to 110 mm
Hg within the next 2 to 6 hours.
 Precipitous drops in BP may cause end-organ ischemia or
infarction.
 If BP reduction is well tolerated, additional gradual decrease
toward the goal BP can be attempted after 24 to 48 hours.
 Nitroprusside is the agent of choice for minute-to-minute control in
most cases.
 Continuous IV infusion at a rate of 0.25 to 10 mcg/kg/min.
 Onset of hypotensive action is immediate and disappears within 1
to 2 minutes of discontinuation.
 When the infusion must be continued longer than 72 hours,
measure serum thiocyanate levels, and discontinue the infusion if
the level exceeds 12 mg/dL (~2.0 mmol/L).
Drugs Safe for the Treatment of Hypertension in Pregnancy
Summary of HTN
Increase
Sympathetic
Vascular
Inhibitors
Vasodilators Resistance Alpha Blocker
Venodilators Beta-Blocker
Mixed dilators Mixed-Blocker
Arteriolar Central acting
dilators
 Hypoertension Increase BV
Increase CO
RAAS
ACEIs Diuretics
ARBs Increase venous Thiazeds
return Loop diuretics
Drugs Used in Heart Failure..\Diuretics.pptx
 Out-Line
Introduction
Pathogenesis of CHF
Drug classification
 Drug with positive intropic effect
 Drugs without positive intropic effect
Patient case
 K.S. is a 76-year-old woman with obesity who presents with mild
exertional dyspnea, which she noticed recently while walking
around her neighborhood. She becomes SOB when walking fast or
on hills but still walks about ¼ mile per day. She also admits
having 1 pillow orthopnea and paroxysmal nocturnal dyspnea. She
has had mild edema in the evenings for many years. She denies
angina, palpitations, or syncope. She is a nonsmoker. She has a
history of HTN, myocardial infarction (MI) 2 years ago,
depression, gastroesophageal reflex disease, and hyperlipidemia.
Her medications consist of metoprolol succinate 150 mg daily,
lisinopril 10 mg daily, furosemide 20 mg daily, aspirin 81 mg daily,
sertraline 50 mg daily, omeprazole 20 mg daily, and simvastatin 20
mg at bedtime.
Cont..
Her vital signs today include blood pressure 178/85 mm Hg and heart
rate 62 beats/minute. Her physical examination is positive for
jugular venous pulsation (JVP), S3 present; trace edema in both
extremities; and lungs with slight crackles. Laboratory findings
show SCr 2.5 mg/dL and K 4.5 mEq/L. Her electrocardiogram
(ECG) reveals normal sinus rhythm (NSR).
1. Given K.S.’s clinical presentation, which symptom has the
greatest sensitivity to detect HF?
2. Which best describes K.S.’s stage and NYHA of HF? why?
3. Identify Beta-blocker, ACEI and Diuretic drugs from K.S
pharmacology therapy.
Introduction to Heart Failure
 It is inadequate ability of the heart to pump enough blood to
meet the blood flow and metabolic demands of the body or
 When cardiac output is inadequate to provide the oxygen needed
by the body.
 It is often accompanied by abnormal increases in blood volume
and interstitial fluid, hence the term congestive HF
 Almost all forms of cardiac diseases can lead to heart failure
 Classification
 Right ventricular vs left ventricular failure
 Acute vs chronic heart failure
 Diastolic (stiffening and loss of adequate relaxation) vs systolic (reduced mechanical

pumping action (contractility)) heart failure
Cont…
 most common causes of HF are

 CAD, hypertension, and dilated cardiomyopathy.
 Others cause are
 Viral illness, thyroid disease, excessive alcohol use, illicit drug use,
pregnancy-related heart disease, familial congenital disease, and
valvular disorders
Pathogenesis of CHF
 Lack or loss of contractile force ,then decreased ventricular
function , lastly reduced CO
 As a result a variety of adaptive mechanisms are activated:
 Increased sympathetic activity (increased after load by 
mediated vasoconstriction, ß mediated heart work load),
 Activation of the renin-angiotensin system(Blood volume
increases, and more blood is returned to the heart),
myocardial hypertrophy-increase in no of cells(diminishes
the ability to eject blood)
Decompensated heart failure
Pathophysiology of cardiac performance
 It is a function of four primary variables
 Increased preload
 Increased afterload
 Depressed intrinsic contractility of myocardium
 Increased HR due to sympathetic over activity
Symptoms and Signs Typical of HF
Symptoms Signs
SOB Elevated JVP

