Cardiovascular Pharmacology
Drug
Mechanism
©2010 Mark Tuttle, Nasser El-Okdi
Reflex
Indication/Contraindication
Side Effects
Pharmacokinetics
- Coughing (30%) &
angioedema due to
bradykinin ↑ (an
endogenous vasodilator)
because breakdown
pathway is inhibited
- Renal damage in those with
preexisting kidney disease
(but protective of diabetic
kidney)
- Reduces N+/H+ exchanger
activity in PCT and thus
bicarbonate reabsorption
- Hyperkalemia
- African Americans are less
sensitive unless given a
diuretic concomitantly
- Asian Americans experience
more coughing and
- angioedema with ACE
inhibitors, so use ARBs
Renin-Angiotensin-Aldosterone Pathway Inhibitors
ACE inhibitors:
 Captopril
 Enalaprilat
 Enalapril (prodrug)
 Lisinopril
- Minimal: No reflex
- Indicated for:
tachycardia due to ↓
o Myocardial Infarction
resetting of the
o Hypertrophic myopathy
baroreceptors and
o Type I diabetic
↑parasympathetic
nephropathy
- No sympathetic reflex
o Renal insufficiency
 ↓ Filtration pressure
Endogenous actions of angiotensin II (Inhibited by ACEIs)
 ↓ Systemic pressure
- Rapid: TPR
- Slow: Kidney effects
- Slow: CV remodeling
+
 Dilate efferent arteriole
o Vasoconstrict (IP3)
o ↑ Na reabsorption
o Hemodynamic:
 ↓ Cell growth
o ↑Sympathetics
in proximal tubule
↑preload + afterload
 Ang II is a growth factor
o ↑ NE release &
o ↑ Aldosterone from
↑ CV tension
 ↓ Fibrosis
reuptake
adrenal ctx, H2O
o Non-hemodynamic:
 Protect structure of at
reabsorbtion in
↑ protooncogenes
the expense of function
distal tubule
↑ growth factor
o Hypertensive
o Δ Renal blood flow
↑ EC matrix
nephrosclerosis
 Constrict EA
protein
- Contraindicated for:
Angiotensin Receptor - Specific to AT1 R
- Minimal. Same as
o Pregnancy (because of fetal
Blockers (ARBs)
- Blocking the receptorACE Inhibitors
renal toxicity)
effector
coupling
not
 Losartan
o Renal artery bilateral
only reduces TPR but
 Valsartan
stenosis
also vascular
 Ang II effects on EA
remodeling
predominate so GFR ↓
with ACEIs b/c EA dilates
Renin Inhibitors
- Non peptide inhibitor - Can be used in monotherapy
of renin’s action on
or with other hypertensives
 Aliskiren
angiotensinogen
like HCTZ
Aldosterone inhib’s
 Spironolactone
 Epeleronone
- Inhibit conversion of
angiotensin I to
angiotensin II
- Acts via Ca2+, PLC-β,
ROS, Tyrosine kinase
- Competitively inhibits - None (!)
cytoplasmic
aldosterone R’s in the
collecting tubules
- ↓ Cardiac remodeling
- ↑ Na+ and H2O
excretion
- ↓ K+ wasting in kidney
- Can be classified as K+sparing diuretic
- ↓ Mortality
- Indications:
o Chronic Heart Failure
o Post-MI
o Aldosteronism (cirrhosis,
adrenal tumor, other)
o Hypertension
o Hypokalemia due to other
diuretics
- Contraindications:
o Additive use w/ other RAAS
o Liver disease
- Hyperkalemia
- No cough!
- Headache
- Diarrhea
- Hyperkalemia
- Hyperkalemia
- Gynecomastia (Spiro only)
- Acute Renal Failure
- Kidney stones
- Hyperchloremic
- Metabolic Acidosis
- Adequate but incomplete
absorption orally.
- Take on empty stomach to
↑ absorption.
- Pro-drugs (except Captopril)
that require hydrolysis by
hepatic enzymes.
- Mostly renal elimination
(except fosinopril)
- Orally active – once daily
- Highly plasma protein
bound (>90%), high volumes
of distribution.
