Transcript Nursing 220: Pharmacology Module II: Cardiovascular Drugs

Drugs in Cardiovascular system
Overview
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Anti-Hypertension Drugs
Vasodilators
Cardiac Glycosides
Antidysrhythmic
Medications
Anticoagulants
Antiplatelets
Fibrinolytic drugs
Antifibrinolytic drugs
Lipid regulating drugs
Blood pressure = CO × SVR
• CO = cardiac output
• SVR = systemic vascular resistance
Hypertension = high blood pressure
Four stages, based on BP measurements
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Normal
Prehypertension
Stage 1 hypertension
Stage 2 hypertension
Table 24-1 Classification and Management of Blood Pressure
Mosby items and derived items ©
2005, 2002 by Mosby, Inc.
Classification of BP
Hypertension can also be defined by its
cause
• Unknown cause
– Essential, idiopathic, or primary hypertension
– 90% of the cases
• Known cause
– Secondary hypertension
– 10% of the cases
Figure 24-1 Normal regulation of blood pressure and corresponding
mechanisms.
Mosby items and derived items ©
2005, 2002 by Mosby, Inc.
• High diastolic BP (DBP) is no longer
considered to be more dangerous than
high systolic BP (SBP)
• Studies have shown that elevated SBP is
strongly associated with heart failure,
stroke, and renal failure
• Thiazide-type diuretics should be the initial
drug therapy for most patients with
hypertension (alone or with other drug
classes)
• The previous labels of “mild,” “moderate,”
and “severe” have been dropped
Anti-Hypertensive Drugs
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Diuretics
ACE Inhibitors
Calcium Channel Blockers
Sympatholytics (Adrenergic Antagonists)
– Beta-Adrenergic Blockers
– Alpha1 Blockers
– Alpha/Beta Blockers
– Centrally Acting antihypertensives
– Adrenergic Neuron Blockers
Diuretics
• Diuretics are drugs that increase renal
excretion of water, sodium & other
electrolytes, thereby increasing urine
formation & output
• Used in the management of heart failure,
renal & hepatic disease, hypertension
Thiazide diuretics:
• Decrease reabsorption of Na, water, Cl &
bicarbonate in the distal convoluted tubule
• Hydrocholorothiazide
• Indapamide
• Contraindicated in severe renal and hepatic
impairment, hypokalaemia, hyponatraemia
• Side effects are postural hypotension,
hyperglycemia
Loop Diuretics:
• Inhibit Na & Cl reabsorption in the ascending loop
of Henle
• Frusemide
• Bumetanide
• CI : renal failure with anuria
• SE: hyponatraemia
Potassium-Sparing Diuretics:
• Act directly on the distal tubule to decrease
the exchange of Na for K
–Amiloride
–Triamterene
• Spironolactone
–Block the Na-retaining effects of
aldosterone in the distal tubule
• CI: hyperkalaemia, renal failure
• SE: dry mouth, rashes, with
spironolactone gynaecomastiya can occur
ACE Inhibitors
– There are 2 families of drugs:
• Angiotensin-converting enzyme (ACE)
inhibitors
–Block the enzyme (ACE) that
normally converts angiotensin I to
angiotensin II
–Decrease vasoconstriction &
decrease aldosterone production,
reducing retention of Na and water
• Used to treat hypertension, heart failure, myocardial
infarction, and nephropathy
–Enalapril
–Captopril
–Lisinopril
• Side Effects:
–Can produce serious first-dose hypotension
–Cough, due to accumulation of bradykinin
–Hyperkalaemia, due to inhibition of aldosterone
release
•CI: In hypersensitivity to drug
Angiotensin II receptor blockers (ARBs)
–Compete with angiotensin II for tissue binding
sites & prevent angiotensin II from combining
with its receptors in body tissues
–Used for hypertension, may be used as an
alternative to ACE inhibitors in the management
of heart failure and diabetic nephropathy.
