Agents used in HT, CHF, Dysrhythmia and Angina

Drug Class

Hypertension

HF

Beta-Blockers (BBs)

Ca++-Channel
blockers (CCBs)

ACEI / ARBs /
Aliskiren

Diuretics (Thiazides)

Cardiac glycosides
Digoxin
Vasodilators

Angina

Na+-Channel
blockers
Nitrates

Arrhyth
mia

Regulation of Blood Pressure

Regulation of Blood Pressure

Sympathoplegics

Direct Vasodilators

Diuretics

Anti-angiotensins

Sympathoplegic Drugs
CNS
Sympathoplegics
Methyldopa
Clonidine

Ganglion Blockers
Hexamethonium

Adrenergic Neuron
Blockers
Guanethidine
Reserpine

Adrenoceptor
Antagonist

Propanolol
Metoprolol
Atenolol
Prozasin
Terazosin
Doxazosin

Centrally Acting Sympathoplegic

Drugs
The Good:
Treat moderate to severe hypertension
Reduce sympathetic outflow from
vasomotor centers in brain
MECHANISM OF ACTION
Reduce release of NE
Retain baroceptor control
Rarely used now (exception: clonidine)

Centrally Acting Sympathoplegic

Drugs
The Bad:
Tend to cause sedation, depression,
nightmares
Toxicity associated with sympathetic
blockade
Occasionally orthostatic hypotension
Severe depression not given to suicidal
patients
Profound sympathetic blockade
Lactation in men and women
Inhibition of ejaculation

Centrally Acting Sympathoplegic

Drugs
Clonidine and Methyldopa
Primary antihypertensive activity due to
agonist activity in brainstem,
decreasing sympathetic stimulation
Bind more tightly to 2 than 1

Adrenergic Neuron Blocking

Agents
Definition
Lower BP
Block NE release from postganglionic
sympathetic neurons

Examples
Guanethidine
Reserpine

Adrenergic Neuron Blocking

Agents
Guanethidine
Profound sympathoplegia at high doses
Too polar to enter CNS no CNS effects
Rarely used due to toxicities
Orthostatic Hypotension
Diarrhea
Ejaculation impairment

Adrenoceptor Antagonist
Propanolol
Lowers BP, prevents reflex tachycardia
Antagonizes 1 & 2 receptors
Decreases cardiac output
Inhibits renin production
Toxicity associated with blockade

Adrenoceptor Antagonist
1 Blockers
Prazosin, Terazosin, Doxazosin
Block 1 receptors in arterioles and
venules
Dilates both resistance and capacitance
vessels
BP is reduced more in upright position

Vasodilators
Hydralazine
Dilates arterioles
Pharmacokinetics
A: Well absorbed
M: Rapid first pass metabolism (low
bioavailabilty ~ 25%)

Toxicity
HA, nausea, sweating, flushing
Worse in slow acetylators
Symptoms similar to SLE

Vasodilators
Minoxidil
Mechanism
Opens K+ channels in smooth muscles
Stabilizes potential, less likely to contract

Dilates arteries, arterioles

Pharmacokinetics
A: Well absorbed orally, topically (Rogaine)
M: Initially converted to active metabolite in
liver, then degraded in liver (4 hours)

Vasodilators
Sodium Nitroprusside
HT emergencies, Cardiac failure
Dilates arterial and venous vessels
Mechanism
Relaxes vascular smooth muscle
Breaks down in blood to release NO
Increases intracellular cGMP

Vasodilators
Sodium Nitroprusside
Rapidly lowers BP
Effects disappear 1-10 min after d/c

Continuous IV infusion
Protect from light

Usual dosage
0.5 mcg/kg/min to 10 mcg/kg/min
Higher rates cause toxicity

Vasodilators
Sodium Nitroprusside
CN slowly eliminated by kidney
CN accumulation
Metabolic acidosis, arrhythmias, death
Worse in patients with renal insufficiency
Sodium thiosulfate facilitates metabolism of
cyanide

Vasodilators
Fenoldopam
Peripheral arteriolar dilator
HTN emergencies, post-op HTN
Mechanism
Agonist of D1 receptors

ACE Inhibitors
Captopril
Mechanism
Decrease PVR
CO and HR not significantly changed
Eliminated primarily in kidneys

Toxicity
Severe hypotension
Contraindicated in hypovolemic patients, pregnancy
Drug interactions
K+ supplements can lead to hyperkalemia
NSAIDS block some effects

Angiotensin Receptor
Blockers
Losartan and Valsartan, others
Similar toxicity to ACE inhibitors
No effect on bradykinin
More complete effect on angiotensin
action

Outpatient Therapy of Hypertension

Initial Behavioral (sodium, weight)
Evaluate use of drugs increasing BP in pt.
Decongestants, NSAIDs, contraceptives,
some herbal medications

Mild hypertension
Single drug
First line drugs: Best guess, play the odds
Beta blocker
Low dose diuretic