- Losartan – high first-pass
metabolism (unlike others)
- Given orally
- Metabolized by CYP3A4 in
liver
- 25% excreted in urine
- Slow onset and offset of
effect (several days)
- Duration 24-48 hours
- Substantial inactivation
occurs in the liver
Drug
Mechanism
Reflex
Indication/Contraindication
Side Effects
Pharmacokinetic
- ↓CO via β1 in heart
via ↓ and ↓ PKA
- ↓ BP from ↓RAAS
activity via β1 in
kidney mesangial cells
- Prevent NE effects
o ↓ Cardiac remodel
o ↓ Cell death
- CV ↓ initially, but CV
↑ in long term
- Baroreceptor reflex
blocked  postural
hypotension
- Indicated for:
o Hypertension
o Heart disease
o Angina Pectoris
o Arrhythmias
- Contraindicated for:
o Type I diabetes bc it masks
hypoglycemic tachycardia
o Asthma
o Heart block
o Peripheral vascular disease
o Variant (Prinzmetal) angina
- Oral
- Duration of action is 10-12
hours
- Once-a-day treatment
α1-Blockers
 Doxazoxin
 Prazosin
 Terazosin
Mixed α/β-Blockers
 Carvedilol (β > α)
 Labetalol (β > α1)
Partial β2 agonist
-
- Orthostatic
hypotension
- LDL and triglycerides ↑
- Bronchospastic disease
- Bradycardia, AV block, MI
- Acute cardiac decompen.
- Withdrawal syndrome
o Can lead to myocardial
ischemia since β1 Rs
have been up-regulated
- Fatigue
- Cold hands
- Central actions: Sedation,
Depression, vivid dreams
- Impotence
- Abrupt discontinuation can
lead to myocardial
ischemia since β1 Rs have
been up-regulated
-
-
-
Central α2 agonists
 α-methyldopa
 Clonidine
Peripheral antagonist
 Reserpine
- Inhibits adrenergic
neuronal outflow from
brainstem
- Inhibit vesicular
uptake of NE
- Indicated for:
o Pheochromocytoma
- Contraindicated for:
o Decompensated HF
o Asthma
o 2nd/3rd degree AV block
-
- Depression
- Ulcers
-
- Helps block
pseudohypertension, but no
end-organ protection
- Depression, more so than
the Central α2 agonists
- Ulcers
-
©2010 MT,NE
Adrenergic Drugs
β-Blockers
 Metoprolol (β1 » β2)
 Nadolol
(β1 = β2)
 Propanolol (β1 = β2)
- ↑ Exercise tolerance
in angina patients
since limiting factor
was chest pain
- ↓ exercise tolerance
in normal patients
since CO is limiting
- Better than α /βblocker alone because
of α-block: ↓afterload
- Also an antioxidant
- Monotherapy may increase
risk of CHF, but LDL ↓ and
HDL ↑
-
Direct Vasodilators
Drug
K+ Channel Openers
 Diazoxide
 Minoxidil (Rogaine)
Mechanism
- ↓ afterload
(selective for arterial
vascular beds)
- K+ leak hyperpolarizes
smooth m., relaxing
Reflex
- Severe reflex
hypertension 
pseudohypertension
- Use in combination
with a drug that
opposes this reflex
Organic Nitrates
 Isosorbide dinitrate
(ISDN)
 Isosorbide-5mononitrate (oral)
 Amyl Nitrate
 Nitroglycerin
- ↓ preload
- Peripheral veins >
resistance vessels
- Large arteries >
small arteries
- NO ↑, cGMP ↑,
activating Protein
Kinase G which dePlates part of the
myosin light chain,
relaxing the muscle
- Hypotension
- Tachycardia
o ↓ Perfusion time
- Contractility ↑
o ↑ O2 demand
Inorganic Nitrates
 Sodium
Nitroprusside
- ↓ preload and ↓
afterload
(act arterial + venous)
- Donates NO, same
mechanism as organic
nitrate
- Na+ and H2O
retention
Nesiritide
Synthetic Brain
Natriuretic Pept (BNP)
- ↑cGMP relaxes arteries
-
2nd Messenger Inhibs
 Hydralazine
and veins
Indication/Contraindication
- Contraindicated as
monotherapy due to
pseudohyptertension
- Indicated for heart failure
patients with renal
dysfunction that can’t
tolerate ACE inhibitiors
- Indicated for:
o Acute MI
o Heart failure
o Malignant hypertension
