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Diuretics and Drugs used in

cardiovascular diseases

Khanh Doan, Pharmacist, Ph.D

Objectives

 By the end of this course, the students are able to:

 Remember the agents of the following classes:
• Diuretics
a-blockers
b-blockers
• Calcium-channel blockers (CCBs)
• Angiotensin-converting enzyme inhibitors (ACEIs)
• Angiotensin receptor blockers (ARBs)
• Anti-arrhythmic agents
 Explain the mechanisms of action, pharmacological
effects, clinical uses, contraindications, side effects of the above
classes of drugs.
 Describe the important pharmacokinetic characteristics and drug
interactions of drugs used in cardiovascular diseases.

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Cardiovascular system

Cardiovascular system

 The heart:
 Myocardial cells (require oxygen)
 Nodes and electric conduction system (the rate and the rhythm)
 System of blood vessels:
 Arterioles (capillaries) and Veins
 Has limited volume capacity (vascular volume)
 Regulatory systems:
 Autonomic nervous system (sympathetic and parasympathetic)
 Kidney
 Renin-angiotensin-aldosterone system (RAAS)

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Regulation of cardiovascular function

ANS in control of cardiovascular function

Source: http://doctorlib.info/pharmacology/pharmacology/21.html

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Renin-angiotensin-aldosterone system (RAAS)

Angiotensin function is required for the development of normal kidney morphology!

(the maturational growth of the renal papilla)
https://en.wikipedia.org/wiki/Angiotensin

Cardiovascular disorders

 Arrhythmias:
 Tachycardia: atrial fibrillation, supraventricular tachycardia,
ventricular tachycardia, ventricular fibrillation.
 Bradycardia: heart block/arrest, asystolic arrest.

 Ischemic heart disease:

 Angina (chest pain):
• Myocardial cells are not getting enough oxygen.

 Myocardial infarction:
• Myocardial cells of oxygen-starved areas begin dying.

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Cardiovascular system and its disorders

 Hypertension:
 Mean Arterial pressure = Cardiac output x Vascular resistance
• Cardiac output: heart rate, myocardial contractility and vascular volume.
• Vascular resistance: diameter of the blood vessels, vascular volume.

 Heart failure:
 The heart does not pump enough blood to meet the metabolic
demands of the body.

Cardiovascular disorders

 Vascular occlusion:
 Atherosclerosis:
 Thrombosis:

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Ischemic heart disease

Ischemic heart disease

http://medicalassessmentonline.com/terms.php?R=24&L=A

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Heart failure

Anti-hypertensive drugs

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Hypertension_Pathogenesis

GRA:Glucocorticoid-remediable Aldosteronism AME:apparent mineralocorticoid excess

Ann Intern Med.2003;139:761-776.

Hypertension_Stages

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Hypertension_Complications

Goal BP

AHA, American Heart Association;

JNC-7, The Seventh Report of the Joint National Committee on Detection,
Evaluation, and Treatment of High Blood Pressure.

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Anti-hypertensive drugs:
1. Sympatholytic agents.
 b-blockers.
 a1-blockers.
2. Direct vasodilators.
 Calcium-channel
blockers (CCB).
 NO-releasing agents.
3. Agents target RAAS.
• ACE inhibitors.
• ARBs.
4. Diuretics.

Direct vasodilators

4) Hydralazine

1) CCBs
3) Fenodopam

K+-channel
5) Minoxidil

2) Nitrates, Nitroprusside
CM: Calmodulin
MLCK: Myosin light chain kinase
MLCP: Myosin light chain phosphatase
SR: sarcoplasmic reticulum (endoplasmic reticulum of smooth muscle cells)

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GC*: activated guanylyl cyclase;

MLCK*, activated myosin light-chain kinase
PDE, phosphodiesterase;
eNOS, endothelial nitric oxide synthase

Renin-angiotensin-aldosterone system (RAAS)

Angiotensin function is required for the development of normal kidney morphology!

(the maturational growth of the renal papilla)
https://en.wikipedia.org/wiki/Angiotensin

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Renin activation

PRR: prorenin receptor

Angiotensin-converting enzyme (ACE)

ACE = Kininase II

http://eurheartjsupp.oxfordjournals.org/content/9/suppl_E/E2.article-info

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Inhibitors of RAAS

Drugs that interfere with the RAAS play a critical role

in the treatment of cardiovascular disease.

