Pharmacology of drugs in Heart failure for

Medicine 2nd year students

By TEZERA JEMERE
(MSC in pharmacology)
COLLEGE OF HEALTH SCEINCE
December , 2016

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Presentation outline:
Commonly used drugs in heart failure

Cardiac glycosides
Dopamine
Dobutamine MOA, Uses,
Diuretics PKs, Adv. Effects
Vasodilators & interaction
Betha Blockers
ACE inhibitors

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 Course objectives
At the end of the course students are expected to:
List the commonly used drugs in heart failure
Appreciate the pharmacokinetics and
pharmacodynamics of drugs used in heart failure
Prescribe drugs to appropriate clients with proper
advice to them and to their families.

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 Heart failure: inability of the heart to maintain
cardiac out put sufficient to meet requirement of
metabolizing tissue
Heart failure usually caused by:
Ischaemic heart disease (62%)
Smoking (16%)
Hypertension (10%)
Heart muscle disorders
Valvular heart disease

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 Heart failure Contd
CHF is characterised by inadequate contractility, the
ventricles have difficulty in expelling sufficient blood
=> rise in venous blood pressures
Raised venous pressures impair fluid drainage from
the tissues and produce a variety of serious clinical
effects:
Right sided heart failure- causes lower limb oedema.
Blood pooling lower extremities is associated with
intravascular clotting and thromboembolism
Left sided heart failure- produces pulmonary
oedema and respiratory distress

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 Pathophysiology of Heart Failure

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Chronic HF is typically managed by;
non pharmacological approaches- a reduction in
physical activity, low dietary intake of sodium (<1500
mg/day).
treatment of comorbid conditions,
And use of diuretics, inhibitors of RAAS & inotropic
agents.
Drugs that exacerbate HF, such as NSAIDs , alcohol,
calcium-channel blockers, and some antiarrhythmic
drugs, should be avoided if possible

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Drugs used to treat heart failure:
1. Drugs with positive inotropic effect
A. Cardiac glycosidesDigoxin
B. Sympathomimetic drugs dopamine, dobutamine
C. Bipyridine derivatives: amrinone & milrinone
2. Drugs without positive inotropic effect
A. Diuretics:
loop diuretics, spironolactone and thiazides

B. ACE inhibitors & AT II antagonists

C. Vasodilators: Nitrates
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 Heart failure
Drugs with positive inotropic effect
1. Cardiac glycosides Includes digoxin and digitoxin
MOA:
It selectively binds to extracellular face of the membrane
associated Na+K+ ATPase of myocardial fibres and inhibits this
enzyme.
Inhibition of this cation pump results in progressive
accumulation of Na+ intracellularly.
This indirectly results in intracellular Ca2+ accumulation.
During depolarization Ca2+ ions enter the cell driven by the
steep Ca2+ gradient through voltage sensitive Ca2+ channels.
This triggers release of Ca2+ stored in sarcoplasmic reticulum
triggers contraction.

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Mechanism of positive inotropic action of cardiac glycosides. SR-
Sarcoplasmic reticulum; TnC-Troponin C; NCX-Na+-Ca2+ exchanger; RyR-
Ryanodine receptor calcium channel; PL-Phospholamban; SERCA-
Sarcoplasmic-endoplasmic reticulum calcium ATPase
Jaypee KD Tripathi. Essentials of medical pharmacology6th edition. Chap.
37 7/31/2017
pp 496 . New Delhi. Jaypee brothers
3:16:57 PM TJA
medical publisher Ltd. 2008. 11
 Digoxin

Glycosides; consist of an aglycone (genin) to which are attached

one or more sugar (glucose or digitoxose) moieties.
The pharmacological activity resides in the aglycone, but attached
sugars modify solubility and cell permeability.
The aglycone consists of a cyclopentano perhydrophenanthrene
(steroid) ring to which is attached a 5 or 6 membered unsaturated
lactone ring.
One or more hydroxyl and other substitutions are present on the
aglycone and determine its polarity, e.g. digoxigenin has an
additional OH group than digitoxigenin and is more polar.

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Therapeutic uses
1.Congestive heart failure CHF occurs when cardiac
output is insufficient to meet the demands of tissue
perfusion.
Heart failure may primarily be due to systolic dysfunction
or diastolic dysfunction.
2. Cardiac arrhythmias: digitalis reduces ventricular rate in
AF by decreasing the number of impulses that are able
to pass down the A-V node and bundle of His.
It increases ERP of A-V node by direct, vagomimetic
and antiadrenergic actions:
the minimum interval between consecutive impulses that
can successfully traverse the conducting tissue is
increased.