o Stable angina
 Dilation of veins: ↓preload
 N.C. in coronary flow,
but ↑ subendocardial flow
 Non-ischemic is unaffected:
no coronary “steal” like
with dipyridamole
o Variant angina: Prinzmetal
 Relieve vasospasm
 ↑ epicardial flow
o Unstable angina
 Unclear, but platelets ↓
- Contraindicated with:
o Concurrent ED drugs
(Sildenafil citrate,
Vardenafil, Tadalafil)
- Indicated for:
o Hypertensive emergency
o Severe heart failure
- Contraindicated for:
o Renal insufficiency
- Endogenous BNP is a marker
for HF! > 100pg/dl
Side Effects
- Lupus-like Syndrome
- Angina
- Tachycardia
- Headache
- Nausea
- Anorexia
- sweating/flushing
- Orthostatic hypotension
o Venous dilation
- Throbbing headaches
o Arteriolar dilation
- Inhibit platelet aggregation
via ↑ cGMP
- Relaxation of non-vascular
smooth mm (ex. GI, airway)
- Tolerance develops
rapidly, so best to have 8
hour periods of non-use
- Cyanide intoxication
o Antidote: Sodium
thiosulfate or
Hydroxycobalamin
- Arrhythmias
- Hypotension (shock)
- Hypothyroidism (rare)
-
Pharmacokinetic ©2010 MT,NE
- 16% in fast acetylators
- 35% in slow acetylators
- High first-pass metab: 90%
- Nitroglycerin t½: 1-3 min
- ISDN t½: ~40 min
- Transdermal Nitrog.t½:6-10h
- Preparations
o Prophylaxis  Oral
o Acute  Sublingual
o ACS  Intravenous
- Intravenous
- Short duration (minutes)
- Metabolized by uptake into
RBC mitochondria and
liberation of cyanide
-
Drug
Mechanism
Reflex
Indication/Contraindication
Side Effects
Pharmacokinetic ©2010 MT,NE
2+
- Generally selective for arterial smooth muscle
- Neurons: N/P-type Ca channels, but these drugs only act on L-Type Ca2+ channels
Calcium Channel
- ↓afterload, not preload
- Skeletal muscle relies on [Ca2+]intracellular but cardiac/smooth m rely on [Ca2+]extracellular
Antagonists
Atherosclerosis ↓via non-channel effects—antioxidant? ↓ Non-voltage gated Ca2+ channel (TRPC3), TNFα-NFκB pro-inflam. signaling ↓, VCAM-1 ↓, monocytes ↓
Dihydropyridine
- Vasculature > Cardiac - Over-use results in
- Stable and prinzmetal angina - Migraine
- Oral/IV preparations
- Blocks L-type Ca2+ ch.
dominance of reflex
- Hypertension
- Preterm labor
- High first-pass metabolism
 Amlodipine
mechanism
Supraventrical
tachycardia
Stroke
- CytP450 3A4 inhibited by
 Nifedipine
o ↑End Diastolic
(arrhythmias)
- Raynaud’s phenomenon
o Grapefruit juice (Anti-taste)
“-ines”
Pressure
and
o Diazepam (Anti-anxiety)
Non-Dihydropyridine - Vasculature = Cardiac
- Contraindicated with:
- Atrioventricular block
2+
ejection
time,
while
o Ketoconazole (Antifungal)
- Blocks L-type Ca ch.
o β-blockers: CO 
- Acute heart failure
 Diltiazem
decreasing heart
- Duration of action: 4-8 hrs
- ↓vascular resistance,
o ↑ [Digoxin] to toxic level - Constipation
 Verapamil
rate,
contractility
- t½: 3-6 hrs
cardiac rate and
o Heart block
- Edema
and arterial
- Significant binding to plasma
cardiac force result in
o Sick sinus syndrome
- Nausea
pressures
proteins (77-99%)
↓O2 demand
o CHF
- Flushing
o Hypotension
- Dizziness
Inotropic Agents
Cardiac glycosides:
- ↓Cardiac Na+/K+ pump - Sensitize
- Indicated for:
- AV blockade
- Sugar residues control
o Digitalis competes w/K+ parasympathetic
o Heart failure
- Ventricular tachycardia
pharmacokinetics
 Digoxin (-OH @ 12)
o
Hyperkalemia:
↓
efx
tone
↑
o
CHF
with
A-fib
GI
effects
Digitoxin is more lipid-soluble
 Digitoxin
o Hypokalemia: ↑ efx
- ↓ Sympathetic
o CHF with dilated heart
o Vomitting
since it has no OH @ pos 12.
