Cardiovascular Drugs

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Normal impulse path Ion channels

Cardiac muscles have a negative membrane potential at rest A stimulation higher than threshold value induces the opening of the ion channel which causes the positively charged ions to enter the cell = depolarization . Depolarization will cause the calcium ions channels to open up allowing Ca+ to cause the muscle contraction. After an absolute refractory period the K channels reopen allowing the flow of K+ out of the cell = repolarization

Origin of arrhythmias

1- Abnormal impulse generation:
· Results from increase automaticity, increase rate of depolarization in pacemaker cell
· Autonomic nervous system
· Drugs, diseases
2- Impulse conduction, heart block
3- Both

The chambers of the heart contract as synchronized rhythmic units driven by electric impulses. The pacemaker cells for the heart lie within the SA node. After the impulse is generated in the SA node it will travel through the atria to the AV node, and then through specialized conduction pathways in the common bundle of His, bundle branches, and purkinje network to reach the ventricular muscle cells.
The heart contains certain electrophysiological properties; automaticity, refractoriness, and conduction velocity. It’s within these parameters that many of the antiarrhythmic drugs have their effect. They are reflected by changes in action potential in various regions of the heart.
1.) Automaticity is a unique feature of the cells of the SA node, AV node, and specialized conducting system to exhibit phase 4 depolarization and thus impulse generation. An increase in automaticity is directly related to an increase in the rate of impulse generation and thus a decrease in automaticity causes a decrease in the rate of impulse generation. The rate at which pacemaker cells initiate impulses depends on the rate of phase 4 depolarization, MDP (maximum diastolic potential), and the magnitude of the threshold potential. These functions can be altered by drugs.
2.) Refractoriness is the period after initiation of an action potential during which another action potential cannot be initiated and propagated regardless of stimulus is called effective refectory period or ERP. A change in the action potential duration or APD is accompanied by a similar change in the duration of the ERP; the ratio of change may not be 1:1. This is another way drugs with antiarrhythmic effects can affect the hearts action potentials. Some drugs will prolong the ERP, and some will decrease it.
3.) The rate of phase 0 depolarization influences conduction velocity. When the antiarrhythmic drug decreases the rate of the phase 0 depolarization, it thereby reduces the conduction velocity.

Arrhythmias classifications:

· Supraventricular = originating in the atria or conducting system not in the ventricular
· Ventricular= most common


Antiarrythmias drugs:

- Depends on the type of the arrhythmia
- The most common classification = The Vaughan William classifications
- The Vaughan William classifications
o Based on the primary mechanism of action
o Has limitation since many agents has more than one action
o There are five main classes in the Vaughan Williams classification of antiarrhythmic agents:
1- Class I agents that interfere with Na+ channels
2- Class II agents = ant sympathetic Nervous system , beta blocker
3- Class II = affect K+ efflux
4- Class IV = affect C+ and AV node


Class I in subdivided according to the agent’s effect on the depolarization
Na+ channels exist in three stages: open, inactivated, closed
Class 1A, IC drugs bind more selectively to the open state of the channel
Class IB binds more to the inactivated channel stage.
Note: class IB can block Na+ channel more effectively because the Na+ remain in an inactivated state for longer period during systole.

Drug Class

Example

Mechanism

Pharmacological effect

Adverse effect

IA
Quinidine
Procainamide
Disopyramide

medium Na + block
lengthens the action potential

Ventricular arrhythmias
Atrial tachyarrhythmia
Reduces automaticity and conduction velocity
Increases refraction

Quinnidine:
..Peripheral vasodilatation
...Myocardial depression ...Induce myocardial contractibility
..Cause cinchonism = blurred vision, vertigo, tinnitus, tremor, light headness, nausea ....hypotension, bronchial asthma, anaphylactic shock
Procainamide :
Anorexia, diarrhea, vomiting, allergic Rxn,
SLE like syndrome.
Disopyramides:
Urinary retention, dryness of the eye, nose, mouth, throat.


IB
Lidocaine
Tocainide
Mexiletine

Fast Na+ block
Shortens the action potential duration.