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In general, cardiac Glycosides:

Improve cardiac performance (=positive inotrope)

Increases cardiac output

Decreased sympathetic tone
Increase urine output
Decreased renin release
Does not prolong life (only symptom relief)
Digoxin levels must be closely monitored in the
presence of renal insufficiency

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Pharmacokinetic properties of digoxin and digitoxin
Jaypee KD Tripathi. Essentials of medical pharmacology 6th
edition.Chap.37 pp 497. New Delhi. Jaypee brothers medical
publisher Ltd.
7/31/2017 3:16:57 PM 2008. TJA 15
 ADVERSE EFFECTS
Toxicity is high, margin of safety is low (TI 1.5-3).
Higher cardiac mortality has been reported among
patients with steady-state plasma digoxin levels > 1.1
ng/ml during maintenance therapy.
About 25% patients develop one/more toxic symptom.
Extracardiac Anorexia, nausea, vomiting and
abdominal pain are due to gastric irritation, mesenteric
vasoconstriction and CTZ stimulation.
Fatigue, malaise, headache, mental confusion,
restlessness, hyperapnoea, disorientation, psychosis
and visual disturbances are the other complaints.

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 Cardiac almost every type of arrhythmia can be
produced by digitalis: pulsus bigeminus, nodal and
ventricular extrasystoles, ventricular tachycardia and
terminally fibrillation.
Partial to complete A-V block may be the sole
cardiac toxicity or it may accompany other
arrhythmias. Severe bradycardia, atrial
extrasystoles,
A.Fibrillation or A.flutter have also been noted. In
about 2/3 patients showing toxicity.
The central actions of digitalis appear to contribute
to the development of arrhythmias by inducing fast
and irregular activity in the cardiac sympathetic and
vagus nerves.
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PRECAUTIONS AND CONTRAINDICATIONS
A. Hypokalemia: enhances digitalis toxicity by
increasing its binding to Na+ K+ ATPase.
B. Elderly, renal or severe hepatic disease:
patients are more sensitive.
C. Severe arrhythmias are more likely. Digitalis
should be used after MI only when heart failure
is accompanied with AF and rapid ventricular
rate.
D. Thyrotoxicosis: reduces responsiveness to
digitalis, but these patients are more prone to
develop digitalis arrhythmias.
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E. Myxoedema: these patients eliminate digoxin
more slowly; cumulative toxicity can occur.
F.Ventricular tachycardia: digitalis is
contraindicated may precipitate ventricular
fibrillation.
G. Partial A-V block: may be converted to
complete A-V block.
H. Acute myocarditis: Diphtheria, acute
rheumatic carditis, toxic carditis-inotropic
response is poor, more prone to arrhythmias.

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G. Wolff-Parkinson-White syndrome:
Digitalis is contraindicated-decreases the
ERP of bypass tract in 1/3 patients.
In them rapid atrial impulses may be
transmitted to ventricles lead to ventricular
fibrillation.
Digitalis can increase the chances of reentry
by slowing conduction in the normal A-V
bundle and accelerating it in the aberrant
pathway.

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 INTERACTIONS
1. Diuretics: cause hypokalemia which can precipitate
digitalis arrhythmias; potassium supplements may be
given prophylactically.
2. Calcium: synergises with digitalis and precipitates
toxicity.
3. Quinidine: reduces binding of digoxin to tissue
proteins as well as its renal and biliary clearance by
inhibiting efflux transporter P-glycoprotein lead to
plasma concentration is doubled and toxicity can
occur. Verapamil, diltiazem, captopril and
amiodarone: increase plasma concentration of
digoxin to variable extents.

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4. Adrenergic drugs: can induce arrhythmias in
digitalized patients; both increase ectopic
automaticity.
5. Digoxin absorption can be reduced by
metoclopramide (gastrointestinal hurrying) and
sucraljate which adsorbs digoxin. Antacids,
neomycin, sulfasalazine also can reduce digoxin
absorption; stagger their administration.
Absorption is increased by atropinic drugs,
including tricyclic antidepressants, by delaying
gastric emptying. Erythromycin, omeprazole
and tetracycline increase bioavailability of
digoxin.
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6. Propranolol, verapamil, diltiazem and
disopyramide: may additively depress A-V
conduction and oppose positive inotropic
action.
7. Phenobarbitone and other enzyme inducers
expedite digitoxin metabolism and decrease
its t1/2; no effect on digoxin t1/2 as it is not
metabolized significantly.
8. Succinylcholine: causes arrhythmias in
digitalized patients.