»Irbesartan
»Losartan
»Valsartan
• Side-effects
–Hypotension
–Less likely to cause cough and
hyperkalaemia than ACE inhibitors
ACE inhbitors and Angiotensin II receptor
antagonists may cause first dose
hypotension
Calcium Channel Blockers
• Drugs the prevent calcium ions from
entering cells
• Vascular Smooth Muscle:
– Calcium channels regulate contraction
– If channels are blocked, contraction will be
prevented and vasodilation will result
– Act selectively on peripheral arterioles and
arteries and arterioles of the heart (no effect
on veins)
Calcium Channel Blockers
• Heart:
– Regulate function of myocardium, SA & AV
nodes.
– Myocardium
• Positive inotropic effect (increases force of
contraction)
• Calcium is blocked, contractile force will
diminish
– SA Node:
• Pacemaker activity regulated by calcium
influx
• Calcium is blocked, heart rate is reduced
– AV Node:
• Excitability of AV nodal cells is regulated by
calcium entry
• Calcium is blocked, discharge of Av nodal
cells is suppressed (decreases the velocity
of conduction through the AV node).
Calcium Channel Blockers
• Three chemical families in CCB’s
• Verapamil:
– Blocks calcium channels in blood vessels and
in the heart
– Used for:
• Angina Pectoris (vasodilation)
• Hypertension
• Cardiac dysrhythmias
– Careful administration/contraindications:
• Cardiac failure, AV block, sick sinus
syndrome
• Diltiazem: similar to Verapamil
• Nifidipine
- Relaxes vascular smooth muscle and
dilates coronary and peripheral arteries
- More effect on vessels less on
myocardium
– Used for:
• Prophylaxis of Angina Pectoris
(vasodilation)
• Hypertension
– Careful administration/contraindications:
• Cardiac shock, advanced aortic
stenosis, within one month of MI,
acute attack of angina
Sympatholytics
(Adrenergic Antagonists)
• Suppress the influence of the sympathetic
nervous system on the heart, blood
vessels, and other structures
• Five Subcategories:
– Beta blockers
– Alpha1 blockers
– Alpha/beta blockers
– Centrally acting antihypertensives
– Adrenergic neuron blockers
Beta-Adrenergic Blockers
• Most widely used antihypertensive drugs
• Four useful actions in hypertension:
– Blockade of cardiac beta1 receptors
• Decreases heart rate and contractility
(decreases cardiac output)
• Suppress reflex tachycardia caused by
vasodilators in the regimen
• Blockade of beta1 receptors on
juxtaglomerular cells of kidney reduce
release of renin
–Reduces Angiotensin II vasoconstriction,
aldosterone mediated volume expansion
• Long term use reduces peripheral vascular
resistance
– Adverse effects:
• Bradycardia, decreased AV conduction,
reduced contractility
– Contraindicated:
• Sick sinus syndrome/ AV blocks/ asthma
(bronchoconstrictive effects)
Beta-Adrenergic Blockers
• Two subgroups:
– Nonselective Beta Blockers (Propanolol Beta1
& Beta2)
• Reduce heart rate, decrease force of
ventricular contraction, suppress impulse
conduction through the AV node, suppress
secretion of renin, bronchoconstriction,
inhibition of glycogenolysis.
– Cardioselective Agents (Metoprolol-Beta1
only)
• Same as nonselective except it does not
block bronchial beta2 receptors so does not
increase airway resistance.
Non selective Beta blockers
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Propranolol hydrochloride
Sotalol
Timolol
Pindolol
Levobunolol
Nadolol
Metipranolol
Cardioselective Beta blockers
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Atenolol
Acebutolol
Metoprolol
Bisoprolol
Esmolol
Betaxolol
Nebivolol
Alpha1 Blockers
• Prevent stimulation of alpha1 receptors on
arterioles and veins, thereby preventing
sympathetically mediated vasoconstriction.
• Resultant vasodilation results in lowered blood
pressure
• Blockade of Alpha1 receptors can cause
orthostatic hypotension, reflex tachycardia.
– 1% of patients lose consciousness 30-60
minutes after receiving their first dose
– NOT be used as first line therapy for
hypertension.
