Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.

1
Diuretics: General comments
- Mainstay of antihypertensive Rx, of which the goal is to morbidity and death; also potentiates other antihypertensives
- Also affect the renal system as its functional target on nephron (targets in nephron are drug-dependent)
- Salt intake effects of diuretics; NSAIDs inhibit activity (dose-dependent, but also drug-dependent)
Diuretics: Loop diuretics (High-ceiling diuretics)
Drug
Furosemide
(Lasix)

Pharmacokinetics/Action
Effects and Uses
Action: Blocks Cl reabsorption in thick ascending loop
Cl-, Na+, H2O, K+, Mg2+, Ca2+ excretion
+
+
of Henle (and thus K and Na reabsorption as well)
Used in Rx of CHF (to load on heart)
Note: Extremely potent b/c thick ascending loop is a
Used in Rx of HTN (but not often)
major site of Na+ reabsorption
Can help w/hypercalcemia (but risk of kidney stones)
Ethacrynic acid Action: Blocks Cl reabsorption in thick ascending loop
Cl-, Na+, H2O, K+, Mg2+, Ca2+ excretion

+
+
(Edecrin ) of Henle (and thus K and Na reabsorption as well)
Used in Rx of CHF (to load on heart)
Note: Extremely potent b/c thick ascending loop is a
Used in Rx of HTN (but not often)
major site of Na+ reabsorption
Can help w/hypercalcemia (but risk of kidney stones)
Structure: Not related to sulfas
Bumetamide
Action: Blocks Cl reabsorption in thick ascending loop
Cl-, Na+, H2O, K+, Mg2+, Ca2+ excretion

+
+
(Bumex )
of Henle (and thus K and Na reabsorption as well)
Used in Rx of CHF (to load on heart)
Note: Extremely potent b/c thick ascending loop is a
Used in Rx of HTN (but not often)
major site of Na+ reabsorption
Can help w/hypercalcemia (but risk of kidney stones)

Adverse Effects
Ototoxicity, esp. if used with other ototoxic drugs
Interactions see general comments for diuretics
Hypokalemia
Interactions see general comments for diuretics
Hypokalemia

Interactions see general comments for diuretics

Hypokalemia

Diuretics: Thiazides
Drug

Pharmacokinetics/Action

Hydrochlorothiazide Action: Interferes w/Cl reabsorption in distal tubule

Chlorhalidone
Indapamide

Note: The three thiazides listed differ in potency but

have similar effects.

Effects and Uses

Cl-, Na+, H2O, K+ excretion
( Na+ excretion plasma volume BP)
Ca2+ reabsorption (mechanism unclear)
- Useful for pts. with kidney stones

Adverse Effects
Na+ excretion renin angiotensin (thus BP)
- Combination w/-blockers used to reduce this effect
Hypokalemia (dose-dependent) b/c Na+/K+ exchanger in
distal tubule K+ excretion
Hyperlipidemia (dose- and time-dependent): questionable
Hyperglycemia problems with diabetics
Hyperuricemia problems in pts. with gout
Interactions see general comments on diuretics

Effects and Uses

Blocks Na+ channels (needed for K+ excretion) in
collecting duct
Can be used to Rx HTN in patients w/ renal function
Note: this class has less diuretic activity because it

Adverse Effects

Diuretics: K+-sparing
Drug
Spironolactone

Pharmacokinetics/Action
Action: Acts on aldosterone receptor thus does not
need to enter lumen to act

spares the loss of K+. Thus, it is often used in

Amiloride
Triamterene

Action: Acts on Na+ channels in collecting duct needs

to enter lumen to act

combination with other diuretics (i.e. loop diuretics)

Blocks Na+ channels (needed for K+ excretion) in
collecting duct
Can be used to Rx HTN in patients w/ renal function
Note: this class has less diuretic activity because it

spares the loss of K+. Thus, it is often used in

combination with other diuretics (i.e. loop diuretics)

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.2

Diuretics: Miscellaneous
Drug
Acetazolamide

Pharmacokinetics/Action
Action: Inhibits carbonic anhydrase (in cell and lumen)
in the proximal tubule, thus preventing HCO3 reabs.

Mannitol
Admin: IV only
(osmotic diuretic) Action: osmotic pressure, water excretion

Effects and Uses

HCO3 reabsorption Na+ reabsorption, but also
Cl reabsorption b/c of neg. charges in lumen
Note: Acetazolamide is a weak diuretic b/c Na+ can
be reabsorbed elsewhere in the nephron
Slight in K+ excretion b/c of Na+ reabsorption in the
collecting duct
Bottom line Urine: HCO3, Na+, Cl, H+;
pH of urine (acidic cell & blood metab. acidosis!)
Used in Rx of glaucoma b/c it ciliary body secretions
in the eye (other CA inhibitors as well)
Used to body H2O quickly (i.e. to intraocular
pressure)

