Presentation is loading. Please wait.

Presentation is loading. Please wait.


Similar presentations

Presentation on theme: "CLINICAL OVERVIEW ON CV DRUGS"— Presentation transcript:









9 Digitalis. Digitalis:- increases the strength of the heart's contractions, - reduces heart size, - reduces certain arrhythmias. * It is derived from the foxglove plant, it has been used to treat heart disease since the 1700s and is still the only oral inotropic agent in general use

10 > digitalis does not reduce mortality rates,
* In general, > digitalis does not reduce mortality rates, > although it improves symptoms; > patients who take digitalis are also hospitalized slightly less often than those not taking the drug.

11 ** Many experts now believe that patients should first be prescribed drugs proven to prolong life, such as an ACE inhibitor or the beta blocker carvedilol, before digitalis is recommended.

12 > systolic dysfunction ( low EF%)
** Digitalis may be useful for patients with: > systolic dysfunction ( low EF%) > heart failure & atrial fibrillation, ** Digitalis may even be harmful in some patients with HF, particularly when caused by diastolic dysfunction characterized by normal EF..

13 > Most physicians prescribe digoxin (Lanoxin).
> The most serious side effects are arrhythmias, abnormal heart rhythms that can be life-threatening. > Factors which increase the risk of toxicity include advanced age, low blood potassium levels , hypothyroidism, anemia, valvular heart disease, and impaired kidney function

14 - Early signs of toxicity :
- Digitalis interacts with many other drugs, including,>> quinidine, amiodarone, verapamil, flecainide, amiloride and propafenone. - Early signs of toxicity : >arrhythmia, nausea and vomiting, stomach pain, fatigue, visual disturbances (e.g., yellow vision, seeing halos around lights, which may also flicker or flash), and emotional and mental disturbances.

15 > Toxic side effects used to be experienced by nearly 25% of patients taking digitalis, but now that a blood test can be used to monitor the level of the drug in the blood, toxicity is down to 2%.

16 > If side effects exist, but are mild, patients should still consider continuing with digitalis if other benefits are experienced. > It was found that patients who stopped taking digoxin after using it in combination with ACE inhibitors were at risk for worsening HF.

17 Vasopressors And Inotropes
- Useful for resuscitation of seriously ill patients, and for the treatment of hypotension in theatre. - Act directly or indirectly on the SNS, but the effect of each varies according to which sympathetic receptor the drug has greatest affinity for.

18 -The duration of action also varies.
- Direct acting drugs act by stimulating the SNS receptor whereas indirect acting drugs cause the release of noradrenaline from the receptor . - Some drugs have a mixed effect

19 > A1 Peripheral arteriolar vasoconstriction
> B1  Cordiac increased heart rate and force of conctraction

20 > B2  Bronchial smooth muscle dilation, vasodilation in skeletal muscle, also some cardiac effects > D  Increased renal blood flow .

21 Adrenaline (Epinephrine)
Adrenaline acts on a1, b1 and b2 receptors. It is said to prepare the body for a "fight or flight" response

22 Ephedrine Ephedrine acts directly on b1 and b2 receptors, and indirectly on a1 receptors by causing noradrenaline release

23 * Indications: > Low blood pressure due to vasodilation e.g. following spinal or epidural anaesthesia and drug overdoses. Best vasopressor to use in pregnancy as it does not reduce placental blood flow * Dose 3-10 mg boluses iv, repeat until effective. Maximum dose is 60mg. > Duration of action 5-15 minutes, repeated doses less effective (i.e. it demonstrates tachyphylaxis

24 Methoxamine - Side effects May produce bradycardia
- Methoxamine acts on a1 receptors - Actions Increases blood pressure. There may be a reflex decrease in HR, and therefore it is good for hypotension with tachycardia. >> Useful during spinal anaesthesia - Side effects May produce bradycardia - Dose 2-4mg boluses IV, repeated as necessary

25 Phenylephrine - Acts directly on a1 receptors
- Action Hypertension and a reflex decrease in heart rat - Dose 2-5mg im or sc, mg iv, by infusion 20-50mcg/min

26 Noradrenaline - Acts mainly on a1 receptors with few effects on b receptors - Actions Increases blood pressure by vasoconstriction. Less likely to cause tachycardia than adrenaline - Indications Septic shock where peripheral vasodilation may be causing hypotension

27 > Cautions Acts by increasing afterload and therefore not appropriate for use in patients in cardiogenic shock. Blood supply to kidneys and peripheries may be reduced > Dose mcg/min > Add 4mg to 250ml 0.9% NaCl or 5% dextrose to give 16mcg/ml. Run at 0-112ml/hr

28 Dopamine - Actions Dose dependent.
- Acts on D, b1, b2 and a1 receptors, depending on the dose administered - Actions Dose dependent.