Alpha1 Blockers
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Prazocin
Doxazosin
Indoramin
Terazosin
Alpha/Beta Blockers
• Block Alpha1 and Beta receptors
• Blood pressure drops:
– Alpha1 blockade promotes dilation of
arterioles/veins
– Blockade of cardiac beta1 receptors reduced
heart rate and contractility
– Blockage of beta1 receptors on
juxtaglomerular cells suppresses release of
renin
– Reduce peripheral vascular resistance
• Watch for:
– Bradycardia, AV heart block, asthma, postural
hypotension
• Prototypes: Carvedilol, Labetalol
Centrally Acting
antihypertensives
• Methyldopa
• Use for management of hypertension in
pregnancy
• Block sympathetic activity within the brain
Adrenergic Neuron Blockers
• Decrease blood pressure through actions
in the terminals of the postganglionic
sympathetic neurons.
• Inhibit/deplete norepinephrine release
– Resulting in decreased sympathetic
stimulation of the heart and blood vessels
• Watch for:
– Severe orthostatic hypotension
Adrenergic Neuron Blockers
• Guanethidine monosulphate
• Derisoquine
• Contraindicated in heart failure,
phaeochromocytoma
Vasodilators
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Hydralazine
Sodium Nitroprusside
ACE Inhibitors
Calcium Channel Blockers
Sympatholytics
Nitroglycerin
Vasodilators
• Vasodilators differ in respect to the types of
blood vessels they affect.
– Dilation of arterioles
– Dilation of veins
– Uses:
• Hypertension, Angina, heart failure,
myocardial infarction.
– Adverse Effects:
• Orthostatic hypotension caused by
relaxation of smooth muscle in veins.
(dizziness, lightheadedness)
• Reflex tachycardia places unacceptable
burden on heart, tachycardia rises blood
pressure
• Expansion of blood volume-secretion of
aldosterone—(diuretic may need to be
added)
Vasodilators
• Hydralazine
– Causes selective dilation of arterioles, has
little or not effect on veins
– Peripheral resistance and arterial blood
pressure fall
– Heart rate and myocardial contractility
increase
– Uses:
• Hypertension, heart failure
– Adverse Effects:
• Reflex tachycardia, increased blood volume
(sodium/water retention), Systemic Lupus
Erythematosus-like syndrome (muscle
pain, joint pain, fever, nephritis,
pericarditis).
Vasodilators
• Sodium Nitroprusside:
– Potent and efficacious vasodilator
– Fastest acting antihypertensive agent
available
– Causes venous and arteriolar dilation
– IV infusion, onset is immediate
– Uses:
• Hypertensive emergencies
– Adverse Effects:
• Excessive hypotension
• Thiocyanate Toxicity (patients on med
> 3 days)
– Administration:
• Degraded by light--cover
Anti anginal drugs
• Nitrates
• Calcium channel blockers
• Potassium channel activators
Nitrates
Nitrates are converted to NO in
vascular smooth muscle
NO activates guanylate cyclase
Increase formation of cGMP so that
the intracellular calcium levels
decrease
Vasodilation
• Used to treat or prevent angina
– Relieves anginal pain by relaxing
smooth muscles in the blood vessels
(vasodilation) by several mechanisms
• Dilate veins
• Dilate coronary arteries
• Dilate arterioles
– Adverse Effects
• Headache
• Orthostatic hypotension
–Symptoms include light
headedness and dizziness
• Reflex tachycardia
Examples:
• Glyceryl Trinitrate
• Isosorbide Mononitrate
• Isosorbide Dinitrate
Cardiac Glycosides
• Cardiac Glycosides:
– Profound effects on the mechanical/electrical
properties of the heart
– Most widely used prescription drugs, they are
the most dangerous (toxic—dysrhythmias)
– Prototype (Digoxin—only cardiac glycoside
available in most countries)
– Uses:
• Heart failure, dysrhythmias
Cardiac Glycoside
Digoxin
• Digoxin:
– Exerts a positive inotropic action on the heart
(increases the force of ventricular contraction,
enhancing cardiac output)
Digoxin
• Digoxin Uses:
– Heart failure:
• Increased cardiac output by increasing
myocardial contractility
–Sympathetic tone declines
»Because Digoxin increases arterial
pressure.