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 Dopamine

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Medical uses
Most commonly used in severe low blood pressure,
slow heart rate and cardiac arrest
It increases in sodium excretion by the kidneys, an
increase in urine output.
At low doses it acts through the sympathetic nervous
system to increase heart muscle contraction force
and heart rate, thereby increasing cardiac output
and blood pressure.
Higher doses cause vasoconstriction that further
increases blood pressure.

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Dobutamine
MOA: is direct stimulation of 1 receptors of the
sympathetic nervous system
Clinical uses used in the treatment of heart failure
and cardiogenic shock
Adverse effects: hypertension, angina, arrhythmia,
and tachycardia.

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 Bipyridines(Amrinone & Milrinone)
Mechanism of action
Inhibit PDE III and increase in cAMP in vascular
smooth muscle produces vasodilation by facilitating
calcium uptake by the sarcoplasmic reticulum.
In myocytes, the increase of cAMP concentration
increases the activity of protein kinase A(PKA)
which improves the Ca2+ inward current through the
L-type Ca2+ channels, leads to calcium-induced
calcium release from the sarcoplasmic reticulum,
giving rise to a calcium spark that triggers the
contraction; this results in an inotropic effect.
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 Bipyridines Contd
PKA phosphorylates and deactivates
the phospholambans that inhibit SERCA, an
enzymatic pump that terminate the contraction
by removing Ca2+ from the cytoplasm, stores it
back in the sarcoplasmic reticulum and promotes
the subsequent relaxation as well, producing
a lusitropic effect.
Both inotropic and lusitropic effects are the
reason why amrinone is used to treat heart
failure.
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 Bipyridines Contd
It decreases the pulmonary capillary wedge pressure
increasing cardiac output because it functions as an
arterial vasodilator and increases venous capacitance
while decreasing venous return with a net decrease in
myocardial wall tension and O2 consumption.

It has beneficial effects during diastole in the left

ventricle including relaxation, compliance and filling in
patients with congestive heart failure.

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 Bipyridines Contd

Sites of action by -adrenergic agonists on heart muscle

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 Bipyridines Contd
Effects in congestive heart failure
Amrinone increases cardiac output (CO) and stroke
volume (SV) & concurrently reducing the filling pressure
of the left ventricle and decreasing the resistance in the
peripheral vasculature.
This improvement in performance of the ventricles is
likely to result from a direct stimulation of the depressed
myocardium as well as a decrease in peripheral vascular
resistance
Indications
Short-term management of severe CHF (not used long
term because of increased mortality, probably due to
heart failure).
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 Bipyridines Contd
Pharmacokinetics
Active orally as well as parenterally but available only in
parenteral forms.
Protein binding 10 to 49%
Elimination half-lives of 5 8 hours
Renal excretion 1040% in urine and fecal (18%
Adverse effects
Nausea, vomiting, arrhythmias, thrombocytopenia, and
liver enzyme changes.
Milrinone appears less likely to cause bone marrow and
liver toxicity than amrinone, but it does cause
arrhythmias.
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 Diuretics
Diuretics are chemical compounds that
increases the flow of urine and thus eliminate
accumulations of water in cells, tissues,
blood, and organs.
The retention of excess water may occur
following congestive heart failure, when the
heart pumps insufficient blood to eliminate a
normal volume of fluid; and in a variety of
other disabilities, including hypertension,
cirrhosis of the liver, and kidney diseases.
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 Diuretics Contd
Heart stimulants, such as digitalis, produce a
diuretic effect by increasing blood pressure and
thus increasing the flow of blood through the
kidneys.
Certain alkaloids found in coffee and tea
(caffeine, theobromine, and theophylline, in
increasing order of strength) increase urine
output by counteracting the tendency of blood
proteins to prevent the removal of water from the
blood by the kidneys.