Orthopnea Third heart sound
Paroxysmal nocturnal (gallop rhythm)
dyspnea Laterally displaced
Reduced exercise tolerance apical impulse
Fatigue, tiredness, increased Hepatojugular reflex
time to recover after exercise
Ankle swelling
NYHA classification of HF based on functional and symptom
 NYHA I: Patients with cardiac disease but with no symptoms

during physical activity.
 NYHA II: Patients with cardiac disease who have slight
limitations on physical activity, with symptoms such as fatigue,
palpitations, dyspnea, or angina but Comfortable at rest.
 NYHA III: Patients with cardiac disease who have marked
limitations during physical activity and Comfortable at rest, but
less-than-ordinary activity causes symptoms of HF.
 NYHA IV: Patients with cardiac disease who are unable to
perform physical activity, and who have symptoms at rest.
ACC/AHA Stages of HF:
Stage A: At high risk for HF but without structural heart disease
or symptoms of HF.
Stage B: Structural heart disease but without signs or symptoms
of HF.
Stage C: Structural heart disease with prior or current symptoms
of HF.
Stage D: Refractory HF requiring specialized interventions.
Drug classification
Drugs with positive inotropic Drugs without positive
effect inotropic effect
 Cardiac glycosides  ACE inhibitors

 β blockers
 Β agonists
 Angiotensin receptor
 Bipyridine derivatives
blockers
 Methylxanthines  Diuretics
 Vasodilators
Drug targets
Drugs with positive inotropic effect
 Cardiac glycosides are a group of steroid compounds that
increase cardiac out put and alter the electrical functions
 All cardiac glycosides exhibit similar pharmacodynamic

properties; they inhibit the membrane-bound Na+/K+ ATPase
resulting in an increased intracellular Na+
 Finally leading to an increase in the intracellular calcium that acts
on contractile proteins.
 Their inhibition is potent, selective, and reversible
Pharmacokinetics
Clinical use
 Digoxin is not indicated in patients with diastolic or right-sided
HF
 Because contractility is usually not impaired in this disorder.
 Patients with mild to moderate HF will often respond to
treatment with ACE inhibitors and diuretics, and they do not
require digoxin
 Digoxin therapy is indicated in patients with severe left
ventricular systolic dysfunction after initiation of ACE inhibitor
and diuretic therapy
 Major indication is HF with atrial fibrillation
 At present, no effective oral inotropic agents exist other than
digoxin.
Toxicity of cardiac glycosides
 GI effects:- anorexia, nausea, vomiting, diarrhea
 Cardiac effect:- bradycardia, heart block, arrhythmias
 CNS effects:- headache, malaise, hallucinations, delirium, visual
disturbances (yellow vision)
 Mild toxicities such as gastrointestinal and visual disturbance can
be managed by reducing the dose of the drug.
 For the management of arrhythmias or serious toxicity, potassium
supplementation, administration of anti-arrhythmic drugs (e.g.
lidocaine), and use of digoxin antibodies can be helpful.
Contra-indications and interactions
 Hypokalemia, hypomagnesemia and hypercalcemia increases the
risk of digitalis toxicity.
 Diuretics like thiazides and furosemide (cause hypokalemia and
hypomagnesemia).
 Quinidine and CCB (verapamil, diltiazem) decreases the renal
clearance and thus increases the toxicity by pharmacokinetic
mechanisms.
 Antacids, metoclopramide and sulfasalazine decrease the
absorption of digitalis from GIT.
 Digitalis can convert partial AV block to complete block, so
should not be used in such patients.
Cont…
 Elderly, hypothyroid and patients with renal or hepatic disease