29 Dobutamine - Actions: increases COP and reduces afterload
- Acts on b1 and b2, with minimal action on a1 receptors - Actions: increases COP and reduces afterload ** Indications : - Cardiogenic shock - Severe HF Dose 2-30mcg/kg/min Add 3mg/kg to 50mls 0.9%NaCl or 5% glucose 1ml/hr = 1mcg/kg/min

30 Dopexamine > Acts on b2 and D receptors
> Actions: -It increases COP and reduces afterload. - Increases blood supply to the kidneys and possibly also the GIT . > Dose 0.5-6mcg/kg/min

31 Salbutamol Indications - Acts on b2 receptors
- Actions Relaxes bronchial smooth muscle i.e. bronchodilation, may increase HR Indications Severe acute asthma ** Dose By infusion 5-20mcg/min. ** Can also be given in bolus form iv in the initial treatment of an attack at a dose of 5mcg/kg over several minutes

32 Isoprenaline - Acts on b1 and b2 receptors - Main action is increased heart rate. Also increased force of contraction, and bronchodilation * Indications: >CHB, overdose of B- blocker or severe bradycardia unresponsive to atropine. Can be used to treat asthma, >but less suitable than drugs that act only on b2 receptors e.g. salbutamol

33 Phosphodiesterase inhibitors (e.g. aminophylline, enoximone)
** Prevent breakdown of cAMP this produces effects at b1 and b2 receptors ** Actions  increased rate and force of contraction, vasodilation in skeletal muscle. Also bronchodilation ** Indications : > Aminophylline: asthma, cardiac failure > Enoximone: HF in patients failing to respond to dobutamine

34 * Carvedilol: > As the output of the heart drops in patients with CHF, the body is stressed and releases catecholamines > These adrenergic substances increases HR and stimulates the weak muscle to contract more forcefully. > This is known as a "beta adrenergic effect" and increases the work that the heart has to perform. The sick heart gets sicker as it works harder

35 >The adrenergic substances also cause the arterial walls to constrict or tighten.
> This is known as "alpha adrenergic effect" and helps to raise the blood pressure when the weak heart cannot do so on its own. > However, this increases the resistance putting an additional load on the struggling heart.

36 ** Carvedilol: >> The HR is slowed,
> A drug blocks both the alpha and beta blocking effects. >> The HR is slowed, >> the weak heart muscle is protected from the "whipping" or stimulating effects >> the arteries are dilated so as to make it easier for the heart to empty. >>> Improve symptoms, decrease the need for hospitalization and improve survival in patients with CHF..

37 >> Carvedilol and other agents in its class are always considered in the treatment of CHF unless they are contraindicated or not tolerated. >>They are generally avoided in patients with asthma, extremely slow heart rates and very low blood pressure

38 converting Enzyme Inhibitors (ACEI)
Angiotensin converting Enzyme Inhibitors (ACEI)


40 Adrenomedullin > A potent vasodilator that reduces blood pressure while increasing cardiac output. > It is produced by many tissues, including heart and vascular smooth muscle when stimulated by pro-inflammatory cytokines > It probably acts via nitric oxide and cAMP, but the principal signalling system varies between tissues and species.

41 Aldosterone > It is produced by the adrenal cortex when stimulated by angiotensin II. > It causes sodium and water retention by the kidney, and a urinary potassium losses. > It is also regulates salt resorption in the colon and sweat glands, and promotes collagen synthesis in cardiac muscle leading to myocardial fibrosis.

42 ** Spironolactone is a non-specific aldosterone antagonist that has been in use for several years, but it also binds to sex steroid receptors leading to unwanted side effects. >> It is commonly added to other drug regimes

43 Bradykinin - A vasodilator peptide released from clotting factor XII by a tissue protease called kallikrein. - It plays little role in the regulation of normal blood flow, but becomes more important following injury or infection.

44 Brain natriuretic peptide
- (BNP, nesiritide) has recently been approved for clinical use. - This peptide is released naturally from overstretched ventricular muscle.

45 Calcium sensitizers > There is dispute about their mode of action, and levosimendan also activates the ATP sensitive potassium channel in vascular smooth muscle plasmalemma, leading to an increase in coronary flow

46 Chemokines and cytokines
-They are produced by macrophages and many other cell types. -They are raised in CHF, and there is increased expression within the failing myocardium They are implicated in the pathogenesis of dilated cardiomyopathy

47 - These peptides act on the hypothalamus to increase body temperature, reduce food intake and result in the mobilisation of energy and protein stores. -They stimulate the liver to secrete C-reactive protein and mannan-binding lectin as part of the acute phase response. -Various anti-cytokine trials have so far yielded disappointing result

48 Endothelin - It is a potent vasoconstrictor and smooth muscle mitogen secreted by endothelial cells lining the blood vessel walls. -The endothelin system is activated in several disease states including hypertension and heart failure.