Influence the ventricular function
Lidocaine: May cause convulsion , respiratory depression
Cardiac arrest if given to a pt. With preexisting heart block.
Tocainide: GI = anorexia, vomiting , constipation, pulmonary fibrosis


IC
Flecainide
Propafenone
Moricizine

Slow Na+ block
No affect on APD

reduces conduction velocity
Inhibit phase 0 depolarization
Life threatening ventricular arrhythmias, Atrial fibrillation

CNS toxicity, blurred vision, dizziness, headache, metallic taste
Propafenone ; may increase the anticoagulant effect of wafarin

Class II
Propranolol
Esmolol


Indirect effect and Direct effect
Direct effect: decrease depolarization. Increase EPR
Indirect effect : decrease automaticity and conduction velocity, increase refraction

Reduction heart rate, myocardial contractibility
Congestive heart failure
Brochoconstriction
Bradycardia

Class III
Amiodarone
Bretylium
Sotalol

K+ channel blocker Increases EPR and delay repolariazation
Acute and chronic arrhythmias
Vomiting , parotid pain, hypothyroidism effect
Class IV
Verapamil
Diltiazem

Ca +2 blocking
Reduce the conduction velocity and increase the refraction period.

Antianginal effect
Mild effects
  • Dizziness
  • Headaches
  • Hypotension
  • Constipation
  • Nausea
  • Rash
Serious effects
  • Heart failure
  • Bradycardia
  • AV block
  • Ventricular asystole
  • Ventricular fibrillation
  • Pulmonary edema

Miscellaneous
Adenosine
Unknown
Stimulates the A1 adenosine receptor. Hyperrepolariazation
Useful for o short term treatment of supraventricular tachycardia
Dilation and reduction of contractility

Flushing and dyspnea.

Indication for antiarrhythmic drugs:

Drugs giving orally = prevent the recurrence of arrhythmia
Drugs giving parenetrally = treat acute disorder.

Drug interaction:

Because the margin safety of these drugs as a group is narrow, significant interaction may develop. Examples:
Quinidine may interact with the followings”

- Hepatic enzyme inducers = decrease plasma quinidine concentration ex: rifampin
- Hepatic enzyme inhibitors= increase drug concentration



Implication in dentistry:

There is Potential for an increase incidence of orthostatic hypotension and hypertensive syncope
Epinephrine interaction with propranolol may lead to hypertensive reaction.


Antianginal Drugs

Angina occurs when there is a greater demand for oxygen than can be met by diseased coronary arteries. It is treated with:

  1. Nitrates and nitrites: esters of nitric acid (nitrates) and nitrous acid (nitrites) promote relaxation of vascular smooth muscles. They activate guanylate cyclase and increase cyclic guanine nucleotides, resulting in blood vessel dilation. Venodilation decreases cardio preload, reducing oxygen demand because the workload on the heart is decreased.
  2. Receptor antagonists
  3. Calcium channel blockers
Nitrates: are drugs of choice for relieving acute angina.

Pharmacokinetics:
Are administered sublingually, buccally, as chewable tablets as lingual aerosols or via inhalation are absorbed almost completely because of the rich block supply of mucous membranes of mouth. Swallowed nitrate capsules are absorbed through mucous membranes of GI tract and only about half the dose enters circulation. Transdermal nitrates are absorbed slowly and in varying amounts, depending on quantity of drug applied, the location where the patch is applied surface area of skin used, and circulation to skin. IV nitroglycerin which doesn’t need to be absorbed, goes directly into circulation.

Pharmacodynamics:
Nitrates cause smooth muscle of veins and to a lesser extent, the arteries to relax and dilate. Nitrates work in following way:
  • Veins dilate, less blood return to the heart
  • Reduces amount of blood in ventricles at end of diastole, when ventricles are full.
  • By reducing preload, nitrates reduce ventricular size and ventricular wall tension. This, in turn, reduces oxygen requirements of heart.
Nitrates decrease afterload by dilating arterioles, reducing resistance, easing heart’s workload, and easing demand for oxygen.

Pharmacutherapeutics:
Nitrates are used to relieve and prevent angina. Rapid absorbed nitrates are the drugs of choice for relief of acute angina because they have a rapid onset of action are easy to take, and are inexpensive. Nitroglycerin transdermal patches are longer lasting and are convenient and can be used to prevent chronic angina. Oral nitrates are also used because they seldom produce serious adverse reaction.

Drug interactions:

  • Severe hypotension can result when nitrates ineract with alcohol
  • Sildenafil shouldn’t be taken within 24 hrs of nitrates because of possible enhanced hypotensive effects.
  • Absorption of sublingual nitrates may be delayed when taken with an anticholinergic drug
  • Marked orthostatic hypotension with light headedness, fainting, or blurred vision may occur when calcium channel blockers and nitrates are used together.