Adverse Effects

Sympatholytics
Drug Class
-blockers

Drug Names/Drug Properties & Pharmacokinetics Effects and Uses

Adverse Effects
Propanolol (non-selective, no ISA)
cardiac output
Less effective in blacks (see effects column)
Metoprolol, atenolol (selective for 1, no ISA)
renin this is a problem in blacks, who are mainly
Fatigue, lethargy
low-renin hypertensives
Dyslipidemia ( triglycerides)
Used in HTN, and other conditions
Exacerbation of asthma
Potentiates with diuretics (nice)
blood flow to extremities (thus the in BP may
(Other uses see ANS drugs, p.4)
take a few days)
-blockers
Prazosin (prototype)
vasoconstriction ( peripheral resistance), without
Nasal stuffiness (due to vasodilation of nasal vessels)
Doxazosin (mode widely used, longer-acting)
effects on the heart or orthostatic hypotension
Terazosin (used for BPH and HTN, longer-acting)
Can also be combined with diuretics for HTN
HDL and HDL/LDL ratio nice
-/-blockers
Labetalol (prototype) selective -blocker (1);
CO and BP, but not widely used for HTN
Avoid in heart failure
primarily a nonselective -blocker (1, 2)
Central-acting
Methyldopa (converted to a-norepinephrine in CNS)
CO, BP (can be used for HTN)
Dry mouth, sedation, fluid retention, allergic-type fever
(CNS-acting)
May affect liver; some autoimmune effects
Clonidine (direct-acting)
CO, BP (can be used for HTN)
Like methyldopa, but w/out autoimmune response
Occasionally used for kids with stunted growth
In addition GH levels and effects on libido
Moxonidine (2nd generation -agonist, works on
Effects like clonidine
Like clonidine, but without sedation effects
imidazole receptor)
Nerve terminal
Guanethidine (doesnt enter CNS)
BP; only used in cases of resistance to other drugs Causes orthostatic hypotension, esp. in elderly
blockers Reserpine
Theoretically can be used for HTN; not used b/c of
Suicidal behavior (20%)

side effects

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.3

Renal Angiotensin System (RAS) Inhibitors
Drug Class
Drug Name/Drug Properties/Action
ACE inhibitors
Captopril (prototype): Acts by Inhibiting Angiotensin converting
Enzyme (ACE)
Enalapril: Works like Captopril, but addresses some of the concerns
about the drug. Also, it is a pro-drug, so onset of effect takes
longer than captopril

AT-1 blockers

Losartan: Acts specifically at the Angiotensin I receptor (found in

blood vessels)
Irbesartan (same as Losartan)

Effects and Uses

Angiotensin II (circulating, also localized that found in
tissue and vessel walls, including the kidney)
Aldosterone secretion Na+ excretion
Blunts sympathetic response to BP
Co-morbidity: Protects vital organs, regardless of of BP
- damage of kidney
- Reverse effects of BP on LV hypertrophy
- Cerebral blood flow well-maintained
- insulin sensitivity
Bradykinin side effect of dry hacking, cough
Essentially the same as the ACE inhibitors but without the
effects on bradykinin

Adverse Effects
Cough (20%)
Taste disturbances
Fetal toxicity

Vasodilators: Direct-acting
Drug
Nitroprusside

Hydralazine

Pharmacokinetics/Action
Duration: Short-acting, but dramatic effects
Admin: IV
Metabolism: Produces CN as a by-product
Action: Involves NO
Admin: Parenteral

Effects and Uses

Rx for hypertensive emergencies
Relaxes blood vessels
Titratable
Used by injection for HTN of pregnancy (eclampsia)

Used for hair growth

Used for HTN

Minoxidil

Adverse Effects
Drug must be mixed just prior to use
Need monitoring, b/c CN is a by-product of metabolism
Fluid retention, sympathetic outflow (must be given
in combination
High doses lupus-like syndrome
Fluid retention, sympathetic outflow (must be given
in combination
Fluid retention, sympathetic outflow (must be given
in combination

Vasodilators: Ca2+-blockers: Dihydropyridines (blockers in VESSELS)

Drug
Nifedipine
Amlodipine

Pharmacokinetics/Action
Action: Relaxes smooth muscle of vasculature only
Duration: Short-acting but formulated to last longer

Effects and Uses

Blocks Ca2+ channels, smooth muscle contraction
(so its useful for HTN)

Adverse Effects
Reflex tachycardia from BP

Vasodilators: Ca2+-blockers: Non-dihydropyridines (blockers in HEART, primarily)

Drug
Verapamil

Pharmacokinetics/Action
Action: Affects heart

Diltiazem

Action: Affects heart and blood vessels

Mibefradil

Action: Primary effects on heart

Effects and Uses

CO, HR, BP; also has a mild natriuretic effect
( renal blood flow, thus protecting the kidney)
May reverse LV hypertrophy
CO, HR, BP; also has a mild natriuretic effect
( renal blood flow, thus protecting the kidney)
May reverse LV hypertrophy
CO, HR, BP; also has a mild natriuretic effect
( renal blood flow, thus protecting the kidney)
May reverse LV hypertrophy

Adverse Effects
Headache
Edema
Constipation (depends on patient)
Headache
Edema
Constipation (depends on patient)
Headache
Edema
Constipation (depends on patient)