 Ouabin (possible)
- ↑ intracellular Ca2+ via
activity
- Contraindicated with:
o Diarrhea
o t ½: 168h
↓ Na+/Ca2+ activity
- (may) sensitize
o Quinidine use
- CNS: hallucinations
o Mostly in blood
 No effect on overall
baroreceptors
o Amiodarone use
- EKG changes:
o 90% bound to pp
mortality, but may  Contractility, SV ↑

Heart
rate
↓
o
Verapamil
use
o
PR
int.
↑,
QT
int.
↓
Digoxin is more water-soluble
improve quality of
 AV-conduction rate ↓
o Loop diuretics (since
o T-wave inversion
since it has an OH @ pos 12
life
they ↓ K+)
At toxic levels:
o t ½: 40h
 Used when diuretic  Pre/afterload ↓
- Arrhythmia: delayed after
o Mostly in cells
and ACE inhibitor
repolarization
o 20% bound to pp
fail to control
- Hypokalemia
 Low therapeutic
- Reduced renal clearance
index
w/quinidine + verapamil
- Treat with:
o K+, lidocane, Anti-digoxin
Abs
Newer Anti-Angina Drugs
Metabolic modulators (Trimetazine, ranolazine): pFOX inhibitors  ischemic myocardium shifts to FAO metabolism over glucose which has higher O2 requirement
Direct bradycardic agents: Ivabradine
K+ channel activators: Nicorandil
Rho kinase inhibitors: Fasudil
NO donors: L-arginine
Capsaicin
Amiloride
PKG facilitators: Detanonoate
Thiazolinediones
Diuretics
Drug
Mechanism
Thiazides:
- ↓ NaCl reabsorption
in distal convoluted
 Chlorothiazide
tubule
 Hydrochlorothiazide
- ↓Cardiac O2 consum.
 Chlorothalidone
Loop Diuretics:
- ↓ NaCl and KCl
reabsorption in thick
 Furosemide
ascending limb
 Bumetanide
 Blocks Na/K/2Cl
transporter
- ↓Cardiac O2 consum.
Reflex
- Stimulation of
sympathetic activity
- Activation of RAAS
- Strong reflex response
rules out mono
therapy with diuretics
Indication/Contraindication
- Indicated for:
o Renal failure
o Heart failure, hypertension
o Edematous conditions
o Hyperkalemia/calcemia
- Chlorothalidone no diff than
amlodipine/lisinopril, but
better than α-blker doxazosin
- Contraindicated with:
o Diabetes (high doses)
o Dyslipidemia (high doses)
Side Effects
- Hypokalemia
o Increases digitalis,
quinidine toxicity
(torsades de points)
o V-fib
- Hyperuricemia (gout)
- Hyperglycemia
- Sexual impotence
- Ototoxicity (loop only)
- Teratogenic (loop only)
Pharmacokinetic ©2010 MT,NE
- Chlorothiazide
o 9-56% bioavailable
o 1.5h t½
- Hydrochlorothiazide
o 70% bioavailable
o 2.5h t½
- Chlorothalidone
o 65% bioavailable
o 47h t½
- Loop: ~ 4h t½
Overall Treatment Notes
Hypertension
Common Drug combinations:
Racial considerations
- Reserpine, hydralazine, HCTZ
- African Americans:
- β-blockers and diuretics
Ca2+ antagonists + diuretics
- ACE inhibitors/ARBs + diuretics
- Asian Americans: ARBs
- ACE inhibitors + Ca2+ antagonists
Initial drug choices
- Uncomplicated: diuretics, β-blockers
- Diabetes w/proteinuria: ACE inhibitor
- Heart failure: ACE inhibs, diuretics
Heart Failure
-
-
-
Angina
Chronic Stable Angina
- Nitrates
- Ca2+ Channel Antagonists
- β-Blocker
Vasospastic (Prinzmetal’s) Angina
- Nitrates
- Ca2+ Channel Antagonists
High filling pressure, dyspnea
o Venous dilators: Long-acting nitrates relieve filling pressures and
pulmonary congestion
Fatigue, low LV output
o Arteriolar dilators: Hydralazine (2nd messenger inhibitor/Direct
vasodilator)
Chronic failure
o Need to relieve both
Unstable Angina
-
- Isolated systolic hypertension
(older persons) Diuretics or
long-acting DHP-Ca2+ blockers
- MI: β-blockers (non-ISA), ACE I’s
Platelet inhibitors
Heparin
Nitrates
β-Blocker
Ca2+ Channel Antagonists
Non-pharmacologic intervention (CABG etc)