Renal regulation of vascular volume & Diuretics

(glucose, amino acids, 60% H2O,
65% Na+, 85% NaHCO3, 65% K+, 70% Ca2+, 20-25% Mg2+, 80% PO43-)

(10% Na+, 5% Ca2+, 5% Mg2+)

(25% Na+, 15-25% K+,

25% Ca2+, 60% Mg2+)

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Hypertension treatment guideline

1. Diuretic agents

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Classification
1. Osmotic diuretics:
 Manitol, Glycerine, Isosorbide
2. Carbonic anhydrase (CA) inhibitors:
 Acetazolamide, Methazolamide, Dichlorphenamide
3. Loop diuretics:
 Furosemide, Torsemide, Bumetanide, Ethacrynic acid
4. Thiazides:
 Hydrochlorothiazide, Indapamide, Chlorthalidon, Metolazone
5. K+-sparing diuretics:
 Amelorid, Triamteren
 Spironolacton, Eplerenone (aldosterone antagonists)
6. Natriuretic peptides (NPs):
 ANP (atrial-derived), BNP (brain-derived), CNP (C-type)
7. Anti-diuretic hormone (ADH) antagonists
 Tolvaptan, Conivaptan, Mozavaptan, Lixivaptan

Mechanisms of action of diuretics

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Disadvantage of diuretics

 Compensatory mechanisms (diuretic braking):

 Activate the sympathetic nervous system and RAAS.

 Result in renal epithelial cell hypertrophy.

 Increase renal epithelial transporter expression.

 Alter natriuretic hormones.

 EXCEPT with aldosterone antagonists.

Thiazide diuretics

Therapeutic uses:
 Widely used in the treatment of mild heart failure
and hypertension.
Adverse effects:
 Potassium depletion (hypokalemia).
 Impaired glucose tolerance, and increased serum lipid
concentrations, increased serum uric acid.
 Others: weakness, impotence and skin rashes.

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Loop diuretics

Therapeutic uses:
 Edema (pulmonary edema, moderate and severe
congestive heart failure, renal diseases, hepatic
cirrhosis)
 Hypertension.
Adverse effects:
 Hyponatraemia, hypotension, hypovolaemia.
 Hypokalaemia.
 Hypocalcinemia, hypomagnesaemia.

Potassium-sparing diuretic agents

 Therapeutic uses:
 Hypertension.
 Congestive heart failure.
• Spironolactone, Eplerenone (aldosterone antagonists) show marked
antihypertensive effect and can prolong survival in heart failure (but not with
amiloride, triamterene)
• Usually given with thiazide or loop diuretics to maintain K+ balance.

 Adverse effects:
 Hyperkalemia.
• Caution in patients with impaired renal function, concurrently taking ACEIs,
ARBs, potassium-containing supplements.

 Gynaecomastia, menstrual disorders and testicular atrophy.

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2. ACEIs/ARBs

2.1. ACEI agents

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2.1. ACEIs_Therapeutic uses

 Treatment of hypertension.
 Treatment of left ventricular systolic dysfunction.
 Treatment in acute myocardial infarction (MI).
 Used along with thrombolytics, aspirin, and β-blockers.
 Should be continued long term in high-risk patients with MI.
 Patients with high-risk of cardiovascular events.
 Patients with diabetes mellitus and renal failure.
 Reno-protective effects, decrease the progression of retinopathy
and renal insufficiency .

2.1. ACEIs_Adverse effects

 Hypotension.
 Cough.
 Hyperkalemia.
 Caution in patients with renal insufficiency, concurrently taking K+-
sparing diuretics, K+ supplements, β receptor blockers, or NSAIDs.
 Acute renal failure.
 Bilateral renal artery stenosis, heart failure (acute or severe), volume
depletion.
 Fetopathic effects: ACEIs are contraindicated in pregnancy.
 Angioedema.
 Skin rash.

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2.2. Angiotensin receptor blockers (ARBs)

AT1 receptor affinity:

CandeSARTAN = OlmeSARTAN
> IrbeSARTAN = EproSARTAN
> TelmiSARTAN = ValSARTAN
> LoSARTAN

ARBs versus ACEIs

 The BP-lowering effect of ARBs is comparable with that of ACEIs.