Adverse reactions:

Headaches
Hypotension with dizziness and increased heart rate

Changes to cardiovascular system and reactions usually disappear when dosage is reduced


  • Beta adrenergic antagonist:
Pharmacokinetics:
Metoprolol and propranolol are absorbed almost entirely from GI tract whereas less than half the dose of atenolol or nadolol is absorbed. These beta adrenergic blockers are distributed widely. Propranolog is highly protein bound; the other beta adrenergic blockers are poorly protein bound. Propranolol and metoprolol are metabolized in liver and their metabolites are excreted in urine. Carvedilol is metabolized in liver and excreted in bile and feces. Atenolol and nadolol aren’t metabolized and are excreted unchanged in escretions.

Pharmacodynamics:
Beta adrenergic blockers decrease blood pressure and lock betadrenergic receptor sites in the heart muscle and conduction system. This decreases heart rate and reduces force of heart’s contractions resulting in a lower demand for oxygen.

Pharmacotherapeutics:
Beta adrenergic blockers are indicated for long-term prevention of angina. Metoprolol may be give IV in acute coronary syndrome, followed by an oral dose. Carvedilol and metoprolol are indicated for heart failure. Beta adrenergic blockers are also first-line therapy for treating hypertension.
Drug Interaction:
    • Antacids delay absorption
    • NSAIDs can decreas hypotensive effects of beta-adrenrgic blockers.
    • Lidocaine toxicity may occur when drug is taken with beta adrenergic blockers.
    • Requirements for insulin and oral antidiabetic drugs can be altered by beta adrenergic blockers
    • Ability of theophylline to produce bronchodilation is impaired b nonselective beta adrenergic blockers.

Adverse Reactions:
    • Bradycardia, angina, heart failure, arrhythmias (AV block)
    • Fainting
    • Fluid retention
    • Peripheral edema
    • Shock
    • Nausea and vomiting
    • Diarrhea
    • Significant constriction of bronchioles
Sudden stopping beta adrenergic blocker may trigger angina, hypertension, arrhythmias and acute MI
Calcium channel blockers
Used to prevent angina that doesn’t respond to drugs in either of other antianginal classes. Several of the calcium channel blockers are also used as antiarrhythmics and in treatment of hypertension.

Pharmacokinetics:
Administered orally, and are absorbed quickly and almost completely. Because of the first-pass effect, the bioavailability of these drugs is much lower. Calcium Channel blockers are highly bound to plasma proteins. They are metabolized rapidly and almost completely in the liver.
Pharmacodynamics:
Prevent passage of calcium ions across myocardial cell membrane and vascular smooth muschle cells. This causes dilation of coronary and peripheral arteries which decreases force of heart’s constractions and reduces workload on heart.
Decreases oxygen demand of the heart; some decrease heart rate by slowing conduction through SA and AV nodes. A slower heart rate reduces heart’s need for additional oxygen.


Pharmacotherapeutics:
Used only for long-term prevention of angina, not for short term relief of chest pain. Calcuim channel blockers are particularly effective for preventing prinzmetal’s angina.
Drug interactions
    • Calcium salts and vitamin D reduce effectiveness of calcium channel blockers.
    • Nondepolarizing blocking drugs may enhance muscle relaxant effect when taken with calcium channel blockers
    • Verapamil and diltiazem increase risk of digoxin toxicity and enhance action of carbamazepine.

Adverse Reaction:
    • Cardiovascular reactions
    • Orthostatic hypotension
    • Heart failure
    • Hypotension
    • Arrhythmias
    • Dizziness
    • Headaches
    • Flushing
    • Weakness
    • Persistent peripheral edema.

Heart Failure

  • First Agents Used:
    • ACE inhibitors
    • Diuretics
    • Cardiac Glycosides
    • Beta-blockers

LIPID- LOWERING DRUGS
There are different types of lipoproteins based on density of their complex. Lower density = higher lipid content
VLDL- very low density lipoprotein
IDL- intermediate density llipoprotein
LDL low density lipoprotein
HDL- high density lipoprotein
a- lipoproteins
Hyperlipidemia may originate from genetics or dietary factors, or disease states such as diabetes mellitus, hypothyroidism, uremia. Atherosclerosis is caused by the accumulation of fatty streaks and plaques in arteries. Relationship between lipoproteins and atherosclerosis is that patients with hyperlipidemia can see a reduction in cholesterol with regression of plaque formation and less of a chance to attain atherosclerosis.
Therapeutic measures include starting with altering the patients diet if further help is needed then adminstration of drugs shoud be given based on patients age, gender, ischemic vascular disease. Lipid lowering drugs are commonly used in patitents with ischemic heart disease to prevent MI. Drugs that lower plasma cholesterol are used to delay or reverse progression of atherosclerosis.