»Heart rate is reduced, allowing more
complete ventricular filling
–Increased urine production
»Increased cardiac output increases
renal blood flow
»Loss of water (urine) decreases blood
volume which reduces cardiac
distension, pulmonary congestion,
and peripheral edema.
–Decreased Renin Release
»In response to increased arterial
pressure, decrease in Angiotensin
Decreased aldosterone decreases
retention of sodium/water, reducing
blood volume
Digoxin
• Digoxin overall effects on CHF:
– Cardiac output improves, heart rate
decreases, heart size declines, constriction of
arterioles and veins decrease, water retention
reverses, blood volume declines, peripheral
and pulmonary edema decrease, weight is
lost, exercise tolerance improves, fatigue is
reduced.
Digoxin
• Digoxin treats dysrhythmias:
– Through a combination of actions, digoxin can
alter the electrical activity in noncontractile
tissue (SA & AV nodes, Purkinje fibers), as
well as the ventricular muscle.
Digoxin
• Toxicity:
– Dysrhythmias: AV block, ventricular flutter,
ventricular fibrillation
– Predisposing factors:
• Hypokalemia (usually secondary to the use
of diuretics)
• Elevated digoxin levels
–Narrow therapeutic range
• Heart disease
– Side Effects: anorexia, nausea, vomiting,
fatigue, visual disturbances
– Administration: Count heart rate—less than
60 or change in rhythm detected HOLD THE
DOSE AND CALL THE PHYSICIAN!
Antidysrhythmics
• Dysrhythmia (Arrhythmia):
– Defined as abnormality in the rhythm of the
heartbeat.
– Associated with high degree of
morbidity/mortality
• Types:
– Tachydysrhythmias
– Bradydysrhythmias
Antidysrhythmics
• Vaughan Williams Classification:
– Class I: Sodium Channel Blockers
– Class II: Beta Blockers
– Class III: Potassium Channel Blockers
– Class IV: Calcium Channel Blockers
– Class V: Other Antidysrhythmic Drugs
Class I: Sodium Channel
Blockers
• Sodium Channel Blockers:
– Block cardiac sodium channels
– Decrease conduction velocity in the atria,
ventricles, and Purkinje system
– Class IA agents for atrial fibrillation, flutter;
supraventricular & ventricular
tachyarrhythmias
Eg:Quinidine, procainamide
SE: tachycardia, dry mouth, urinary retention,
blurred vision
– Class IB agents for ventricular
tachyarrhythmias (VT)
Eg:Lidocaine
– Class IC for life-threatening supraventricular
tachyarrhythmias (SVT) and ventricular
tachyarrhythmias (VT)
Eg: Flecainide
These drugs will be contraindicated in
atrioventricular block
Class III: Potassium Channel
Blockers
• Potassium Channel Blockers:
– bind to and block the potassium channels that
are responsible for repolarization
•Bretylium
– For life-threatening ventricular tachycardia
and fibrillation
– can lead to hypotension
• Amiodarone
– Effective against both atrial and ventricular
dysrhythmias (only for life-threatening
because of toxicity—lung damage/visual
impairment)
Other Antidysrhythmic Drugs
• Adenosine:
– Slows conduction through the AV node
– Treats SVT
– Short plasma half life (less than 10 seconds)
• Given IVP—closest IV site to the heart,
followed by push of saline
• Digoxin
Principles of Antidysrhythmic Drugs
• Treat only if there is a clear benefit and
then only if the benefit outweighs the risks
• Treatment reduces:
– Symptoms (palpitations, angina, dyspnea,
and faintness)
– Mortality
Antidysrhythmics:
Bradydysrhythmias
• Atropine:
– Muscarinic Antagonist
• Competitively block the actions of
acetylcholine
• Stimulation of muscarinic receptors
decreases heart rate
–Blocking these receptors will INCREASE
heart rate
• Isoproterenol:
– Acts on Beta-adrenergic receptors
– Activates Beta1 receptors on the heartovercomes AV block, restarts the heart
following cardiac arrest, increases cardiac
output during shock
Anticoagulants
• Prevent formation of new clots and
extension of clots already present
• Heparin and warfarin (Coumadin) are
commonly used
• Used to prevent or manage
thrombophlebitis, DVT, and PE
• Main adverse effect is bleeding
Heparin (unfractionated)
• Intrinsic pathway is affected
• Its major anticoagulant effect by
inactivating thrombin and activated factor
X (factor Xa) through an antithrombin
(AT)-dependent mechanism.