 The pharmacological differences between ARBs and ACEIs result in
significant differences in therapeutic outcomes is an open question.
 ARBs reduce activation of AT1 receptors more effectively than ACEIs.
 ARBs permit activation of AT2 receptors.
 ACEIs may increase levels of other ACE-independent angiotensin-converting
products more than ARBs.

 ARBs DO NOT affect levels of ACE substrates, including bradykinin.

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2.2. ARBs_ Therapeutic uses

 Treatment of hypertension
 Losartan are approved for diabetic nephropathy, LVH due to hypertension.
 Valsartan is approved for congestive heart failure, left ventricular
dysfunction.

 Reno-protection in diabetic patients (drugs of choice)

2.2. ARBs_ Adverse effects

 NOT induce cough and less angioedema than ACEIs.

 Teratogenic potential similar to ACEIs
 Other side effects are similar to ACEIs: hypotension,
hyperkalemia, oliguria, progressive azotemia, or acute
renal failure.

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2.3. Direct renin inhibitors_ Aliskiren

t1/2 is very long (20-45 hours).

Eliminated via feces, NOT via urine.

 Treatment of hypertension.
 Protection against end-organ damage
in CVDs and renal diseases.

Long- term advantages and adverse reactions still need to be established !

(FDA approved in 2007)

3. Calcium channel blockers

(CCBs)

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3. CCBs_ Mechanism of action

SA: sinoatrial node

AV: atrioventricular node

3. CCBs agents

Cardiac Suppression of Suppression of

Generic name Vasodilation contractility automaticality cardiac conduction
suppression (SA node) (AV node)
Dihydropyridines (DHP)
Amlodipine 5 1 1 0
Felodipine 5 1 1 0
Nicardipine 5 0 1 0
Nifedipine 5 1 1 0
Non-DHPs
Diltiazem 3 2 5 4
Verapamil 4 4 5 5

All of CCBs agents are extensively metabolized by hepatic CYP450 3A4 !

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3. CCBs_ Therapeutic uses

 Treatment of hypertension.
 Variant and effort-induced angina.
 Tachy-arrhythmias (only verapamil and diltiazem).

 Myocardial infarction (only verapamil and diltiazem).

 DHPs have NO BENEFIT in treatment or prevention of acute MI, and
even increase mortality.
 Raynaud’s disease (symptoms relief)
 Other indications:
 Verapamil for prophylaxis of migraine.
 Nicardipine for cerebral vasospasm associated with stroke.

3. CCBs_ Adverse effects

 Headache, flushing, dizziness, and peripheral edema.

 Reflex tachycardia.
 Short-acting agents like nifedipine, felodipine,… especially with
immediate-release formulations.
 Amlodipine with slow absorption and long t1/2 (35-50 hours)
DOES NOT cause these adverse effects.
 Constipation (verapamil), gastroesophageal reflux.
 Cardiac depression (verapamil and diltiazem)
 Caution in patients concurrently receiving b-blockers.

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4. Other vasodilating agents

NO-releasing agents (Nitroprusside, organic nitrates)

Hydralazine, Minoxidil, Fenodopam

4) Hydralazine

1) CCBs
3) Fenodopam

K+-channel
5) Minoxidil

2) Nitrates, Nitroprusside
CM: Calmodulin
MLCK: Myosin light chain kinase
MLCP: Myosin light chain phosphatase
SR: sarcoplasmic reticulum (endoplasmic reticulum of smooth muscle cells)

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4.1. Nitroprusside

 Unstable and sensitive to light.

 Release NO and CN- (immediately metabolized to SCN-(NO toxic).
 Very rapid onset (30s), short duration (3 mins)
 Dilates both arterial and venous vessels
 Powerfully and rapidly lowers blood pressure
 Treat hypertensive emergencies, severe congestive heart
failure, and surgical hypertension.
 Accumulation of CN- or SCN- can cause toxicity (only with high
dosing rate or prolonged use)

4.2. Fenodopam

 Selective dopamine receptor D1 agonist (Gs, cAMP).

 Rapid onset (4 mins) and short duration (< 10 mins).
 Cause dilation of peripheral arteries and natriuresis.
 Treat hypertensive emergencies and postoperative
hypertension.
 Reflex tachycardia, headache, and flushing are major side effects.