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.4

Drugs used to Rx Angina Pectoris: Nitrites and Nitrates
Class Pharmacokinetics/Mechanism of Action
Actions:
Relief of angina by Myocardial oxygen demand
- Vasodilation (large veins > large arteries > arterioles); vasodilation less venous return to heart pre-load on heart afterload on heart ( systemic BP)
- Workload of heart = Myocardial oxygen demand and consumption
Preferential redistribution of blood flow to ischemic areas of the heart
- Note: This is NOT a property of all vasodilatory drugs; dipyrimadole is an example of a vasodilator without this redistributory effect
- Dipyrimadole acts mainly on small resistance vessels and also inhibits platelet aggregation (so its good for prophylaxis of angina in pts. with atherosclerosis)
Release of nitric oxide: Nitrates bind to receptor in vascular smooth muscle cGMP Ca2+ smooth muscle relaxation
- Decrease of intracellular Ca2+ by inhibiting Ca2+ entry, extrusion of Ca2+, decreased release of Ca2+ from intracellular stores
Admin/Absorption:
Through sublingual/buccal mucosa; transdermal (this is of toxicological importance). Note: Sublingual is most common administration route
Metabolism:
Denitration in liver (glutathione-organic nitrate-reductase system) virtually all nitrates are denitrated after one circulation through the liver
Side effects:
Postural (orthostatic) hypotension due to venous pooling
Pulsating headache due to dilation of meningeal vessels there is tolerance with prolonged use
Methemoglobinemia b/c nitrate ion oxidizes hemoglobin to methemoglobin. May result in anoxic hypoxia
Flushing due to cutaneous vessel dilatation
Drug interactions with Viagra possibly fatal b/c both cGMP, thus potentiating cGMP-induced hypotension
Drug
Amyl nitrites
Nitroglycerin

Pharmacokinetics
Admin: Inhalation
Admin: Sublingual
Admin: IV
Admin: Buccal (transmucosal)
Admin: Oral
Admin: Transdermal
Isosorbide dinitrate Admin: Sublingual
Admin: Oral
Isosorbide
Admin: Oral
mononitrate
Erithrityl
Admin: Sublingual
tetranitrate
Admin: Oral
Pentaerythritol
Admin: Oral
tetranitrate

Onset/Dur. of Action
2-5 min/15 min (S)
2-5 min/6-30 min (S)
Immediate/Transient (S)
2-5 min/3-6 hrs (L)
20-45 min/2-8 hrs (L)
30-60 min/12-24 hrs (L)
3-20/1-2 hrs (L)
30-60 min/2-10 hrs (L)
15-30 min/6-12 hrs (L)

Effects/Uses
Prinzmetals (Variant), Typical angina:
Prinzmetals (Variant), Typical angina:
Prinzmetals (Variant), Typical angina:
Prinzmetals (Variant), Typical angina:
Prinzmetals (Variant), Typical angina:
Prinzmetals (Variant), Typical angina:
Prinzmetals (Variant), Typical angina:
Prinzmetals (Variant), Typical angina:
Prinzmetals (Variant), Typical angina:

5-15 min/2-3 hrs (L)

30 min/2-6 hrs (L)
30-60 min/2-12 hrs (L)

Prinzmetals (Variant), Typical angina: Maintenance

Prinzmetals (Variant), Typical angina: Maintenance
Prinzmetals (Variant), Typical angina: Maintenance

Emergencies. Also used to Rx cyanide poisoning (see scribe notes!)

Emergencies
Emergencies
Emergencies, maintenance
Maintenance
Maintenance
Maintenance
Maintenance
Maintenance

Drugs used to Rx Angina Pectoris: -adrenergic blockers

General comments
- Pharmacological benefit from in heart rate and contractility, in blood pressure lead to in myocardial oxygen demand during exercise (thus reducing frequency of attacks)
- Used as prophylaxis of typical angina; NOT used for Prinzmetals variant angina b/c -adrenergic constriction of coronary arteries are unopposed
Drug
Propranolol

Type/Receptor
Pharmacokinetics/Action
Non-select. 1, 2 Metabolism: 1st pass: 90%

Nadolol

Non-select. 1, 2 Metabolism: 1st pass: 0%

Effects and Uses

Combination with nitroglycerin reflex tachycardia
and contractility

Metoprolol
Atenolol

Selective 1
Selective 1

Metabolism: 1st pass: 50%

Metabolism: 1st pass: 0%

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.5

Drugs used to Rx Angina Pectoris: Ca2+ channel blockers (Verapamil, Nifedipine, Diltiazem)
Action: Ca2+ entering smooth muscle of systemic and coronary vasculature, resulting in
- Relaxation of coronary arteries ( blood supply to myocardium)
- Relaxation of systemic arterioles ( systemic blood pressure, afterload on the heart) oxygen demand
- Note: Nifedipine may cause a reflex HR due to its depressor effects
Uses: Rx of Prinzmetals variant angina (vasospastic angina)
Ca2+ channel blocker
Verapamil
Nifedipine
Diltiazem

Administration
Oral, IV
Sublingual, Oral, IV
Oral, IV

Absorption (Oral)
90%
90%
90%

Bioavailability (%)
10-20%
65-70%
< 20%

Metabolism
Liver
Liver
Liver

Excretion
Urine
Urine
Feces

Drugs Affecting Hemostasis

Drug Class
Anticoagulants
(Direct-acting)

Drug name
Heparin

Pharmacokinetics/Action
Effects and Uses
Admin: IV, subcutaneous
Drug of choice for clots in pregnancy (no placental dist.)
Note: Not IM b/c of hematoma risk;
Not oral poor membrane solubility
Distribution: Not to placenta
Onset: Immediate upon contact in
Blood
Actions: Binds to AT-III, forming a
heparin AT-III complex, which in
turn rapidly inactivates clotting
Factors II, VII, IX, X (i.e. those
involved w/Vitamin K); also
directly inactivates thrombin

