Cardiovascular+Drugs

=Cardiovascular Drugs = = = = = = = =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: = ·  <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;"><span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">Supraventricular = originating in the atria or conducting system not in the ventricular  ·  <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">Ventricular= most common

=<span style="font-size: 12pt; color: rgb(54,95,145); font-family: 'Comic Sans MS',cursive;">Antiarrythmias drugs: = <span style="font-size: 12pt; line-height: 115%; font-family: 'Comic Sans MS',cursive;"> -  <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;"><span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">Depends on the type of the arrhythmia -  <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">The most common classification = The Vaughan William classifications -  <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">The Vaughan William classifications o <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">Based on the primary mechanism of action o <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">Has limitation since many agents has more than one action o <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">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 <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">

<span style="font-size: 12pt; line-height: 115%; font-family: 'Comic Sans MS',cursive;">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. Procainamide Disopyramide <span style="font-size: 12pt; font-family: 'Times New Roman','serif';"> || <span style="font-size: 12pt; font-family: 'Times New Roman','serif';">medium Na + block lengthens the action potential || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Ventricular arrhythmias Atrial tachyarrhythmia Reduces automaticity and conduction velocity Increases refraction || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">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. <span style="font-size: 12pt; font-family: 'Times New Roman','serif';"> || Tocainide Mexiletine || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Fast Na+ block Shortens the action potential duration. || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Influence the ventricular function || <span style="font-size: 12pt; font-family: 'Times New Roman','serif';"> <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Lidocaine: May cause convulsion, respiratory depression Cardiac arrest if given to a pt. With preexisting heart block. Tocainide: GI = anorexia, vomiting, constipation, pulmonary fibrosis <span style="font-size: 12pt; font-family: 'Times New Roman','serif';"> || Propafenone Moricizine || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Slow Na+ block No affect on APD || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">reduces conduction velocity Inhibit phase 0 depolarization Life threatening ventricular arrhythmias, Atrial fibrillation || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">CNS toxicity, blurred vision, dizziness, headache, metallic taste Propafenone ; may increase the anticoagulant effect of wafarin || Esmolol || <span style="font-size: 12pt; font-family: 'Times New Roman','serif';"> <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Indirect effect and Direct effect || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Direct effect: decrease depolarization. Increase EPR Indirect effect : decrease automaticity and conduction velocity, increase refraction || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Reduction heart rate, myocardial contractibility Congestive heart failure Brochoconstriction Bradycardia || Bretylium Sotalol || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">K+ channel blocker Increases EPR and delay repolariazation || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Acute and chronic arrhythmias || <span style="font-size: 12pt; font-family: 'Times New Roman','serif';">Vomiting, parotid pain, hypothyroidism effect || Diltiazem || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Ca +2 blocking Reduce the conduction velocity and increase the refraction period. || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Antianginal effect || <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Mild effects <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Serious effects || Useful for o short term treatment of supraventricular tachycardia Dilation and reduction of contractility || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Flushing and dyspnea. || <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';"> =<span style="color: rgb(54,95,145); font-family: 'Comic Sans MS',cursive;">Indication for antiarrhythmic drugs: = <span style="font-size: 12pt; color: rgb(0,0,0); line-height: 115%; font-family: 'Times New Roman','serif';">Drugs giving orally = prevent the recurrence of arrhythmia Drugs giving parenetrally = treat acute disorder. =<span style="color: rgb(54,95,145); font-family: 'Comic Sans MS',cursive;">Drug interaction: = =<span style="color: rgb(0,0,0); font-family: 'Comic Sans MS',cursive;"> = <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';"> <span style="color: rgb(0,0,0); font-family: 'Comic Sans MS',cursive;"><span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">Because the margin safety of these drugs as a group is narrow, significant interaction may develop. Examples: Quinidine may interact with the followings” - <span style="color: rgb(54,95,145); font-family: 'Comic Sans MS',cursive;"><span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">Hepatic enzyme inducers = decrease plasma quinidine concentration ex: rifampin - <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">Hepatic enzyme inhibitors= increase drug concentration
 * =<span style="font-size: 12pt; color: rgb(54,95,145); font-family: 'Comic Sans MS',cursive;">Drug Class = || =<span style="font-size: 12pt; color: rgb(54,95,145); font-family: 'Comic Sans MS',cursive;">Example = || =<span style="color: rgb(54,95,145); font-family: Cambria;"> <span style="font-size: 12pt; color: rgb(54,95,145); font-family: 'Comic Sans MS',cursive;">Mechanism = || =<span style="font-size: 12pt; color: rgb(54,95,145); font-family: 'Comic Sans MS',cursive;">Pharmacological effect = || =<span style="font-size: 12pt; color: rgb(54,95,145); font-family: 'Comic Sans MS',cursive;">Adverse effect = ||
 * <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">IA || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Quinidine
 * <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">IB || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Lidocaine
 * <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">IC || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Flecainide
 * <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Class II || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Propranolol
 * <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Class III || <span style="font-size: 12pt; font-family: 'Times New Roman','serif';"> <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Amiodarone
 * <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Class IV || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Verapamil
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Dizziness
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Headaches
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Hypotension
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Constipation
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Nausea
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Rash
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Heart failure
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Bradycardia
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">AV block
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Ventricular asystole
 * <span style="font-size: 130%; font-family: 'Comic Sans MS',cursive;">Ventricular fibrillation
 * <span style="font-family: 'Comic Sans MS',cursive;"><span style="font-size: 10pt; font-family: 'Comic Sans MS',cursive;">Pulmonary edem a
 * <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Miscellaneous <span style="font-family: 'Comic Sans MS',cursive;"> || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Adenosine || <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Unknown || <span style="font-size: 12pt; font-family: 'Times New Roman','serif';"> <span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;"><span style="font-size: 12pt; font-family: 'Comic Sans MS',cursive;">Stimulates the A1 adenosine receptor. Hyperrepolariazation