are pre-disposed to digitalis toxicity.
 In thyrotoxicosis and acute myocarditis, the chances of
developing digitalis induced arrhythmias are high.
 It should be used in MI only when it is accompanied by heart
failure and atrial fibrillation.
Bipyridine derivatives, e.g. amrinone, milrinone
 They possess both positive inotropic effect and vasodilator
effects.
 They cause inhibition of an enzyme known as phophodiesterase
III, which is responsible for the inactivation of cyclic AMP.
 They are used in cases of heart failure resistant to treatment with
cardiac glycosides and vasodilators.
 Thrombocytopenia is most prominent side effect.
 Nausea and vomiting, diarrhea, abdominal pain, liver damage,
fever, hypotension and arrhythmias may also occur.
Beta-adrenergic stimulants
e.g. dobutamine, dopamine
They increase in myocardial contractility and hence
cardiac CO by beta adrenoceptor stimulation
However, positive chronotropic effect of these agents
minimizes the benefit particularly in patients with ischemic
heart disease.
The positive inotropic effect of dobutamine is
proportionally greater than its effect on heart rate.
It is reserved for management of acute failure or failure
refractory to other agents
Methylxanthines,
e.g. theophylline in the form of aminophylline
 It has a positive inotropic effect, bronchodilating effect and a
modest effect on renal blood flow.
 It is used for management of acute left ventricular failure or
pulmonary edema.
Summary of inotropics
Drugs without positive inotropic effect
 Diuretics
 Accumulation of fluid in the lungs and peripheral organs leading

to congestive symptoms.
 For mild HF, a thiazide, but are ineffective at low GFR.
 Moderate or severe failure requires a loop diuretic furosemide and
bumetanide.
 In acute failure, diuretics play important role by reducing
ventricular preload.
 Reduction in venous pressure causes reduction of edema and
reduction of cardiac size which leads to improved efficiency of
pump function.
Cont…
 Elevated levels of aldosterone is found in patients with advanced

Heart disease
 due to angiotensin II stimulation and reduced hepatic clearance
of the hormone
 Spironolactone is a direct antagonist of aldosterone, preventing
salt retention, myocardial hypertrophy, and hypokalemia.
 Spironolactone therapy should be reserved for the most advanced
cases of HF
Angiotensin converting enzyme (ACE) inhibitors
 HF lead to activation of the RAAS via two mechanism

 Increased renin release by the kidney due to decreased renal
perfusion
 Renin release is promoted by sympathetic stimulation
 The consequence is increase in both preload and afterload
 ACE inhibitors reduce angiotensin II formation and hence both
the preload and the after load
 They are the agents of choice in HF
Angiotensin-receptor blockers
 They have the advantage of more complete blockade of
angiotensin action because they act on the receptor
 They are a substitute for ACE inhibitors in patients who can not
tolerate the ACE inhibitors (b/c of severe cough or angioedema)
 They are orally active and require only once-a-day dosing
 They all are highly plasma protein bound (>90%)
 Losartan, differs from the others in that it undergoes extensive