Admin: IV
Only used to Rx Type II thrombocytopenia (Drug of
Distribution: Doesnt cross placenta
choice as a heparin substitute)
Action: Directly inactivates thrombin
Low-MW Heparin Admin: IV, subcutaneous
Acts the same as heparin, but doesnt interact with
(fractionated
Distribution: Doesnt cross placenta
thrombin
heparin)
Advantages over heparin
- 1st order elimination: Easier to control
- Less likely to cause Type II thrombocytopenia
- Doesnt seem to interact with Factor IV
Anticoagulants
Warfarin
Admin: Oral (lipid soluble)
Effect of warfarin (anticoagulant) delayed because
(Indirect-acting;
(prototype)
Distribution: Can cross placenta
pool of Factors II, VII, IX, and X must be depleted
oral)
Onset: 8-12 hrs after admin
before full effect can be seen
Metabolism: Cyt-P-450
Actions: Inhibition of Vitamin K

Adverse Effects
Zero-order metabolism leads to need for monitoring
(a small change in dose large change in response)
Hemorrhage: Use protamine sulfate to inactivate heparin;
be careful, protamine sulfate has anticoagulant properties!
Thrombocytopenia: 2 types
- Type I: Transient, mild, occurs at about 4 days after
heparin is started and usually resolves itself
- Type II: Serious drop in platelets, onset is 5-10 days
after starting on heparin; will only resolve after
heparin is stopped. Continue Rx with lepirudin.
Note: Type II predisposes to clot formation, poss.
by heparin complexing w/Factor IV. Ab developing
to this complex promotes platelet activation and
aggregation.

Lepirudin

Not used for Type II thrombocytopenia b/c of

cross-reactivity

Hemorrhage Rx with Vitamin K

Contraindicated in pregnancy (teratogen)
Displacement of warfarin by other drugs that are also
highly bound to plasma albumin
Any drug inhibiting cyt-P-450 warfarin transient

epoxide reductase, which reduced

Vit. K, which in turn conversion
of descarboxyprothrombin to
thrombin

hemorrhage

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.6

Drugs Affecting Hemostasis, continued
Drug Class
Drug name
Antiplatelet drugs Aspirin

Thrombolytic
drugs

Pharmacokinetics/Action
Action: Inhibits formation of TXA2
by permanently inhibiting COX
Dipyridamole
Admin: Oral
Action: Inhibits PDE, release of
ADP and serotonin from platelets
Ticlopidine
Admin: Oral
Action: ADP receptor antagonist
(blocks platelet aggregation)
Tirofiban
Admin: IV
Action: Antagonist of fibrinogen/
gpIIb/IIIa receptors (also blocks
platelet aggregation
Anticoagulants
Action: Blocks thrombin formation
Streptokinase
Admin: IV
Action: Complexes w/plasminogen,
which in turn facilitates conversion
of free plasminogen to plasmin
Tissue Plasminogen Admin: IV
Activator (tPA)
Action: Directly facilitates conversion
of plasminogen to plasmin

Effects and Uses

Daily prophylaxis of MI for those at high risk for, or
prior episode of, MI
Combination with aspirin (for TIAs of ischemic stroke)
Combination with warfarin (for preventing blood clots
w/prosthetic heart valve patients)
Alternate drug for aspirin, in cases of intolerance or
ineffectiveness

Adverse Effects
risk of hemorrhage
Hemorrhage

Blood dyscrasias

Used post-surgery
Used in combo with aspirin and heparin

Used in combo with other anticoagulants

Dissolves present arterial and venous clots
- Works anywhere in the body
- Clinical effect = that of tPA

Hemorrhage
20% of pts. dont respond to streptokinase
Dont use in pregnant patients!

Dissolves present arterial and venous clots

- Works anywhere in the body
- Clinical effect = that of streptokinase

Hemorrhage
20% of patients dont respond to tPA
More expensive than streptokinase

Antihyperlipidemic Drugs
Drug Class
Statins

Drug name
Simvastatin
Atorvastatin
Pravastatin
Fluvastatin

Pharmacokinetics/Action
Effects and Uses
Admin: Oral single dose, at bedtime LDL (most of all classes); LDL receptors in
Action: Inhibition of HMG-CoA
liver leads to LDL uptake and clearance
reductase, by acting as an analog
Note: Atorvastatin most effective, fluvastatin least
to a hydroxy acid intermediate of
triglycerides;
the rxn HMG-CoA mevalonate
Note: Atorvastatin most effective, fluvastatin least
Potency: High; selectively taken up
HDL
By the liver
Note: Pravasatin most effective, atorvastatin least
Duration: Atorvastatin highest (20 hrs)
(also atorvastatin = fluvastatin in this regard)
Metabolism: CYP3A4/2C9 except
Composition of VLDL is changed; clearance of
for pravastatin, which is met.
VLDL
by sulfation
Used in familial hypercholesterolemia
Excretion: Mostly biliary
Used in polygenic hypercholesterolemia
Distribution: variable (see adverse eff.) Used in familial combined hypercholesterolemia