• Intravenous therapy
• Require aPTT monitoring (Activated partial
thromboplastin time)
Uses: Inhibit additional clotting, allowing body to
lyse
• current clot – Treatment and Preventative uses
(hospital)
• Pulmonary embolism (PE)
• Stroke evolving
• Massive deep venous thrombosis (DVT)
Adverse effects
• Hemorrhage
• Heparin-induced thrombocytopenia
• Hypersensitivity reactions
Contraindications: GI ulcers, blood dyscrasias
• Protamine (reversal agent)
Low-Molecular-Weight Heparin
• Fixed dose schedule, don’t require aPTT
monitoring
• Can be used at home (unlike Heparin)
• Much less likely to cause
thrombocytopenia (than Heparin)
Therapeutic use
• 1st line therapy to prevent and treat DVT
• Prevention of DVT following surgery
• Treatment of established DVT
• Prevention of ischemic complications
Adverse effects and interactions
• Bleeding
Example
• Enoxaprin
Warfarin
• Oral anticoagulant
• Antagonist vitamin K
• Blocks the biosynthesis of factors VII, IX,
X, II
• Anticoagulant effects occur 3-5 days after
oral use
• No effect on circulating clotting factors or
platelets
Therapeutic uses
• Long-term prophylaxis of thrombosis
• Prevention of venous thrombosis and
associated pulmonary embolism
• Prevention of thromboembolism (in
patients with prosthetic heart valves)
• Prevention of thrombosis during atrial
fibrillation
Adverse effects
• Hemorrhage
• Fetal hemorrhage and teratogenesis from
use during pregnancy
• Do not use during lactation
Antiplatelets
• Aspirin
• Clopidogrel
Aspirin
• Suppress the production of prostaglandins
and thromboxanes due to its irreversible
inactivation of the cyclooxygenase (COX)
enzyme
• Normally COX produces prostaglandins,
most of which are pro-inflammatory, and
thromboxanes, which promote clotting.
• Low-dose, long-term aspirin use
irreversibly blocks the formation of
thromboxane A2 in platelets, producing an
inhibitory effect on platelet aggregation
• This anticoagulant property makes aspirin
useful for reducing the incidence of heart
attacks
Adverse effect
• Increase risk of GI bleeding
Clopidogrel
• Irreversibly inhibits ADP receptor on
platelet cell membranes, which is
important in aggregation of platelets and
cross-linking by the protein fibrin.
• Used to inhibit blood clots in coronary
artery disease, peripheral vascular
disease, and cerebrovascular disease
• Adverse effects include hemorrhage,
Severe neutropenia, and Thrombotic
thrombocytopenic purpura (TTP).
• Aspirin and clopidogrel given orally
Fibrinolytic drugs/Thrombolitic
drugs
• First Generation – Streptokinase
• Second Generation – Altepase (tPA)
• Third Generation – reteplase recombinant
(retavase)
Streptokinase
• A protein (secreted by several species of
streptococci) can bind and activate human
plasminogen
Uses
• Acute coronary thrombosis (acute MI)
• Deep venous thrombosis (DVT)
• Massive pulmonary emboli
• Plugged AV shunt, central lines
Adverse effects
• Bleeding
• Antibody production
• Hypotension
• Fever
Contraindications
Absolute
• Previous intracranial bleeding at any time,
stroke in less than a year, active bleeding,
uncontrolled high blood pressure (>180
systolic or >100 diastolic).