first-pass hepatic metabolism
Vasodilators
 Act by reducing preload (venodilators), afterload (arteriolar
dilators) or both (combined arteriolar and venodilators).
 Nitrates preferentially dilate veins therefore benefit in CHF is due
to preload reduction.
 Hydralazine, minoxidil and calcium channel blockers like
nifedipine are primarily arteriolar dilators and cause afterload
reduction.
 These drugs are preferred in forward failure with low cardiac
index (<2.5 L/min/m2) and without markedly increased central
venous pressure (<18 mm Hg).
Cont…
 CCB should not be used in CHF
 because these drugs may increase the mortality in CHF patients
 Due to reflex sympathetic activation in case of nifedipine and direct
cardiodepressant action in case of verapamil and diltiazem.
 Agents reducing both preload and afterload include ACEI, ARBs,
nitroprusside and alpha blockers.
 ACE inhibitors and ARBs are indicated for all grades of CHF
unless these are contraindicated.
Long-term management of chronic heart failure:
 Modify cardiovascular risk factor profile, e.g. Cigarette
smoking, obesity, salt intake
 Underlying causes should be treated, e.g. Anemia, hypertension,
valvular disease
 If this proves inadequate; diuretic should be given, then ACE
inhibitor and digitalis (ACE inhibitors may be used before
digitalis).
 In patients with persisting symptoms give vasodilators besides
increasing the dose of diuretic and ACE inhibitors.
Cont…
 ACC/AHA stage A:
 At high risk for developing heart failure.
 Identifying and modifying risk factors to prevent development of
structural heart disease.
 include smoking cessation and control of hypertension, diabetes
mellitus, and dyslipidemia.
 Treatment must be individualized, ACEIs or ARBs
ACC/AHA stage B:
 structural heart disease but no HF signs or symptoms.
 minimizing additional injury and preventing or slowing the
remodeling process.
 previous MI should receive both ACEIs (or ARBs in patients
intolerant of ACE inhibitors) and β-blockers.
Cont…
 ACC/AHA stage C:
 Structural heart disease and previous or current HF symptoms.
 Treatments for stages A and B, as well as initiation and titration of a
diuretic.
 If symptoms do not improve, an aldosterone receptor antagonist,
ARB (in ACE inhibitor–intolerant patients), digoxin, and/or
hydralazine/isosorbide dinitrate.
 ACC/AHA stage D:
 Symptoms at rest despite maximal medical therapy
 Specialized therapies, including mechanical circulatory support,
continuous IV positive inotropic therapy, cardiac transplantation.
Antianginal drugs
Outline
 Introduction
 Mechanism onset
 Types of angina
 Antianginal agents
 Organic nitrates
 Ca++ channel blockers
 ß-adrenergic antagonists
Antianginal drugs
Introduction
 Ischemia: Is the inadequate blood supply to apart of the body,
even to the point of complete deprivation.
 Ischemic heart disease(IHD): It is defined as acute or chronic
form of cardiac disability arising from imbalance between the
myocardial supply and demand for oxygenated blood
 e.g.. Angina pectoris and myocardial infarction.
 Angina pectoris is acute chest pain caused by insufficient oxygen
to a portion of the myocardium.
 It is is a characteristic sudden, severe, pressing chest pain, occurs.
Antianginal….
 Blood flow to endocardium occurs mainly during diastole.
 In angina, there is a fixed atherosclerotic narrowing of the
coronary arteries.
 Myocardium does not receive enough oxygen to meet the
metabolic demands of the heart, and symptoms of angina begin to
appear.
 CA are the large conducting arteries that run epicardially and
gives collateral vessels to endocardial region.
 Such imbalance may arise during exertion, from a spasm of the
vascular smooth muscle, or from obstruction of blood vessels
caused by atherosclerotic lesions.
Mechanism of onset
Atherosclerosis in the coronary arteries
Types of angina
Cont…
Stable /exertional, typical, classic/ angina
 The most common form
 It is caused by the reduction of coronary perfusion due to
coronary atherosclerosis
 Treatment principles: decrease cardiac load (pre-and after load),
increase myocardial blood flow
 It is promptly relieved by rest or nitroglycerin (a vasodilator).
Cont…
Unstable angina /preinfarction
 Its causes recurrent episodes of small platelet clots.
 It lies between stable angina on the one hand and myocardial
infarction on the other
 Treatment principles: inhibit platelet aggregation and thrombus
formation, decrease cardiac load, Vasodilator coronary arteries.
 The symptoms are not relieved by rest or nitroglycerin.
 Unstable angina requires hospital admission and more aggressive
therapy to prevent death and progression to myocardial infarction.
Prinzmetal's or variant or vasospastic angina
 It is caused by spontaneous vasospasm (work or rest) rather than
increased myocardial oxygen demand
 It is an uncommon pattern of episodic angina that occurs at rest and
is due to coronary artery spasm.
 Generally responds promptly to coronary vasodilators, such as
nitroglycerin and calcium-channel blockers.
Antianginal agents
1. Organic nitrates
2. Ca++ channel blockers
3. ß-adrenergic antagonists
4. Drugs for hyperlipidemia
5. Antithrombotic drugs (e.g., aspirin).
Cont…
 Antianginal drugs act by several mechanisms to reduce myocardial
oxygen demand.
 β-blockers and ivabradine both decrease heart rate, while β-blockers also
decrease cardiac contractility.
 Organic nitrates, CCBs, and ranolazine reduce ventricular wall tension
and oxygen demand via their effects on ventricular volume and pressure.
 Dilation of veins decreases venous pressure, cardiac filling pressure, and
ventricular diastolic pressure (preload).
 Dilation of arteries decreases arterial and aortic pressure and thereby reduces
ventricular systolic pressure (afterload) and impedance to ventricular ejection of
blood.
 Organic nitrates act primarily on venous tissue and predominantly affect
preload, whereas the CCBs act mostly on arteriolar muscle to reduce
afterload.