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 B. Loop diuretics e.g. furosemide
Mechanism of Action:
Simply inhibit the coupled Na/K/2Cl cotransporter
in the loop of Henle & Both Mg2+ and Ca2+
enter the interstitial fluid via the paracellular
pathway.
1. they have potent pulmonary vasodilating effects
(via prostaglandins).
2. They induce the synthesis of prostaglandins in
kidney which dilate the renal lumen & increase
renal perfusion in renal failure.
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 Diuretics Contd
Medical uses
Furosemide is primarily used for the treatment of
hypertension and edema.
It is the first-line agent in most people with edema
caused by congestive heart failure.
Also used for hepatic cirrhosis, renal impairment,
nephrotic syndrome
In adjunct therapy for cerebral or pulmonary edema
where rapid diuresis is required (IV injection)
Management of severe hypercalcemia in
combination with adequate rehydration(NaCl)
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 Diuretics Contd
Pharmacokinetics
Oral Bioavailability 43-69%
Plasma protein binding 91-99%
Metabolism hepatic and renal glucuronidation
Onset of action 30 to 60 min (PO), 5 min (IV)
Biological half-life up to 100 minutes
Volume of distribution 0.07 - 0.2 L/kg
Excretion renal 66%, biliary 33%
Adverse effects
Ototoxicity,hyperuricemia,Hyperglycemia &
hypokalemia
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 Hydrochlorothiazide

MOA: Inhibit Na+ via inhibition of Na+/Cl- cotransporter.

Clinical uses:
A. Hypertension Drug of Choice
B. Refractory Edema.
C.Nephrolithiasis(Renal stone) due to idiopathic
hypercalciuria .
D. hypocalcemia.
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 Diuretics Contd
E. Nephrogenic Diabetes Insipidus. (it decreases flow
of urine more reabsorption)
Indapamide is a potent vasodilator
Pharmacokinetics
Oral bioavailability ~ 70%
Metabolism does not undergo significant
metabolism (>95% excreted unchanged in urine)
Biological half-life 5.614.8 h
Excretion Primarily excreted unchanged in urine

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 Diuretics Contd
Side effects:
Headache,nausea,vomiting, Photosensitivity, Weight
gain, Pancreatitis
hypercalcemia due to PTH(bone resorption &
decrease renal excretion), more hyponatremia,
hypomagnesemia,hyperglycemia,hyperlipidemia,
hyperurecemia and hypokalemic metabolic alkalosis

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Spironolactone

MOA: Aldosterone cause K and H+ secretion and Na

reabsorption & spironolactone is the opposite
Medical uses
Used in heart failure, essential hypertension, nephrotic
syndrome(ascites),hypokalemia 20 hyperaldosteronism
(hepatic cirrhosis) and Conn's syndrome (primary
hyperaldosteronism).

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 Diuretics Contd
It is an antagonist of androgen receptor (AR) and
inhibitor of androgen production and used off-label
to treat dermatological conditions.
At low doses or topical formulation for androgenic
alopecia in men and hirsutism, acne & seborrhea,
hyperandrogenism in polycystic ovary syndrome in
women.
Pharmacokinetics
Protein binding 90%
Metabolism Hepatic CYP450
Biological half-life 1.3-2 hours
Excretion Urine, bile
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 Diuretics Contd
Adverse effects
urinary frequency, ataxia, drowsiness, dry skin, rashes.
In males breast tenderness, gynecomastia, physical
feminization, testicular atrophy, reversible infertility, and
sexual dysfunction, including loss of libido and erectile
dysfunction.
In females menstrual irregularities and breast tenderness
and enlargement.
Hyperkalemia, immunosuppressive in the treatment of
sarcoidosis.
Rarely cause more severe anaphylaxis, renal failure,
hepatotoxicity, agranulocytosis, DRESS syndrome,
Stevens-Johnson Syndrome or toxic epidermal necrolysis
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 Heart failure
Vasodilators
They provide reduction in preload (through venous
dilation) or reduction in afterload (through arteriolar
dilation) or both
Hydralazine: direct arteriodilator; reduce vascular
resistance and increase cardiac output
Sodium nitroprusside: mixed venous and arteriolar
dilator used for acute reduction of BP
Vasodilator agents: reserved for patients who are
intolerant of or who have contraindications to ACE
inhibotors
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 Hydralazine
Mechanism of vascular smooth muscle relaxant action of
hydralazine is not clearly known.
It is partly endothelium dependent: may involve
generation of NO (nitric oxide) and stimulation of cGMP.
Direct effects on membrane potential and on Ca2+
fluxes have also been proposed.
Medical use
used to treat severe hypertension, but not a first-line
therapy for essential hypertension.
used in combination with isosorbide dinitrate for the
treatment of congestive heart failure in African American
populations
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 Vasodilators Contd
Pharmacokinetics
Oral bioavailability 26-50%
Protein binding 85-90%
Metabolism Hepatic
Biological half-life 2-8 hrs,7-16 hrs(renal impairment)
Excretion Renal
Adverse effects
Headache, High heart rate, Palpitations, flushing,
hypotension, anginal symptoms, joint ache,
gastrointestinal disturbances, diarrhoea,nausea,
vomiting, joint swelling, muscle aches and Oedema
(sodium and water retention)
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 Sodium
nitroprusside
MOA: Endothelial cells, RBCs (other cells) split
nitroprusside to generate NO which relaxes vascular
smooth muscle.
The enzymes involved are different from those that
produce NO from glyceryl trinitrate.
Nitroprusside is non enzymatically converted to NO (and
CN) by glutathione.
This may be responsible for the different pattern of
vasodilator action compared to nitrates, as well as for
the fact that no nitrate like tolerance develops to
nitroprusside action.
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 Sodium nitroprusside Contd
Medical use
It has potent vasodilating effects in arterioles and
venules, Nitric oxide reduces both total peripheral
resistance and venous return, thus decreasing both
preload and afterload.
Used in severe congestive heart failure and severe
hypertension.
Pharmacokinetics
Bioavailability 100% (Intravenous)
Metabolism By haemoglobin being converted to
cyanmethaemoglobin and cyanide ions
Biological t1/2 <2 minutes (3days for thiocyanate
metabolite)
Excretion Renal (100%; as thiocyanate)
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 Sodium nitroprusside Contd
Adverse effects
Bradyarrhythmia (low heart rate), hypotension(low
BP), Palpitations, tachyarrhythmia(high heart rate),
apprehension, restlessness, confusion, dizziness,
headache,somnolence,rash,sweating,thyroid
suppression, muscle twitch, Oliguria, renal azotemia