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4.3. Hydralazine

 Dilates only arterioles (NOT veins), more specifically acting on large

arterioles (coronary, cerebral, and renal circulations)
 Treat heart failure, severe hypertension and is useful in
treatment of hypertensive emergencies in pregnant women
(preeclampsia).
 Adverse effects:
 Headache, nausea, flushing, hypotension, reflex tachycardia
(may provoke angina or myocardial ischemia).
 Drug-induced lupus syndrome (serum sickness, hemolytic anemia,
vasculitis, and glomerulonephritis).
 Polyneuropathy (decrease vit. B6 absorption).
 Undergo acetylating metabolism.

4.4. Minoxidil

 Dilates arterioles (NOT veins), more specifically acting

on small arterioles (skin, skeletal muscle, the
gastrointestinal tract, and the heart)
 Reserved for treatment of severe resistant hypertension.
 Adverse effects:
 Reflex increase in heart rate, myocardial contractility, and O2
consumption due to compensatory activation of the sympathetic
nervous system.
 Hypertrichosis:  hair growth on the face, back, arms, and legs

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5. Sympatholytic agents

5.1. Centrally sympatholytic agents

Methyldopa, clonidine:

a2 receptor: Gi proteins

Methyldopa: prodrug
Clonidine: a2 agonist

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5.2. Adrenergic receptor blockers

5.2. b-blockers

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5.2. b-blockers_ Therapeutic uses

 Ischemic heart diseases (angina and myocardial

infarction).
 Congestive heart failure.
 Tachy-arrhythmias.
 Hypertension.
 Other clinical uses:
 Glaucoma (open-angle)
 Hyperthyroidism (propranolol, metoprolol)
 Prophylaxis of migraine (propranolol, metoprolol)
 Anxiety, benign essential tremor (propranolol)

5.2. b-blockers_Adverse effects

 Bradycardia, cardiac depression.

 Bronchoconstriction.
 Blunt hypoglycemic response
 Fatigue.
 Cold extremities.

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Drugs in Treatment of
Myocardial Ischemic disease

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Ischemic heart disease

Coronary heart disease:

 Atherosclerosis: plaque, blood clot = thrombosis
(platelet)
 Dislipidemia.

Source:
https://en.wikipedia.org/wiki/Angina_pectoris
http://nursingcrib.com/nursing-care-plan/nursing-care-plan-myocardial-infarction/

Ischemic heart disease

http://medicalassessmentonline.com/terms.php?R=24&L=A

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Ischemic heart disease

 Myocardial infarction (MI):

 ST-segment elevation myocardial infarction (STEMI)
 Non ST-segment elevation myocardial infarction (NSTEMI)
 Acute coronary syndrome:
 = Unstable angina and acute MI

STEMI vs NSTEMI

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Principle of pharmacotherapy in ISHD

Management of dislipidemia Prevention of blood clot

(statins, ezetimibe, fibrates, niacin,…) (anti-platelet Rx: Aspirin, Clopidogrel)

Drugs used in treatment of ISHD

 Restore blood flow:

 Thrombolytic therapy: heparin, enoxaparin, fondaparinux, alteplase
 Percutaneous coronary intervention (formerly known as angioplasty),
coronary artery bypass surgery
 Prevent blood clot by anti-platelet therapy:
 Aspirin
 Clopidogrel/ Prasugrel/ Ticagrelor
 Release/control chest pain (angina) and prophylaxis treatment:
 Organic nitrates
 Beta-blockers
 Calcium channel blockers (CCBs)
 Ranolazine (acts on cardiac myocyte Na+ channels)
 Decrease recurrent myocardial infarction and mortality:
 Statins, ezetimibe, …(manage dislipidemia)
 ACEIs/ARBs, b-blockers, anti-platelet therapy

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1. Organic nitrates
Nitroglycerine
Isosorbide di-nitrate
Isosorbide mono-nitrate

1.1. Nitrates_ Agents

Generic name Dosage formulations

Nitroglycerine • Oral tablets/ capsules (immediate or sustained-release),
(Glycerine • Sublingual tablets.
trinitrate) • Lingual spray, transdermal patch, buccal (transmucosal)
tablets, ointments.
• I.V solutions.
Isosorbide • Sublingual tablets,
di-nitrate • Oral tablets/ capsules (immediate or sustained-release)
Isosorbide mono- • Sublingual tablets,
nitrate • Oral tablets/ capsules (immediate or sustained-release)

 Very low bioavailability with oral dosage forms (<10-20%) due to high
first-pass metabolism (except isosorbide mono-nitrate)
 Undergo extensively hepatic metabolism.