Blood Vessel Contraction

Relaxing Vascular Tone

Block calcium influx

Prevent
depolarization
by
Potassium
efflux

Increase cAMP

Increase cGMP

Actions on Vascular Smooth Muscle

NO, Nitrates, Nitrites
Activate GC, increase cGMP - Relaxtion

Beta-2 Agonists
GPCR cAMP Relaxation (mainly respiratory)

Beta-blockers
Decrease demand (decrease heart)

Calcium Channel Blockers

Less total calcium - Relaxation

Sildenafil
Blocks PDE5, increase cGMP - Relaxation

Nitrates & Nitrites

Nitroglycerin
Mechanism
NO release in vascular smooth muscle

Pharmacokinetics
A: Low oral bioavailability (10-20%)
M: High 1st pass metabolism
Nitrate reductase in liver
E: Kidneys

Nitrates & Nitrites Nitroglycerin

Pharmacokinetics
T1/2 = 2-8 minutes in blood
Metabolites
Dinitroglycerin
Longer T1/2 (3 hours)
efficacious

Mononitro forms
Available for clinical use (isosorbide dinitrate)
Higher oral bioavailability (~100%)

Nitrates & Nitrites - Actions

Vascular Smooth Muscle
The Good
venous capacitance, ventricular preload
heart size, CO

The Bad
Orthostatic hypotension, syncope, HA

The Ugly
Reflex tachycardia
Hemoglobin interactions

Nitrates & Nitrites

Clinical Use
SL Nitroglycerin
Immediate
Onset : 1-3 minutes
Duration: 20-30 minutes

IV nitroglycerin
Severe, recurrent, non-effort angina
Termination of effects rapid after d/c
infusion

Calcium Channel Blockers

Toxicity
Serious cardiac suppression (rare)
Bradycardia, arrest
AV block
CHF

Immediate acting nifedipine, diltiazem,

and verapamil

*Note*
Therapy directed at non-cardiac
targets may be more useful for longterm treatment of heart failure
ACE inhibitors
Angiotensin receptor blockers
Beta-blockers
Aldosterone receptor antagonists
Vasodilators

Control of Normal Cardiac Contractility

1. Trigger
calcium
enters
cell
2. Binds to
channel
in SR,
release
stored
calcium
3. Frees
actin to
interact
with
myosin

Pharmacotherapy
Therapy directed at cardiac and noncardiac factors

Digoxin Pharmacokinetics
A: Well absrobed (Foral = 65-80%)
(may be inactivated by gut bacteria in
some)

D: Wide in tissues and CNS

M: Not extensive in humans
T1/2 = 36-40 hours
E: 2/3 excreted unchanged by kidneys

Digoxin
Direct therapeutic
Inhibits Na+/K+ ATPase
Maintains normal resting potential
Positive inotrope

Disturbance in Impulse
Formation
Interval between depolarizations
= duration of AP + duration of diastolic
interval
Shortening of either duration results in an
increased pacemaker rate

Disturbance in Impulse
Formation

Disturbance of Impulse
Conduction
In order for reentry to occur:
There must be an obstacle (scar tissue)
Block must be unidirectional
Conduction time must be long enough to
reenter same areas after refractory
period

Sodium Channel Blockers

Class IA
Quinidine
Oral, declining in use
Cardiac effects

Depresses pacemaker rate

Binds and blocks activated sodium channels
Lengthens QT interval
Depresses conduction and excitability
Especially in depolarized tissue

Sodium Channel Blockers

Class IA
Quinidine
Also blocks K+ channels with
repolarizing outward current (prolong
QT)
Enhances Na+ blockade

Reduces the maximum reentry

frequency
Procainamide
Slow tachycardias

Electrophysiologic effects similar to Quinidine

Less prominent antimuscarinic action
Toxicity similar to Quinidine
Some SLE-like symptoms (arthralgia)

Sodium Channel Blockers

Class IB
Lidocaine
IV (3% oral bioavailability)
Low toxicity, high effectiveness
Acts exclusively on the sodium channel
Supress abnormal cardiac activity
Blocks both activated and inactivated
channels
Recovery from block between action
potentials due to rapid dissociation

Phenytoin Seizures Gingival

hyperplasia

Drugs that Prolong Action Potential

Class III
Prolong AP usually by:
Blocking cardiac K+ channels
Enhancing inward current
Na+ or Ca2+ channels

Drugs that Prolong Action Potential

Class III
Reverse use-dependence
Fast rates: least marked action potential
prolongation (desirable effects)
Slow rates: most marked AP
prolongation contributes to TdP

Considerations for Treating

Dysrrhythmias
1. Acute vs chronic treatment
2. Ventricular vs supraventricular
Acute

Chronic

Supraventricular

Adenosine
Digoxin, CCBs

Beta-blocker
Calcium antagonist

Ventricular

Amiodarone
Procainamide
Sotalol, Bretylium
Lidocaine

Amiodarone
Sotalol
Flecainide