Adverse Effects
Mild GI upset most common
Headache, loss of conc.
- Simvastatin penetrates CNS
- Atorvastatin doesnt enter CNS
Hepatotoxicity: Usually resolves on its own, but if lvls
of enzymes rise to 3x normal, stop drug Rx
- Underlying liver disease/alcohol use risk
Contraindicated in pregnancy/nursing mothers
risk of myopathy in combo with fibrates or niacin
Drug interactions
- Inhibiting statin metabolism: Macrolides (except
(excepting azithromycin), cyclosporins, azole
antifungals, fluoxetine (Prozac), ritonavir, zafirlukast,

metronidazole
- Promoting statin metabolism: Barbiturates, rifampin,
carbamazepines, phenytoin

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.7

Antihyperlipidemic Drugs, continued
Drug Class
Bile-acid binding
Resins

Drug name
Colestipol
Cholestyramine

Pharmacokinetics/Action
Admin: Oral
Action: Binds bile acids; reuptake
excretion/clearance of LDL

Niacin

Niacin
(nicotinic acid)

Admin: Oral
Duration: Short (3 doses/day);
dose is 1-3 g (cp. RDA of 20 mg)
Excretion: Urine

Fibrates
(fibric acid
derivatives)

Gemfibrozil
Fenofibrate
Clofibrate

Admin: Oral
Distribution: Crosses placenta;
extensively protein-bound
Duration: t = 1.5 hrs
Metabolism: liver (conjugation)
Excretion: Renal

Effects and Uses

Alternate for statins in familial or polygenic
hypercholesterolemia

Adverse Effects
Palatability tastes like sand
GI: bloating, flatulence, constipation ( dietary fiber
or laxative may relieve this); impactions w/inappropriate
use, steatorrhea (esp. with pre-exiting bowel disease)
triglycerides
Dry, flaking skin (cream used to treat this)
Rarely, malabsorption of Vitamin K, folic acid (children)
Drug interactions: Bile acid binding resins interfere with
absorption of cardiac glycosides, statins, warfarin,
thiazides, aspirin, vancomycin, iron salts, Vitamin C
Note: Niacin absorption is NOT interfered with
plasma levels of cholesterol by:
Flushing in head/trunk (aspirin relives this); with time,
- VLDL secretion
subsides due to tolerance, but if dose, symptom gets
- apoprotein synthesis (apo-C)
more severe
- clearance of VLDL by activating lipoprotein lipase GI: vomiting, diarrhea, dyspepsia; taking with meal
- 20-80% VLDL in 1-4 days
or non-Al3+-containing antacids, may relieve this
- Inhibits intracellular lipase
Dry skin
- clearance of HDL ( HDL content); variable
glucose, glucose tolerance (dont give to diabetics)
- HDL initially < 30 g/mL: 5-10 g/mL
uric acid gout (20%)
- HDL initially normal (> 35 g/mL): 20-30 g/mL Conjunctivitis
- Note: Niacin HDL the most
Nasal stuffiness
- LDL (10-15%) in 3 weeks
Risk of arrhythmias (dose-dependent)
- lipoprotein-a (25%)
Hepatotoxicity (dose of 2g/day or more)
Used in familial hypercholesterolemia (w/resin)
- If 3x normal levels of enzymes or jaundice, stop Rx
Used in familial combined hyperlipidemia
Risk of myositis (with statins)
Used in familial hypoalphaproteinemia (low HDL synd)
lipoprotein lipase VLDL
GI upset (5%)
apo A-I gene HDL
Skin rashes
apo C-III (inhibitor of lipoprotein lipase)
Muscular pain
- Effects mediated by PPAR
aminotransferases
oxidation of fatty acids in liver and muscle
Myopathy when given with statins
Used in familial hypertriglyceridemia
Gallstone formation esp. in women, overweight, Native
Used in familial dysbetalipoproteinemia
Americans
May displace warfarin from binding sites

 Not to be used in pregnancy or children

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.8

Drugs used for Congestive Heart Failure
Drug or Class Pharmacokinetics/Action
Amrinone Action: cytoplasmic level of Ca; doesnt poison
Na-K-ATPase
1-agonists
Dobutamine
Prenalterol
2-agonists
Salbutamol
Pirbuterol
Nitroglycerin

Digitalis
glycosides

Effects and Uses

Positive ionotropic effect on heart (short term Rx only)

Admin: Parenteral, Oral

Structure: Lactone ring required for activity; hydroxyl
group influences lipid solubility
Note: Digitoxin lacks this OH group and is thus more
lipid-soluble. Its t is >> digoxins (168 h vs. 40 h)
Action: Inhibits Na-K-ATPase
Note: This inhibition leads to changes in the T-wave