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Mechanism of action

1.2. Nitrates_ Therapeutic uses

 Stable angina (help to relieve/prevent chest pain)

 Unstable angina and acute myocardial infarction,
NSTEMIs (help to relieve ischemic pain, NOT improve
mortality in myocardial infarction)

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1.2. Nitrates_ Adverse effects

 Headache, dizziness, postural hypotension, reflex tachycardia.

 High doses cause methemoglobin, which may result in tissue
hypoxia and death.
 Tolerance
 Frequently repeated/ continuous exposure to high doses leads to
marked decrease of pharmalogical effects.
 An interruption of therapy for 8-12 hours/day helps to restore the
responsiveness.
 Use together with PDE5 inhibitors (sildenafil, tadanafil,
vardenafil) causes extreme and life-threatening hypotension.
 May produce nitrosamines which cause carcinogenicity (no available
evidence)

2. b-blockers
The most extensive, favorable clinical trial data are available for
Propranolol, Metoprolol, and Timolol.

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3. Calcium channel blockers (CCBs)

SA: sinoatrial node

AV: atrioventricular node

4. Trimetazidine

J Am Coll Cardiol. 2009;54(18):1637-1646. doi:10.1016/j.jacc.2009.07.024

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5. Ranolazine

Ranolazine are only the second-line treatment in chronic angina (stable angina)

Scientific Reports 5: 17969 (2015). doi:10.1038/srep17969

Drugs in Treatment of Congestive

Heart Failure

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Heart failure (HF)

Heart failure (HF)

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Stages of HF

NYHA: New York Heart Association

LVD: Left Ventricular Dysfunction
HF: Heart Failure

Management of Heart Failure

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Management of Heart Failure

Drugs used in Heart failure

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Drugs used in Heart failure

1. ACEIs/ ARBs:
 ACEIs are drugs of choice for initial therapy in HF, which
are proved to reduce morbidity and mortality in patients
with HF, especially those with LVH.
 ARBs were shown to be as effective as ACEIs in HF
treatment, however, FDA has been currently approved
only candesartan and valsartan for the treatment of HF.
 Losartan has also been widely used but is not approved by FDA.

Drugs used in Heart failure

2. b-blockers:
 β-blockers are considered first-line agents in combination
with ACEIs in treatment of HF.
 Improve quality of life, decrease hospitalizations, and decrease
mortality.
 Metoprolol succinate and carvedilol are FDA-
approved b-blockers for use in HF.
 Bisoprolol has also been used but is not approved by
FDA for treatment of HF.

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Drugs used in Heart failure

3. Diuretics:
 Reduce edema and symptoms of congestive HF.
 Loop diuretics (furosemide, bumetanide, torsemide) are
preferred.
 Aldosterone antagonists (spironolactone, eplerenone)
are proved to decrease morbidity and mortality in severe
HF.

Drugs used in Heart failure

4. Vasodilators:
 Hydralazine/Isosorbide dinitrate combination is approved by
FDA for treatment of HF in patients who cannot tolerate
ACEIs/ARBs.
 All of CCBs agents are NOT approved by FDA to treat HF.
 Verapamil and diltiazem are safe to use and may improve symptoms in
patients with HF.
 Amlodipine and felodipine have minimal beneficial effect of improved
survival in HF.
 Other DHP CCBs (other than amlodipine, felodipine) are
CONTRAINDICATED in patients with HF.

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Drugs used in HF

5. Digoxin
(digitalis glycosides)
- Positive inotropic effect
 enhance myocardial
contractility
- ↓ the conduction velocity.
-  the refractory period of the
AV node.
 slow the ventricular
response rate

K+ and digoxin compete each

other to bind to Na+,K+ATPase !