=<span style="color: rgb(0,49,255); font-family: 'Comic Sans MS',cursive;">Implication in dentistry: = <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">There is Potential for an increase incidence of orthostatic hypotension and hypertensive syncope Epinephrine interaction with propranolol may lead to hypertensive reaction.

Angina occurs when there is a greater demand for oxygen than can be met by diseased coronary arteries. It is treated with: Nitrates: are drugs of choice for relieving acute angina. <span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">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.
 * <span style="font-size: 16pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">Antianginal Drugs **
 * 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

<span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">Pharmacodynamics: Nitrates cause smooth muscle of veins and to a lesser extent, the arteries to relax and dilate. Nitrates work in following way: Nitrates decrease afterload by dilating arterioles, reducing resistance, easing heart’s workload, and easing demand for oxygen.
 * 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.

<span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">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.

<span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">Drug interactions: <span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">Adverse reactions: Headaches Hypotension with dizziness and increased heart rate Changes to cardiovascular system and reactions usually disappear when dosage is reduced <span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">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.
 * 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.
 * Beta adrenergic antagonist **:**

<span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">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.

<span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">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. <span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">Drug Interaction: <span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">Adverse Reactions: 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.
 * 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.
 * Bradycardia, angina, heart failure, arrhythmias (AV block)
 * Fainting
 * Fluid retention
 * Peripheral edema
 * Shock
 * Nausea and vomiting
 * Diarrhea
 * Significant constriction of bronchioles

<span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">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. <span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">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.

<span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">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. <span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">Drug interactions <span style="font-size: 10pt; color: rgb(54,95,145); font-family: 'Comic Sans MS';">Adverse Reaction:
 * 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.
 * 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

<span style="font-size: 12pt; color: rgb(0,0,255); line-height: 115%; font-family: 'Times New Roman',serif;">**<span style="font-family: 'Comic Sans MS',cursive;">LIPID- LOWERING DRUGS ** <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';"> <span style="font-size: 12pt; line-height: 115%; font-family: 'Comic Sans MS',cursive;">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. <span style="font-family: 'Comic Sans MS',cursive;"><span style="font-size: 12pt; color: rgb(0,0,255); line-height: 115%; font-family: 'Times New Roman',serif;">**Properties of lipid lowering drugs:** <span style="font-size: 12pt; line-height: 115%; font-family: 'Times New Roman','serif';">