Vasodilators
 Organic nitrates/nitrites: Nitroglycerin/glyceryl trinitrate,
isosorbide mononitrate/dinitrate, amyl nitrile-
 They are prodrugs
 MOA : act by releasing NO, which increase cGMP and results in
venodilation.
 At high doses arteriolar dilation can also occur.
 Cause a rapid reduction in myocardial oxygen demand through
decreasing preload and afterload and also increasing myocardial
oxygen supply
 They are effective in all forms of angina
 In addition, they inhibit platelet aggregation

MOA

Pharmacokinetics
 Lipid soluble well absorbed from buccal mucosa, intestine and
skin.
 Duration of action from10–20min (sublingual) to 8–10h
(transdermal).
 They under go extensive first past metabolism in liver.
 Rapidly denitrated by glutathione reductase and mitochondrial
aldehyde dehydrogenate.

Cont…
 They have two major effects at therapeutic doses
First, dilation of the large veins resulting in pooling of blood
in the veins.
This diminishes preload (venous return to the heart) and
reduces the work of the heart.
Second, nitroglycerin dilates the coronary vasculature,
providing an increased blood supply to the heart muscle.

Cont..
 They differ in their onset of action and rate of elimination
 Significant first-pass metabolism of nitroglycerin occurs in the
liver
 Common to take the drug either sublingually (10–20min) or via a
transdermal patch (8-10hr).
 Isosorbide dinitrate can be given orally
 For prompt relief of attack of angina precipitated by exercise or
emotional stress, sublingual (or spray form) nitroglycerin is the
drug of choice.

Uses
 Angina pectoris
 Acute coronary syndromes
 Myocardial infarction (MI)
 CHF and acute LVF
 Biliary colic
 Esophageal spasm
 Cynaide poisoning

Cont…
 Most common adverse effect of nitrates is headache

 High doses of organic nitrates can also cause postural
hypotension, facial flushing, and tachycardia
 Tolerance to the actions of nitrates develops rapidly (blood vessels
become desensitized to vasodilation)
 This can be overcome by providing a daily nitrate-free interval
(usually at night) to restore sensitivity to the drug

ß-adrenergic blockers (atenolol, propranolol metoprolol, labetalol)
 They reduce the work of the heart by decreasing heart rate and
contractility both during exertion and at rest.
 β-blockers are not effective in variant angina because they do not
counteract vasospasm and increase coronary blood flow.
 Reduce coronary blood flow by blocking the vasodilation effect
of epinephrine, an effect that is mediated by β2-adrenoceptors in
coronary smooth muscle.
 The selective ß blockers such as metoprolol or atenolol are
preferred in patients with asthma, diabetes, peripheral vascular
disease, or COPD.
 The dose should be gradually tapered off over 5 to 10 days to
avoid rebound angina.

Calcium-channel blockers
 They protect the tissue by inhibiting the entrance of calcium into
cardiac and smooth muscle cells of the coronary and systemic
arterial beds
 At clinical doses, these agents affect primarily the resistance of
vascular smooth muscle and the myocardium
 Verapamil mainly affects the (heart) myocardium, whereas
nifedipine exerts a greater effect on smooth muscle in the
peripheral vasculature where as diltiazem is intermediate

Agents That Alter Metabolism
 reduce angina episodes by improving myocardial metabolism without
altering heart rate or blood pressure.
 These agents include ranolazine and trimetazidine.
 Ranolazine first-line agent for chronic stable angina and is
particularly useful for patients with a heart rate less than 70/min or
low blood pressure.
 Primary mechanism is to block excessive prolongation of the late
inward sodium current (INa-L) in myocardial.
 Abnormal current leads to increased sodium-calcium exchange,
intracellular calcium accumulation, and increased left ventricular wall
tension.
 Blocking INa-L, ranolazine decreases diastolic wall tension, improves
diastolic subendocardial perfusion, and reduces oxygen consumption
Cont…
 Heart uses glucose, fatty acids, and lactate as sources of energy.
 Although fatty acids are the major fuel for the heart, glucose is
metabolized more efficiently and generates more energy per unit of
oxygen used.
 Trimetazidine inhibits ketoacyl coenzyme-A thiolase, a key
enzyme in the β-oxidation pathway of fatty acid metabolism.
 Resulting decrease in fatty acid oxidation evokes a compensatory
increase in glucose metabolism and reduces oxygen consumption
by about 20%.
 Increase ejection fraction in persons with left ventricular
dysfunction.