5. Digoxin

Therapeutic uses:
 Limitedly used in congestive HF patients with left
ventricular systolic dysfunction despite maximal
therapy with ACEIs and β-blockers.
 Treat supraventricular arrhythmias including atrial
fibrillation.
 Narrow therapeutic range (1-2 ng/mL)
• Optimal serum levels: 0.5 -1 ng/mL

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5. Digoxin

Pharmacokinetics:
 Accumulated in the skeletal muscle.
 Excreted by the kidney (NOT well removed by
hemodialysis).
 t1/2 is very long, 36-48 hours.
 Dosing should be based on the renal function,
lean mass.

5. Digoxin

Toxicity:
 Sinus bradycardia, sinoatrial arrest, ventricular
arrhythmias (ventricular tachycardia and fibrillation).
 CNS and GI symptoms including anorexia, nausea,
vomiting and diarrhea.
 Digoxin immune Fab is an antidote for treating
life-threatening digoxin’s overdose toxicity.
 Ca2+ increases, but Mg2+ decreases digoxin’s effects .

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6. Other agents used in HF

 Dopamine
 Dobutamine (b1 agonist)
 Milrinone (PDE inhibitors)
 Nesiretide (Brain natriuretic peptide, BNP)
 -vaptan drugs (ADH or vasopressin antagonists)
 Mozavaptan, Tolvaptan, Conivaptan, Lixivaptan
 Only used in treatment of acute decompensated
congestive HF.

Antidiuretic hormone (ADH, vasopressin)

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ADH (vasopressin) antagonists

 Mozavaptan (only in Japan):
 Tolvaptan:
 Conivaptan (IV only):
 Lixivaptan:
 Used to treat hyponatremia
in syndrome of
inappropriate ADH
secretion (SIADH),
congestive heart failure.

Natriuretic peptides
Inner medullary collecting duct
 Atrial natriuretic peptide (ANP):
Carperitide

 Brain natriuretic peptide (BNP):

Nesiretide
 Used to treat acute decompensated
congestive heart failure.

CNGC: cyclic nucleotide gated cation (CNG)

channel

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Anti-arrhythmic drugs

The heart physiology

Cardiac rate and rhythm

Cardiac contraction
Myocardial oxygen consumption and coronary
blood flow.

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Cardiac rate and rhythm

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Cardiac rate and rhythm

Cardiac rate and rhythm

Sinoatrial (SA) node, atrioventricular (AV) node

 Slow-response cells
His-Purkinje system (bundle of His, Purkinje
fibres), cardiac muscle cells
 Fast-response cells

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Cardiac electrophysiology
Fast-response cells Slow-response cells

- Long-action potential (plateau) phase - Pacemaker activity

(influx of Ca2+) - Absence of fast Na+ current
- Refractory period in the plateau phase (slow inward Ca2+ current initiates
action potentials)

Refractory period

ADP: Action potential duration

ERP: Effective refractory period
RRP: Relative refractory period

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Mechanisms of arrhythmias

Abnormal impulse generation:

 Enhanced automaticity
• Due to increased phase 4 slope
 Triggered automaticity (after-depolarizations)
Abnormal impulse conduction:
 Anatomically defined re-entry
• Wolff–Parkinson–White (WPW) syndrome
 Functionally defined re-entry

Abnormal impulse generation

After-depolarizations:

Delayed afterdepolarization (DAD) Early afterdepolarization (EAD)

DADs caused by digitalis EADs caused by hypokalemia, QT
or catecholamines prolongation caused by
antiarrhythmic drugs (class IA and III),
slow stimulation rate

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Abnormal impulse conduction

Wolff–Parkinson–White (WPW) syndrome:

An accessory atrioventricular (AV)

connection is present (light blue)

Abnormal impulse conduction

Functionally defined re-entry:

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Classification of cardiac arrhythmia

Classification bases on:

 The site of origin of the abnormality: atrial, junctional or
ventricular.
 Increased rate (tachycardia):
 Atrial fibrillation (AF): heartbeat is completely irregular
 Supraventricular tachycardia (SVT): heartbeat is rapid but regular
 Ventricular tachycardia
 Ventricular fibrillation
 Decreased rate (bradycardia):
 Many types of heart block: sinus bradycardia, sinus arrest, sick
sinus syndrome, AV block, asystolic arrest,…