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 Isosorbide
dinitrate
MOA: Organic nitrates are rapidly denitrated
enzymatically in the smooth muscle cell to release the
reactive free radical nitric oxide (NO) which activates
cytosolic guanylyl cyclase increased cGMP causes
dephosphorylation of myosin light chain kinase (MLCK)
through a cGMP dependent protein kinase.
Reduced availability of phosphorylated (active) MLCK
interferes with activation of myosin, it fails to interact with
actin to cause contraction.
Consequently relaxation occurs. Raised intracellular
cGMP may also reduce Ca2+ entry-contributing to
relaxation.
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 Isosorbide dinitrate Contd
Medical uses
used for angina, congestive heart failure and
esophageal spasms.
Pharmacokinetics
Oral bioavailability 1090%, average 25%
Metabolism Hepatic
Biological half-life 1 hour
Excretion Renal
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 Isosorbide dinitrate Contd
Adverse effects
Throbbing headache, flushing, rash, weakness,
sweating, palpitation, dizziness and fainting.
Methemoglobinemia it can reduce oxygen carrying
capacity of blood in severe anaemia.
Some degree of tolerance develops on continued
use.

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 Metoprolol
Medical uses
used in hypertension, angina, acute myocardial infarction,
supraventricular tachycardia, ventricular tachycardia, congestive
heart failure, adjunct in treatment of hyperthyroidism and
prevention of migraine headaches.
Long QT syndrome, especially for patients with asthma, as
metoprolol's 1 selectivity tends to interfere less with asthma
drugs, which are often 2-adrenergic receptor-agonist drugs.
Prevention of relapse into atrial fibrillation (controlled-
release/extended-release form)
Metoprolol is also prescribed for off-label use in performance
anxiety, social anxiety disorder and other anxiety disorders.
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 Metoprolol Contd
Pharmacokinetics
Bioavailability 50%
Protein binding 12%
Metabolism Liver via CYP2D6, CYP3A4
Biological half-life 3-7 hours
Excretion Kidney
Adverse effects
dizziness, drowsiness, fatigue, diarrhea, unusual
dreams, ataxia, trouble sleeping, depression, and
vision problems.
Reduce blood flow to the hands and feet, causing
feel numb and cold.
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 Metoprolol Contd
High penetration across the blood-brain barrier,
lipophilic cause sleep disturbances such as
insomnia and vivid dreams and nightmares.
Serious symptoms of bradycardia (dizziness,
fainting and unusual fatigue, bluish discoloration of
the fingers and toes, numbness, tingling, swelling of
the hands or feet.
sexual dysfunction impotence, hair loss, mood
changes, depression, trouble breathing, cough,
dyslipidemia and increased thirst.