• Streptokinase is contraindicated in
patients who have been previously treated
with streptokinase, as there is a risk of
anaphylaxis, a life-threatening allergic
reaction, due to the production of
antibodies against the enzyme.
Contraindications
Relative
• Current anticoagulant use, invasive or
surgical procedure in the last 2 weeks,
prolonged cardiopulmonary resuscitation
(CPR) defined as more than 10 minutes,
known bleeding diathesis, pregnancy,
hemorrhagic or diabetic retinopathies,
active peptic ulcer, controlled severe
hypertension
Recombinant tissue plasminogen
activator (t-PA, alteplase)
• t-PA is produced by endothelial cells
• It is nonantigenic and causes a more
selective thrombolysis than streptokinase.
• Alteplase, the recombinant t-PA, is
produced by recombinant DNA
technology.
Uses:
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Acute myocardial infarction.
Acute cerebrovascular thrombosis.
Pulmonary embolism.
Central venous catheter occlusion
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Major bleeding.
Cardiac arrhythmias.
Anaphylactoid reaction.
Cerebrovascular accident.
Intracraneal hemorrhage.
Reteplase
• It has an increased half life than t-PA and
increased specificity for fibrin.
• Its efficacy and adverse effect profile are
similar to those of streptokinase and t-PA.
Antifibrinolytic drugs
• Interfere with the formation of the
fibrinolytic enzyme plasmin from its
precursor plasminogen by plasminogen
activators
• Block the binding sites of the enzymes or
plasminogen respectively and thus stop
plasmin formation
• Aminocaproic acid and tranexamic acid
• Use in bleeding tendencies
Lipid regulating drugs
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HMG-CoA reductase inhibitors
Fibric acid derivatives (Fibrates)
Bile-acid sequestrants
Nicotinic acid (niacin)
HMG CoA reductase inhibitors
(Statins)
– Inhibits HMG CoA reductase, the ratelimiting enzyme in cholesterol synthesis
– Increase LDL receptors in hepatocytes
• This enables hepatocytes to remove
more LDLs from the blood
– Also decrease VLDL levels and increase
HDL levels
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Atorvastatin
Fluvastatin
Pravastatin
Simvastatin
– Adverse Effects
• Headache, GI side effects (e.g.
abdominal pain, flatulence, diarrhoea,
nausea and
vomiting)
• Hepatoxicity
• Myopathy
Fibric acid derivatives (Fibrates)
– Increase oxidation of fatty acids in liver
and muscle tissue, decrease hepatic
production of triglycerides, decrease
VLDL cholesterol and increase HDL
cholesterol
– Main indication is hypertriglceridemia
(high plasma triglycerides)
• Clofibrate
• Fenofibrate
• Gemfibrozil
– Adverse Effects
• Nausea, vomiting and GI upset
• Cholelithiasis (stones in the gall
bladder) and cholecystitis
(inflammation of the gallbladder)
• Myopathy
Bile acid sequestrants
– Bind bile acids in the intestinal lumen.
This causes the bile acids to be
excreted in faeces and prevents them
being re-circulated to the liver
– Mainly used as an adjunct to Statins to
decrease LDL cholesterol levels
Cholestyramine
• Adverse effects
–Constipation, diarrhoea, nausea,
vomiting, gastro-intestinal
discomfort
–Decreased absorption of fat-soluble
vitamins
Nicotinic acid
– Inhibits mobilization of free fatty acids
from peripheral tissues, thereby
reducing hepatic synthesis of
triglycerides and secretion of VLDL,
which leads to decreased production of
of LDL cholesterol
– Besides reducing LDL and VLDL levels,
also effective in increasing HDL levels
– Adverse effects
• Flushing, itching, nausea, vomiting,
diarrhoea
• Hepatotoxic
• Hyperglycaemia and hyperuricaemia