EKGs of normal and abnormal cardiac rhythms

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Anti-arrhythmic drugs

 Class I: Fast sodium (Na) channel blockers (depress phase 0)

 IA - Quinidine, procainamide, disopyramide
 IB - Lidocaine, mexiletine
 IC - Flecainide, propafenone, moricizine
 Class II: Beta blockers
 Propranolol, Esmolol, Timolol, Metoprolol, Atenolol.
 Class III: Potassium (K) channel blockers
 Amiodarone, Sotalol, Ibutilide, Dofetilide
 Class IV: Slow calcium (Ca) channel blockers
 Verapamil, Diltiazem
 Class V: Miscellaneous mechanisms
 Digoxin, Adenosine, Magnesium sulfate

Blocking of Na+ channels by

Class I anti-arrhythmic agents

Quinidine, Procainamide
(Class IA)

Flecainide, propafenone
(Class IC)

Lidocaine
(Class IB)

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Anti-arrhythmic mechanism of b-blockers and

calcium channel blockers

Anti-arrhythmic mechanism of b-blockers

and calcium channel blockers

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Multiple anti-arrhythmic mechanisms of

Amiodarone

K+ channel blocker

Na+ channel blocker
Non-selective b-blocking properties
Calcium channel antagonism (weak)
 mimics classes I, II, III, and IV

Anti-arrhythmic mechanism of Adenosine

Xanthines (caffeine, theophylline)

BLOCK

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Anti-arrhythmic mechanism of Mg2+

Mechanisms are not known.

 Magnesium has been recognized to influence
Na+/K+-ATPase, sodium channels, potassium
channels, and calcium channels.

Anti-arrhythmic drugs

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Anti-arrhythmic drugs_Adverse effects

 Antiarrhythmics can cause arrhythmia!

(biggest problem)
 Example: Treatment of a non-life threatening tachycardia may
cause fatal ventricular arrhythmia.
 Must be extremely cautious in determining dosing, blood levels,
and in follow-up when prescribing antiarrhythmics.

Pacemakers

 Surgical implantation of electrical leads attached to a

pulse generator.
 Pulse generator can sense electrical activity generated
by the heart and only deliver electrical impulses when
needed.
 Pacemakers can only speed up a heart experiencing
bradycardia, they cannot alter a condition of
tachycardia.

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Anti-arrhythmic drugs_Adverse effects

 Quinidine:
 Cinchonism (diarrhea, nausea, tinnitus, visual changes,
dizziness, headache), mostly due to muscarinic receptor block.
 Hypotension
 Prolong QT interval, torsades de pointes
 Thrombocytopenia, hemolytic anemia
 Drug interactions (many agents):
• Displace digoxin from binding sites   digoxin’s toxicity
• Hyperkalemia increases quinidine’s toxicity
• Drugs altering hepatic CYP450s function affect quinidine metabolism

Anti-arrhythmic drugs_Adverse effects

 Procainamide:
 Systemic lupus erythematosus (SLE)–like syndrome
• More likely with slow acetylators (procainamide is metabolized via acetylation)

 Hypotension.
 QT prolongation, torsades de pointes
 Hematotoxicity: thrombocytopenia, agranulocytosis
 Hypersensitive reactions: skin rash, fever.
 GI disturbances
 Less muscarinic receptor block compared to quinidine.

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Anti-arrhythmic drugs_Adverse effects

 Flecainide:
 Pro-arrhythmogenic effects cause sudden death
(  limited use)
 CNS effects (blurred vision, drowsiness, lightheadedness)
 GI upset (nausea and vomitting)

Anti-arrhythmic drugs_Adverse effects

Amiodarone:
 t1/2 extremely long (15 –100 days), large Vd,
extensively metabolized by liver (99%)
• Slow onset of action (oral administration)
• Large total loading doses required (10 grams)
• High potential of drugs interaction
 Side effects:
• Pulmonary fibrosis
• Blue pigmentation of the skin (“blue‐gray” skin = “smurf skin”)
• Thyroid dysfunction: hypothyroidism (6%) due to T4T3 inhibition,
hyperthyroidism (1%)
• Corneal microdeposits
• Increased hepatic enzymes, hepatitis (rare)
• Bradycardia, torsades de pointes (rare), hypotension (I.V)

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From Knowledge to The Star

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