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 Metoprolol Contd
Precautions
It may worsen the symptoms of heart failure in some
patients, who may experience chest pain or
discomfort, dilated neck veins, extreme fatigue,
irregular breathing, an irregular heartbeat, shortness
of breath, swelling of the face, fingers, feet, or lower
legs, weight gain, or wheezing

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 Carvedilol

Mechanism of action
It reversibly binds to beta adrenergic receptors on
cardiac myocytes.
Inhibition of these receptors prevents a response to
the sympathetic nervous system, leading to
decreased heart rate and contractility.
This action is beneficial in heart failure patients
where the sympathetic nervous system is activated
as a compensatory mechanism.

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 Carvedilol Contd
Blockade of 1 receptors causes vasodilation of
blood vessels, lead to decreased PVR &
antihypertensive effect.
There is no reflex tachycardia response due to
its blockade of 1 receptors on the heart
Medical use
Used in congestive heart failure commonly adjunct
to ACE inhibitors and diuretics.
It reduces mortality &hospitalizations in CHF
patients.
It also used in treatment of hypertension either
alone or with other anti-hypertensive agents
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 Carvedilol Contd
Pharmacokinetics
Bioavailability 2535%
Protein binding 98%
Metabolism Liver (CYP2D6, CYP2C9)
Biological half-life 710 hours
Excretion Urine (16%), Feces (60%
Side effects
Dizziness, fatigue, low blood pressure, diarrhea,
weakness, slowed heart rate and weight gain.

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 Carvedilol Contd
Contraindications
It should not be used in people with bronchial
asthma or bronchospastic conditions.
It should not be used in people with second- or
third-degree AV block, sick sinus syndrome, severe
bradycardia (unless a permanent pacemaker is in
place), or a decompensated heart condition.
People with severe hepatic impairment are also not
advised to take it.

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Angiotensin Converting enzyme inhibitors
Human angiotensinogen Synthesized in the liver is
453 amino acids long, but other species have
angiotensinogen of varying sizes.
The first 12 amino acids are the most important for
activity.
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-...
Angiotensin I is formed by the action of
renin(synthesized in the kideny) on angiotensinogen.
Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu | Val-Ile-...
Renin cleaves the peptide bond between the leucine
(Leu) and valine (Val) residues on angiotensinogen,
creating deca peptide angiotensin I.
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 ACEIs Contd
Renin is produced in the kidneys in response to renal
sympathetic activity, decreased intrarenal BP
(<90mmHg systolic BP ) at the juxtaglomerular cells,
or decreased delivery of Na+ and Cl- to the macula
densa. If less Na+ is sensed by the macula densa,
renin release by juxtaglomerular cells is increased.
Angiotensin I is converted to angiotensin II (AII)
through removal of two C-terminal residues by the
enzyme angiotensin-converting enzyme (ACE),
primarily through ACE within the lung (but also
present in endothelial cells and kidney epithelial
cells) Asp-Arg-Val-Tyr-Ile-His-Pro-Phe | His-Leu
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 ACEIs Contd
Angiotensin II increases BP by stimulating the Gq
protein in vascular smooth muscle cells (which in
turn activates an IP3-dependent mechanism leading
to a rise in intracellular calcium levels and ultimately
causing contraction).
In addition, angiotensin II acts at the Na/H
exchanger in the proximal tubules of the kidney to
stimulate Na reabsorption and H excretion which is
coupled to bicarbonate reabsorption.
This ultimately results in an increase in blood
volume, pressure and pH.
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 ACEIs Contd
constriction of the efferent arterioles of the kidney
leads to increased perfusion pressure in the glomeruli.
It contributes to ventricular remodeling and ventricular
hypertrophy of the heart through stimulation of the
proto-oncogenes & transforming growth factor beta
(TGF-B),through fibrogenesis and apoptosis
(programmed cell death).
Stimulation by AII of the adrenal cortex to release
aldosterone which causes sodium and chloride ions
retention and potassium excretion.
Sodium is a "water-holding" ion & water is retained,
which leads to increased blood volume, hence an
increase in BP.
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 ACEIs Contd
ACE inhibitors block the conversion of angiotensin
I to angiotensin II prevent the occurrence of the
above effects and used in the treatment of
ACE inhibitors can be divided into three groups
based on their molecular structure:
Sulfhydryl-containing agents: Captopril, Zofenopril
Dicarboxylate-containing agents(largest group)
Enalapril, Ramipril, Quinapril, Perindopril,
Lisinopril, Benazepril, Imidapril, Trandolapril,
Cilazapril
Phosphonate-containing agents: Fosinopril
Naturally occurring: Casokinins, lactokinins,
lactotripeptides
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Medical use
ACEIs Contd
Acute myocardial infarction (heart attack)
Cardiac failure (left ventricular systolic dysfunction)
Kidney complications of diabetic nephropathy)
in chronic kidney failure and kidney involvement in systemic
sclerosis (hardening of tissues, as scleroderma renal crisis).
used to help decrease excessive water consumption
in schizophrenic patients with psychogenic polydipsia by
decreasing consumption (determined by urine output and
osmolality).
They are considered a head of cardiac glycosides in
chronic heart failure
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 Captopril
Medical uses
Captopril's main uses are based on its vasodilation and
inhibition of some renal function activities.
These benefits are most clearly seen in:
1. Hypertension
2. Cardiac conditions such as congestive heart failure and
after myocardial infarction
3. Preservation of kidney function in diabetic nephropathy
It has also been investigated for use in the treatment of
cancer.
Captopril stereoisomers were also reported to inhibit
some metallo - -lactamases.
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 Captopril Contd
Pharmacokinetics
Bioavailability 7075% ( is reduced by
presence of food in stomach)
Metabolism Hepatic
Biological half-life 1.9 hours
Excretion Renal