Adverse Effects
Vomiting (dangerous for patients in CHF)
Less toxic
Positive ionotropic effect on heart
HR and myocardial O2-demand
preload (ventricular filling pressure)
Cannot be used if patient has ischemic heart disease
Used intermittently to help some CHF patients
Prolonged treatment leads to tachyphylaxis
Decreases afterload by relaxing smooth muscle
(causing vasosdilation)
Allows in CO
Selectively dilates veins, redistributing blood to
ischemic areas
Used in pts with acute CHF for (dramatic) relief
Therapy for heart failure (CHF)
Cellular toxicity b/c inhibition of Na-K-ATPase results
- Vagomimetic: HR, suppresses A-V conduction
to Na/Ca exchange, which allows Ca to enter the cell;
Used to control supraventricular arrhythmias
this will cause after-depolarizations, premature
- Paroxysmal atrial tachycardia (PAT)
ventricular contractions (PVCs)
- Atrial flutter/atrial fibrillation, by depressing A-V
- Regular PVCs: bigeminy
nodal conduction; doesnt work for Wolf-Parkinson- One PVC at the wrong time can initiate vent. fib.
White syndrome b/c of accessory A-V pathway
Ventricular arrhythmias (mostly vent. fib), especially
- Prevention of paradoxical ventricular tachycardia,
during first 48 hrs after MI; with plasma K+,
which may occur with Rx of atrial fibrillation with
plasma Ca2+ (never give Ca salts!), sympathetic tone
quinidine
CNS disturbances (halo vision, altered color vision,
CV effects (bottom line): HR due to SNS drive;
giddiness, neuralgic pain involving lower 1/3 of face,
force of contraction, preload and afterload;
delirium, convulsions, hallucinations)
efficiency of myocardial O2 utilization
Vomiting (bad for patient in CHF)
blood flow to kidneys stops homeostatic mechanisms Skin rashes
responsible for Na and water retention
Gynecomastia in males (estrogen-like activity)

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.9

Class I Antiarrhythmics: Na+ channel blockers
General comments:
- Use-dependence: Na+ channel blockers affect high HRs more!
Class IA: General Comments
- Actions:
Blocks Na+ channels in the activated state
- Moderate depression of phase 0 (rising phase of AP)
- Moderate depression of conduction velocity
- Moderate decrease in fast inward sodium current, prolong repolarization
Some effect on K+ channels
Drug

Pharmacokinetics/Actions/Mechs of Action

Effects and Uses

Admin: Oral preferred (see side effects for why

IM or IV, although possible, are not preferred)
Other actions:
- Blocks a-adrenergic receptors
- Vagolytic (atropine-like) effects
Mechanisms of action
- Works on diseased fibers better, also has higher
affinity for fibers firing abnormally high rates
- slope of phase 4 depolarization of cells expressing
abnormal automaticity (i.e. atrial or ventricular fibers)
- rate of rise of phase 0: This reduces the chance
of transmitting an AP from an ectopic focus to
another cell. Also, this in rate of rise of phase 0
may block re0entrant arrhythmias (i.e. it will convert
a unidirectional block to a bidirectional one)

EKG: PR interval (due to ERP in AV node)

QRS duration (rate of rise of phase 0 )
QT interval (AP duration in vent. muscle cells,
b/c of delay in opening K+ channels)
Uses:
- Supraventricular arrhythmias: premature atrial beats,
restoration of normal sinus rhythm (note: administer
digitalis first to prevent paradoxical in HR);
repetitive tachycardia in Wolff-Parkinson-White
syndrome; maintenance of normal sinus rhythm after
electrical conversion of atrial arrhythmias
- Ventricular arrhythmias: Premature ventricular beats,
ventricular tachycardia

Adverse Effects

Quinidine

Procainamide

Structure: Derivative of procaine (local anesthetic)

Admin: Oral (chronic treatment), IM, IV (life-threatening
arrhythmias but monitor BP b/c of CO)
Metabolism: In liver, to N-acetylprocainamide (also active)
Mechanisms of action: Similar as quinidine

EKG: Similar to quinidine

Uses:
- Same as quinidine, PLUS
- Arrhythmias associated with MI

Systemic lupus-like syndrome (arthralgia, arthritis)

Nausea, diarrhea
Agranulocytosis vulnerability to 2 infections
CNS: Depression, hallucinations
Atropine-like effect < than that of quinidine

Disopyramide

Admin: Oral
Distribution: 30% bound to plasma proteins
Metabolism: Liver
Mechanisms of action: Similar to quinidine

EKG: Similar to quinidine

Uses:
- Same as quinidine
- In US, approved for ventricular arrhythmias

Atropine-like effect >> than that of quinidine; digitalis MUST be

used before it is administered during atrial fib. or atrial flutter
May precipitate arrhythmias
May cause heart failure in some patients
Urinary retention (antimuscarinic effects)

Atropine-like effect in AV conduction, which leads

to a paradoxical in HR
Blockade of -adrenergic receptors can lead to
hypotension and reflex tachycardia; this may induce
quinidine syncope from drug-induced vent. tachycardia
Sick sinus syndrome can be exaggerated
GI disturbances (nausea, vomiting, diarrhea)
MOST COMMON side effect
Cinchonism: Headache, dizziness, tinnitus
Arrhythmias (Conc > 5 g/mL, K+ > 5 mM, QRS widens > 30%)
Drug interactions
- Oral anticoagulants: May cause bleeding
- Digoxin/digitoxin: May displace them from binding sites
( tissue blood levels)
- Phenytoin and phenobarbital may metabolism

Moricizine
Amiodarone

(Not discussed)
Admin/Absorption: Oral (slow, variable absorption)
Metabolism: t = 13-103 days when used long-term;
15-30 days required to load body stores to check efficacy
Mechanisms of action:
Prolongation of APD (mechanism unknown, but may
involve its blockade of K+ channels)
- May also block Na+ and Ca2+ channels (Na+ channel
blockade is more pronounced in depolarized cells)
- Blockade conduction velocity and makes it more
likely that APs will be blocked
Other actions:
- - and -adrenergic receptor blocking activity
(Used in Europe in Rx of angina pectoris)