Concentrations || Plasma concentration || Plasma Triglyceride || Toxicity || Drug Interactions || (fibrin acid Derivatives) Example: Atomid-S || <span style="font-family: 'Comic Sans MS',cursive;">↓VLDL,↓ IDL || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">Nausea, diarrhea, myositis, abnormal liver function test, skin rash, ventricular octopi, increased incidence of noncardiac death || <span style="font-family: 'Comic Sans MS',cursive;">Enhanced effect of coumadin and anticoagulants || (fibrin acid Derivatives) Example: Lopid || <span style="font-family: 'Comic Sans MS',cursive;">↓VLDL,↓ IDL ↑HDL || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">Abnormal pain, epigastric pain, diarrhea, nausea, vomiting, flatulence, rash, headache, dizziness, anemia, eosinophilia || <span style="font-family: 'Comic Sans MS',cursive;">Enhanced effect of coumadin anticoagulants, myopathy with HMG-CoA reductase inhibitors || Example: Niacor || <span style="font-family: 'Comic Sans MS',cursive;">↓VLDL,↓ IDL ↓LDL, ↑HDL || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">Flushing, pruritus, nausea, diarrhea, glucose intolerance, hyperuricemia, hepatotoxicity || <span style="font-family: 'Comic Sans MS',cursive;">Increased hypertensive action of ganglionic blocking agents || (bile acid sequestrants) Example: Questran || <span style="font-family: 'Comic Sans MS',cursive;">↑VLDL, ↓ LDL || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">May increase modestly in some pts. || <span style="font-family: 'Comic Sans MS',cursive;">Constipation, nauseas, abdominal pain, flatulence, biliary tract calcification, streatorrhea, hyperchloremic acidosis || <span style="font-family: 'Comic Sans MS',cursive;">Decreased absorption of thiazides, tetracycline, Phenobarbital, thyroxine, digitalis, coumadin anticoagulants || Example: Lorelco || <span style="font-family: 'Comic Sans MS',cursive;">↓ LDL, ↓HDL || <span style="font-family: 'Comic Sans MS',cursive;"> || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">Diarrhea, flatulence, abdominal pain, nausea, excess perspiration angioedema, increased QT interval || <span style="font-family: 'Comic Sans MS',cursive;"> || Reductase Inhibitors Example: Lovastatin || <span style="font-family: 'Comic Sans MS',cursive;">↓ IDL ↓LDL, ↑HDL || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">Headache, flatulence, abdomindal pain, diarrhea, rash, increased creatine knase and other enzyme activities, myopathy || <span style="font-family: 'Comic Sans MS',cursive;">Enhanced effect of coumadin anticoagulants, myopathy, rhabdomyolysis, renal failure with nicotinic acid, gemfibrozil, erythromycin, cyclosporine || Example: Zetia || <span style="font-family: 'Comic Sans MS',cursive;">↓ LDL, ↓HDL || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">↓ || <span style="font-family: 'Comic Sans MS',cursive;">Headache, sinusitis, pharyngitis || <span style="font-family: 'Comic Sans MS',cursive;">Cholestyramne binds ezetimibe and lowers its bioavailablity of digitalis or coumadin anticoagualants || <span style="font-family: 'Comic Sans MS',cursive;"> 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.  <span style="font-family: 'Comic Sans MS',cursive;">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. <span style="font-size: 16px; line-height: normal; font-family: 'Comic Sans MS',cursive;">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. <span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">The Cardiac Glycosides (Cardenolides) - the Digitalis Preparations Drug Members :
 * || Lipoprotein
 * Clofibrate
 * <span style="font-family: 'Comic Sans MS',cursive;">Gemifibrozil
 * <span style="font-family: 'Comic Sans MS',cursive;">Nicotinic acid
 * <span style="font-family: 'Comic Sans MS',cursive;">Cholestyramine, colestipol
 * <span style="font-family: 'Comic Sans MS',cursive;">Probucol
 * <span style="font-family: 'Comic Sans MS',cursive;">HMG-CoA
 * <span style="font-family: 'Comic Sans MS',cursive;">Ezetimibe

<span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">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. Additional Mechanisms Of Action : 1. The glycosides enhance vagal tone over the heart which :
 * 1) <span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">Digitoxin (Crystodigin)
 * 2) <span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">Digoxin (Lanoxin)
 * 3) <span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">Deslanoside (Cedilanid-D)
 * <span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">Summary : **<span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;"> 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.

<span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">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
 * <span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">slows the heart rate
 * <span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">slows the AV node conduction velocity
 * <span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">increases the AV nodal refractory period

<span style="font-weight: normal; font-family: 'Comic Sans MS',cursive;">Adverse Side Effects Of The Glycosides :

vit. K antagonist || blocks g -carboxy glutamate synthesis || liver ||
 * ~ 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

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