Properties of lipid lowering drugs:


Lipoprotein
Concentrations
Plasma concentration
Plasma
Triglyceride
Toxicity
Drug
Interactions
Clofibrate
(fibrin acid
Derivatives)
Example:
Atomid-S
↓VLDL,↓ IDL


Nausea, diarrhea, myositis, abnormal liver function test, skin rash, ventricular octopi, increased incidence of noncardiac death
Enhanced effect of coumadin and anticoagulants
Gemifibrozil
(fibrin acid
Derivatives)
Example:
Lopid

↓VLDL,↓ IDL ↑HDL


Abnormal pain, epigastric pain, diarrhea, nausea, vomiting, flatulence, rash, headache, dizziness, anemia, eosinophilia
Enhanced effect of coumadin anticoagulants, myopathy with HMG-CoA reductase inhibitors
Nicotinic acid
Example:
Niacor

↓VLDL,↓ IDL
↓LDL, ↑HDL



Flushing, pruritus, nausea, diarrhea, glucose intolerance, hyperuricemia, hepatotoxicity
Increased hypertensive action of ganglionic blocking agents
Cholestyramine, colestipol
(bile acid sequestrants)
Example:
Questran

↑VLDL, ↓ LDL

May increase modestly in some pts.
Constipation, nauseas, abdominal pain, flatulence, biliary tract calcification, streatorrhea, hyperchloremic acidosis
Decreased absorption of thiazides, tetracycline, Phenobarbital, thyroxine, digitalis, coumadin anticoagulants
Probucol
Example:
Lorelco

↓ LDL, ↓HDL


Diarrhea, flatulence, abdominal pain, nausea, excess perspiration angioedema, increased QT interval

HMG-CoA
Reductase
Inhibitors
Example:
Lovastatin

↓ IDL
↓LDL, ↑HDL



Headache, flatulence, abdomindal pain, diarrhea, rash, increased creatine knase and other enzyme activities, myopathy
Enhanced effect of coumadin anticoagulants, myopathy, rhabdomyolysis, renal failure with nicotinic acid, gemfibrozil, erythromycin, cyclosporine
Ezetimibe
Example:
Zetia

↓ LDL, ↓HDL


Headache, sinusitis, pharyngitis
Cholestyramne binds ezetimibe and lowers its bioavailablity of digitalis or coumadin anticoagualants

Other antihyperlipidemic include fish oils. They can ↓ plasma cholesterol, ↓ triglycerides, ↓ VLDL, ↑ HDL. However, this needs to be further tested to prove its efficacy with further studies.
Combined Drug Therapy is used for three main reasons:
1. Combined drug therapy can produce a higher reduction in lipid levels than compared to using one single drug.
2. Some drugs have certain unwanted side effects such as increasing lipid levels. Thus, combining drugs can counteract another one.
3. By combining these drugs they can be administered in lower doses decreasing side effects.



Heart diseases can be primarily grouped into three major disorders: cardiac failure, ischemia and cardiac arrhythmia.
Cardiac failure can be described as the inability of the heart to pump blood effectively at a rate that meets the needs of the metabolizing tissues. This occurs when the muscles that perform contraction and force the blood out of heart are performing weakly. Thus cardiac failures primarily arise from the reduced contractility of heart muscles, especially the ventricles. Reduced contraction of heart leads to reduced heart output but new blood keeps coming in resulting in the increase in heart blood volume. The heart feels congested. Hence the term congestive heart failure.

Congested heart leads to lowered blood pressure and poor renal blood flow. This results in the development of edema in the lower extremities and the lung (pulmonary edema) as well as renal failure.

The Cardiac Glycosides (Cardenolides) - the Digitalis Preparations
Drug Members :