Use: Ventricular arrhythmias, esp. those due to MI

EKG: effective refractory period of AV node
PR interval
AP duration
QT interval
sinus rate due to -blocking property
Uses:
- Life-threatening ventricular arrhythmias, when other
interventions fail
- Supraventricular and ventricular arrhythmias

Dry mouth (antimuscarinic effects)

Blurred vision (antimuscarinic effects)
Constipation (antimuscarinic effects)
Aggravation of glaucoma (antimuscarinic effects)
(Not discussed)
Bradycardia and heart block
Fatal lung fibrosis
Hepatocellular necrosis
Altered thyroid function (it contains 2 iodine atoms)

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.10

Class I Antiarrhythmics: Na+ channel blockers, continued
Class IB: General Comments
- Actions:
Blocks Na+ channels in the activated state (but will AP duration!!)
- Minimal depression of phase 0
- Minimal depression of conduction velocity
- Minimal decrease in fast inward sodium current
Drug
Lidocaine
anesthetics

Tocainide
Mexiletine

Phenytoin

Pharmacokinetics/Actions/Mechs of Action
Admin: IV preferred; IM

Effects and Uses

EKG: NO changes

Metabolism: Extensively, by liver ( not effective orally) Uses:

Mechanisms of action: Similar to quinidine
- Ventricular tachycardia, vent. fibrillation, after MI
At therapeutic doses, ventricular muscle is more
sensitive than atrial muscle to its actions, possibly
b/c the AP duration of ventricular muscle > than
atrial muscle (Na+ channels remain in inactivated
state longer)
Admin: Oral
Uses:
Metabolism: Resistant to first-pass hepatic metabolism
- Ventricular arrhythmias
Mechanisms of action: Similar to lidocaine
- Premature ventricular beats
- Ventricular tachycardia
Admin/Absorption: Oral (slow absorption); IV (divided EKG: NO changes
doses to avoid CV collapse)
Uses:
Distribution: 90% Plasma protein binding
- Ventricular arrhythmias due to digitalis toxicity
Metabolism: Hydroxylation in liver
Other actions:
- CNS: exaggerated SNS activity caused by digitalis
- Effective anticonvulsant
Mechanisms of action: Similar to lidocaine

Class IC: General Comments

- Actions:
Blocks Na+ channels in the activated state (No effect on AP duration!)

Adverse Effects
Side effects are similar to overdose of local
- Convulsions
- Hearing/speech disturbances
- Nausea of central origin

Tocainide: Serious, poss. fatal hematological disorders

CNS: Depression, anxiety, vertigo

GI: Anorexia, vomiting
Hypersensitivity: Stevens-Johnson syndrome
Hyperglycemia: Inhibits insulin secretion
Megaloblastic anemia: Altered folate metabolism
Gingival hyperplasia: Altered collagen metabolism
Drug interactions
- Oral anticoagulant (dicoumarol) and INH metabolism
- Phenobarbital metabolism

- Marked depression of phase 0

- Marked depression of conduction velocity
- Marked decrease in fast inward sodium current
Drug
Flecainide

Propafenone

Pharmacokinetics/Actions/Mechs of Action
Effects and Uses
Mechanisms of action:
Uses:
- VERY pronounced effect on rate of rise during
- Premature ventricular contractions (PVCs)
phase 0 of AP
- Supraventricular arrhythmias
- Likely to conduction velocity of myocardial impulses
(Not discussed)
Use: Supraventricular arrhythmias

Adverse Effects
Excessive mortality/nonfatal cardiac arrest
(Use with caution!!)

(Not discussed)

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.11

Class II: -blockers (-adrenergic receptor antagonists)
General Comments:
- Actions:

Slows conduction and effective refractory period of ventricular AP

Slows spontaneous phase-4 depolarization of SA node cells (i.e. HR)

Drug

Pharmacokinetics/Actions/Mechs of Action

Propranolol
Metoprolol
asthma
Timolol
Esmolol

Admin/Absorption:
EKG: PR interval
- Oral: Excellent absorption but 1st-pass metabolism
Uses:
bioavailability
- IV: Much lesser doses required
Distribution: 90% Plasma binding
Mechanisms of action: Blocks -adrenergic receptors
- automaticity in SA node cells (esp. during exercise
or emotional disturbances)
- automaticity of ectopic pacemakers
- rate in phase 0 of AP (only with high plasma levels)
- in effective refractory period of AV node
- Abolishes supravent. tachycardia due to nodal re-entry
- Helps to prevent in ventricular rate during atrial
fibrillation when digitalis fails

Effects and Uses

Adverse Effects
CV: HR, BP, myocardial contractility
Dont give to asthmatics bronchoconstriction in

- Non-selective (propranolol, timolol) and cardioselective

-blockers (esmolol, metoprolol):
- Premature ventricular contractions; post-MI pts.
have survival rate, possibly b/c of blockade of
excessive adrenergic activity on HR
- Wolff-Parkinson-White syndrome (WPW)
- Esmolol only: Intraoperative and acute arrhythmias

Class III: K+ channel blockers

General Comments:
- Actions:

AP duration, ERP
Inhibits K+ repolarization current
- Reverse use-dependence: Na+ channel blockers affect low HRs more!