Efficacy of Drugs Used in the Treatment of Coronary Heart Disease

Review Questions
1. Which mechanism is responsible for the vasodilation effect of verapamil?
(A) increased levels of cGMP
(B) decreased binding of calcium to calmodulin
(C) decreased formation of IP3
(D) increased myosin light-chain kinase activity
(E) increased metabolic efficiency
2. What is the mechanism by which isosorbide dinitrate increases
cyclic GMP levels?
(A) inhibition of phosphodiesterase
(B) inactivation of aldehyde dehydrogenase
(C) blockade of β-adrenoceptors
(D) release of nitric oxide
(E) blockade of calcium channels

Cont….
3. A man with obstructive pulmonary disease requires therapy to prevent
anginal attacks. Which drug should be avoided in this patient?
(A) Verapamil (B) felodipine (C) isosorbide mononitrate (D) diltiazem
(E) propranolol
4. Which agent prevents myocardial cell calcium overload and thereby
decreases ventricular wall tension?
(B) Ranolazine (B) nitroglycerin (C) amlodipine (D) ivabradine (E)
trimetazidine
5. Which effect is caused by both atenolol and diltiazem?
(A) decreased cAMP levels (B) increased cGMP levels (C) decreased
heart rate (D) relaxation of arterial smooth muscle (E) inhibition of
sodium influx

Cardiovascular Drugs Part One

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Cardiovascular Drugs Part One

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Cardiovascular Drugs

 It is persistently elevated arterial blood pressure (BP).

 Isolated systolic hypertension is DBP values less than 90 mm Hg

and SBP values of 140 mm Hg or more.

 Hypertensive emergency (extreme BP elevation with acute or progressing

target organ damage

High Normal 120-139 80-89

 E.g. Decreased BP leads to reflex response of increased

 The renin-angiotensin-aldosterone system

 Humoral mechanism: kidney provides for the long-term control of

blood pressure by altering the blood volume

stimulated by reduced arterial pressure (and to sympathetic

to angiotensin II in the presence of angiotensin-converting enzyme

 Is potent vasoconstrictor (both arterioles and veins) causing an

reabsorption and increased blood volume which contribute to a further

Non-Pharmacological therapy Pharmacological therapy

 The sensitivity of patients differs to non-pharmacological

relative safety and freedom from side effects, compared with

 Used as first-line drug therapy for hypertension unless there are

compelling reasons to choose another agent

 Thiazide diuretics: hydrochlorothiazide

 Initially the BP is lowered by increasing sodium and water

excretion which causes a decrease in extracellular volume,

 Non selective -blockers: - Propranolol, Sotalol, Timolol,

o Labetalol and carvedilol

block both 1- as well as ß 1- and ß 2- receptors

Reduce BP without reflex tachycardia

Fatigue, impotence, orthostatic hypotension may occur

Labetalol is used in the management of gestational hypertension

and hypertensive emergencies.

 It is a pro drug, in CNS α – methylnorepinephrine to exert

 Dry mouth, nausea, vomiting, diarrhea, postural hypotension,

impotence, haemolytic anemia, hepatotoxicity, weight gain may

 Adrenergic neuron – blocking agents

 Guanethidine and reserpine

when others fail but it is rarely used

Dihydropyridines are useful in the treatment of hypertensive patients

They should be avoided in patients with CHF or with AV block

 Dilates both arteriolar and venular vessels with reflex tachycardia.

 Activates guanylyl cyclase via release of NO

 Has rapid onset (30s) and brief duration of effect (3 min)

 Poisonous if given orally because of its hydrolysis to cyanide, so is

 Metabolically degraded by the liver to thiocyanate, which are

It relaxes arteriolar smooth muscle

It is used to treat moderately severe hypertension

Headache, tachycardia, nausea, sweating, arrhythmia,

and precipitation of angina some side effect of

 It causes dilation of resistance vessels (arterioles)

 Metabolized by hepatic sulfotransferase to the active molecule

 Administered orally for treatment of severe to malignant

hypertension that is refractory to other drugs

 It is now used topically to treat male pattern baldness.

 Drug with positive intropic effect

 Drugs without positive intropic effect

 Right ventricular vs left ventricular failure

 Acute vs chronic heart failure

 Diastolic (stiffening and loss of adequate relaxation) vs systolic (reduced mechanical

 most common causes of HF are

 It is a function of four primary variables

 Depressed intrinsic contractility of myocardium

 Increased HR due to sympathetic over activity

SOB Elevated JVP

 NYHA I: Patients with cardiac disease but with no symptoms