      1. Digitoxin (Crystodigin)
      2. Digoxin (Lanoxin)
      3. Deslanoside (Cedilanid-D)
Natural plant analogs of today’s modern glycoside preparations have been used for at least 3,000 years. Cardiac glycosides were used for heart conditions by the Egyptians, Romans and the early Europeans. The cardiac glycosides are commonly found in plants such as Milkweed, Lilly of the Valley, the Oleander plant, and in the Foxglove plant. This is a very good reason to preserve the earth’s rain forests because of the very real chance they hold plants that will one day cure diseases.
Mechanisms of Action :
The main action of the Cardiac Glycosides is to increase the force of cardiac contraction. They do this in the following ways :
1. A Rise In The Concentration Of Intracellular Sodium. An enzyme called Na+- K+ ATPase cleaves ATP to ADP and Pi. The energy released from the hydrolysis of ATP drives the Na+-K+ pump which normally pumps Na+ out of the cell and K+ into the cell. If, however, this pump is disabled by the inhibition of this enzyme, the net effect is the malfunction of the pump and an increase of sodium inside the cell with a loss of intracellular potassium to the extracellular space. The influx of Na+ is partly due to the passive re-entry of sodium inside the cell while the efflux of K+ is passive to the outside of the cell.
2. A Rise In The Concentration Of Intracellular Calcium . In the heart, there is a second pump called the Na+-Ca2+ pump. This pump normally takes 1 intracellular Ca2+ ion out of the myocyte in exchange for 4 extracellular Na+ ions brought into the myocyte. This pump is turned on by a diffusion gradient difference in extracellular to intracellular sodium when the extracellular sodium concentration is higher than the intracellular sodium concentration. When the [Na+]Outside drops because the [Na+]Inside rises, then the pump becomes deranged and stops pumping Ca2+ out of the cell. When the Na+ - K+ pump is disabled, there is a rise of [Na+]Inside the cell as well as a rise in the [Ca2+]Inside . The [Ca2+]Inside will rise because of passive diffusion back into the cell coupled with the fact that the cell is not pumping any Ca2+ ions out.

Summary : Since the cardiac cell experiences a rise in [Ca2+] inside the cell, the force and velocity of contraction in greatly increased. This is the prime mechanism of action of all cardiac glycoside drugs.
Additional Mechanisms Of Action :
1. The glycosides enhance vagal tone over the heart which :


      • slows the heart rate
      • slows the AV node conduction velocity
      • increases the AV nodal refractory period
The net effect of the glycosides on the heart is as follows :
a. heart rate is slowed
b. contraction is greater due to increased filling volumes - Starling’s Law
c. ejection fraction is improved
d. increased ejection velocity


Adverse Side Effects Of The Glycosides :

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Check list of common cardiac drugs
Drugs
Main effects
Mechanism
Sites of action
abciximab
anticoagulant stops platelet activation
monoclonal antibody to fibrinogen receptors
platelets
amiloride (combination with frusemide is frumil)
potassium sparing diuretic
plasmalemma sodium & chloride channels
kidney (distal tubules)
amiodarone
class III anti-arrhythmic
prolongs action potential duration
myocardium
aspirin
anticoagulant stops platelet activation
COX inhibitor, blocks TXA2 synthesis
platelets
atropine (sometimes used to stop vagus bradycardia)
parasympatholytic, increases heart rate
blocks muscarinic AcCh receptors
pacemaker cells (sino-atrial node)
captopril
reduces arterial blood pressure
ACE inhibitor
relaxes vascular smooth muscle
clopidogrel
anticoagulant stops platelet activation
blocks ADP receptor
platelets
digitalis and ouabain
increase cardiac contractility, delay AV node triggering
block Na / K ATPase raising intracellular sodium, then calcium
all tissues, but the Na/Ca exchanger is mainly in heart
dipyridamole (often used for X-ray imaging)
coronary vasodilation
inhibition of adenosine uptake
coronary vasculature
furosemide (= frusemide)
diuretic
plasmalemma sodium & chloride channels
kidney (loop of Henle)
isoprenaline (and other adrenaline analogues)
increase cardiac contractility
beta agonist raises cyclic AMP
many tissues
losartan
reduces arterial blood pressure
angiotensin AT1 receptor blockade
relaxes vascular smooth muscle
lovastatin
reduces blood cholesterol levels
HMG-CoA reductase inhibitor
liver
morphine
pain relief (mainly)
opiate receptors
brain
nitroglycerine (and many other organic nitrates)
reduce cardiac work load
metabolised to NO
relaxes vascular smooth muscle
propranolol
reduces cardiac contractility, class II anti-arrhythmic
beta blocker lowers cyclic AMP
many tissues
quinidine, novocaine and other local anaesthetics
class I anti-arrhythmics
delay recovery of sarcolemma sodium channels after AP
myocardium
spironolactone (usually added to other diuretics)
reduces diuretic potassium losses
aldosterone antagonist
kidney (distal tubules)
urokinase (streptokinase is cheaper but antigenic)
dissolves blood clots (fibrinolytic)
activates plasminogen to plasmin (protease)
blood clots
verapamil, nifedipine and other dihydropyridines
reduce cardiac work load, class IV anti-arrhythmic
block sarcolemma calcium channels
myocardium; relax vascular smooth muscle
warfarin
anticoagulant
vit. K antagonist
blocks g-carboxy glutamate synthesis
liver