Drug

Pharmacokinetics/Actions/Mechs of Action

Bretylium

Admin: Short IV or IM use

Metabolism: Not significant; t: 9 hrs
Excretion: Unchanged, by kidney
Mechanisms of action:
- Restores AP duration and effective refractory period
in ischemic ventricular cells (no effect on atrial cells)

Effects and Uses

EKG: PR interval may be

Uses:
- Ventricular arrhythmias, but only in emergency
situations, and when lidocaine and other interventions
fail

Adverse Effects
Hypotension

Amiodarone

Sotalol

Other actions: Taken up & concentrated in adrenergic

nerve terminals; later prevents NE release
Admin/Absorption: Oral (slow, variable absorption)
Metabolism: t = 13-103 days when used long-term;
15-30 days required to load body stores to check efficacy
Mechanisms of action:
Prolongation of APD (mechanism unknown, but may
involve its blockade of K+ channels)
- May also block Na+ and Ca2+ channels (Na+ channel
blockade is more pronounced in depolarized cells)
- Blockade conduction velocity and makes it more
likely that APs will be blocked
Other action: - and -adrenergic receptor blocking activity
(Used in Europe in Rx of angina pectoris)
Mechanisms of action: See general comments
Other action: -blocker

EKG: effective refractory period of AV node

PR interval
AP duration
QT interval
sinus rate due to -blocking property
Uses:
- Life-threatening ventricular arrhythmias, when other
interventions fail
- Supraventricular and ventricular arrhythmias

Bradycardia and heart block

Fatal lung fibrosis
Hepatocellular necrosis
Altered thyroid function (it contains 2 iodine atoms)

Uses:
- Paroxysmal supraventricular tachycardia
- Supraventricular tachycardia associated with accessory
pathway (WPW syndrome for example)
- Re-entrant arrhythmias w/AV node as re-entrant pathway

Torsade de pointes

Pharmacology Review Sheets: Drugs Affecting the Cardiovascular System, p.12

Class IV: Ca2+ channel blockers
General Comments:
- Actions:

Inhibition of slow inward Ca2+ current conduction velocity in AV node at therapeutic levels b/c Phase 4 depolarization depends on Ca2+ channels
(Note: At heavy doses this effect can result in AV block)
Minimum effect on ventricular AP
Slows conduction and refractoriness in the AV node

Drug

Pharmacokinetics/Actions/Mechs of Action

Effects and Uses

Adverse Effects

Verapamil

Admin: Oral, IV
Absorption: Oral (90%)
Bioavailability: Oral (10-20%)
Duration of action: Onset in < 30 min, peaks in 5 hrs
Distribution: 90% protein binding
Metabolism: Liver
Excretion: Urine
Mechanism of action: see above
Admin: Oral, IV
Absorption: Oral (90%)
Bioavailability: Oral (< 20%)
Duration of action: Onset in < 30 min, peaks in 30-40 min
Distribution: 80% protein binding
Metabolism: Liver
Excretion: Feces
Mechanism of action: see above

Uses:
- Supraventricular arrhythmias
(ex. paroxysmal atrial tachycardia)
- Limited success with atrial flutter and atrial fibrillation

(Not really discussed)

Uses:
- Supraventricular arrhythmias
(ex. paroxysmal atrial tachycardia)
- Limited success with atrial flutter and atrial fibrillation

(Not really discussed)

Effects and Uses

Adverse Effects

Uses:
- Mainly used for CHF
- Atrial flutter
- Atrial fibrillation
Note: NOT used for WPW (b/c of use of bundle of Kent)

See CV drugs, p.8

Diltiazem

Digitalis glycosides
Drug
Digoxin
Digitoxin

Pharmacokinetics/Actions/Mechs of Action

Action: Slows conduction and effective refractory

period in AV node
Mechanisms of action:
- Blocks Na+-K+-ATPase
- [Na+]i [Ca2+]I due to Na+/Ca2+ exchanger
- Ca2+ myocardial contractility
- Vagomimetic

- May sensitize baroreceptors ( vagal activity)

- Crosses blood-brain barrier and reaches dorsal motor root
of the vagus ( vagal activity)
- Facilitates muscarinic effects ( vagal activity)
Overall, this AV node conduction (thus it is good for
supraventricular tachycardias such as atrial flutter and atrial
fibrillation). Note, however, that it does NOT affect the
atria; you need to treat atrial problems w/something else.

Miscellaneous
Drug

Pharmacokinetics/Actions/Mechs of Action

Adenosine

Admin/Duration: IV bolus; t: 10 secs

Uses:
Mechanism of action:
- Paroxysmal supraventricular tachycardia
- Opens K+ channels, efflux of K+ during phase 4; this
- Paroxysmal supraventricular tachycardia assoc. w/WPW synd.
rate of spontaneous depol. in SA node cells (restores rhythm)
- rate of rise of AP of AV node cells in Phase 0; this decr.
conduction velocity in AV node cells.
- eff. refractory period of AV node cells; this may prevent
conduction of excessive atrial depolarizations to the ventricle
- NO direct effect on vent. muscle (specific K+ channels absent)
(Not discussed in lecture)
Uses: Torsade de pointes, digitalis-induced arrhythmias,
multifocal atrial tachycardia (MAT)

Magnesium
Chloride

Effects and Uses

Adverse Effects
Chest pain (perhaps due to myocardial ischemia)
Dyspnea (due to bronchoconstrictor actions)
Cutaneous flushing (vasodilator actions)
Drug interactions:
- Caffeine and theophylline completely block effects
- Dipyridamole potentiates action (adenosine uptake blocker)

(Not discussed in lecture)