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 Captopril Contd
Adverse effects
cough due to increase in the plasma levels of
bradykinin, angioedema, agranulocytosis, proteinuria,
teratogenicity, postural hypotension, acute renal failure,
and leukopenia.
Postural hypotension occurs due to short and fast mode of action.
Hyperkalemia can occur, especially if used with other drugs which
elevate potassium level in blood, such as potassium-
sparing diuretics.
Other side effects are: Itching, Headache, Tachycardia, Chest pain,
Palpitations
rash and taste disturbances (metallic or loss of taste), which are
attributed to the unique thiol moiety.

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 Enalapril
Medical uses
used in hypertension, symptomatic heart failure,
and asymptomatic left ventricular dysfunction.
It has been proven to protect the function of the
kidneys in hypertension, heart failure, and
diabetes, and may be used in the absence of
hypertension for its kidney protective effects.
used in chronic kidney failure.
treatment for psychogenic polydipsia to
decreased water consumption (determined by
urine output and osmality) in 60% of patients.
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 Enalapril Contd
Pharmacokinetics
Bioavailability 60% (by mouth)
Metabolism liver (to enalaprilat)
Biological half-life 11 hours (enalaprilat)
Onset of action: about 1 hour
Peak effect: 46 hours
Duration: 1224 hours
Excretion kidney
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 Enalapril Contd
Side effects
increased serum creatinine (20%), dizziness (2
8%), low blood pressure (17%), syncope (2%), and
dry cough (12%).
The most serious common adverse event
is angioedema (swelling) (0.68%)
which often affects the face and lips, endangering
the patients airway.
Angioedema can occur at any point during treatment
with enalapril but is most common after the first few
doses.
Angioedema and fatality is reportedly higher among
black people.
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 Enalapril Contd
Pregnancy and breastfeeding
It is pregnancy category D, cause injury and
death to a developing fetus.
Patients are advised not to become pregnant
while taking enalapril and to notify their doctors
immediately if they become pregnant.
It may result in damage to the fetuss kidneys
and resulting oligohydramnios (not enough
amniotic fluid).
It is secreted in breast milk and is not
recommended for use while breastfeeding.
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 Fosinopril

Medical uses
congestive heart failure, the ability of the heart
to pump enough blood to satisfy the
physiological needs of the body is reduced.
CHF has a variety of causes, including
damaged heart valves, myocardial infarction,
hypertension, vitamin B1 deficiency, and
genetic mutations
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 Fosinopril Contd

Pharmacokinetics
Bioavailability ~36%
Protein binding 87% (fosinoprilat)
Metabolism hepatic, GIT mucosa (to
fosinoprilat)
Biological half-life 12 hours (fosinoprilat)
Excretion renal

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ACE inhibitor equivalent doses in hypertension
They have different strengths with different starting dosages.
Dosage should be adjusted according to the clinical response

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