49 * Two classes of endothelin receptor:
a) ETAR located mainly on vascular smooth muscle cells >>> signaling causes both vasoconstriction and myoproliferation b) ETBR located mainly on the endothelial cells themselves..>>> signals vasodilation when expressed on endothelial cells but vasoconstriction when expressed on smooth muscle cells

50 > Selective and non-selective endothelin receptor antagonists ETRA have been developed.
> Pre-clinical studies have shown limited effects on hypertension, but these drugs have an excellent ability to prevent end organ damage

51 Growth hormone - It is an experimental drug for the treatment of CHF
- Many of the actions of growth hormone are mediated indirectly by locally-produced insulin-like growth factors

52 Vasopeptidase inhibitors
_ Simultaneously inhibit both neutral endopeptidase and angiotensin-converting enzyme (ACE). - Neutral endopeptidase is responsible for the breakdown of both bradykinin and the natriuretic peptides, so inhibition of this enzyme should produce valuable clinical effects

53 Vasopressin There are three classes of vasopressin receptors
Is a powerful vasoconstrictor that also activates water uptake from the kidney collecting ducts, producing a concentrated urine and retaining water within the body. There are three classes of vasopressin receptors

54 > Both V1 and V2 are targets for drug development work.
. V1 in the vascular system, V2 are on the kidney collecting ducts and V3 are in the posterior pituitary. > Both V1 and V2 are targets for drug development work. ** Vasopressin antagonists are only just starting clinical trials, but have already been shown to produce a powerful aquaretic effect in human volunteers.

55 Antiarrhythmic Drugs

56 Pharmacology > Antiarrhythmic drugs act by altering the flux of ions across the membranes of excitable cells in the heart. > The primary mechanisms of action correspond to the mechanisms used in developing the Vaughan Williams classification system,

57 The Vaughan Williams classification scheme is relatively simple and is useful as a conversational shorthand based on mechanism of action, for its ability to predict adverse effects and for preliminary decisions regarding drug therapy.


59 important drawbacks 1-Drugs within a class are not necessarily clinically similar; a patient may respond well to one drug in a given class, but not another 2-Almost all of the currently available drugs have multiple actions ,, it is rarely apparent which of these actions is responsible for suppression of an arrhythmia in a given patient

60 Note that some of the most useful and widely used drugs (quinidine, procainamide, disopyramide, amiodarone, sotalol) have multiple actions * This may explain their utility in treating a broad range of arrhythmias or arrhythmias of unknown cause

61 Sicilian Gambit Classification
An alternative classification system, known as the 'Sicilian Gambit', has been proposed that is based on arrhythmogenic mechanisms

62 This system identifies one or more 'vulnerable parameters' associated with a specific arrhythmogenic mechanism.

63 A vulnerable parameter is an electrophysiological property or event whose modification by drug therapy will result in the termination or suppression of the arrhythmia with minimal undesirable effects on the heart.

64 Unlike the Vaughan Williams classification system, this system can readily accommodate drugs with multiple actions.

65 This multidimensional classification system is significantly more complex than the standard Vaughan Williams system, but provides a more flexible framework for classifying antiarrhythmic drugs based on pathophysiological considerations


67 Pharmacology Antiarrhythmic drugs act by altering the flux of ions across the membranes of excitable cells in the heart. The primary mechanisms of action correspond to the mechanisms used in developing the Vaughan Williams classification system.,

68 They include > inhibition of sodium channels (Class I drugs),
> inhibition of calcium channels (Class IV drugs), > inhibition of potassium channels (Class III drugs), > blockade of beta-adrenergic receptors in the heart (Class II drugs)

69 Use(Rate)-Dependent Blockade by Channel Blockers
An ideal antiarrhythmic drug should target ectopic pacemakers and rapidly depolarizing tissue to a greater extent than normal tissues of the heart

70 Many of the sodium (Class I) and calcium (Class IV) channel blockers have this property because they preferentially block sodium and calcium channels in depolarized tissues

71 Enhanced sodium or calcium channel blockade in rapidly depolarizing tissue has been termed "use-dependent blockade" and is thought to be responsible for increased efficacy in slowing and converting tachycardias with minimal effects on tissues depolarizing at normal (sinus) rates These drugs have little effect on prolonging repolarization in rapidly depolarizing tissue

72 Many of the drugs that prolong repolarization (Class III drugs, potassium channel blockers) exhibit negative or reverse rate-dependence These drugs can cause prolongation of repolarization in slowly depolarizing tissue or following a long compensatory pause, leading to repolarization disturbances and torsades de pointes

73 Modulated Receptor Theory
A theory to explain use-dependent blockade, termed the modulated receptor theory (MRT), has been proposed and used to explain many characteristics of the sodium channel blockers and calcium channel blockers

74 The theory is based on a three-state model for the sodium channel originally proposed by Hodgkin and Huxley:

75 The three normal channel states are: Resting, Open (or Activated), and Inactive
Under normal resting (polarized) conditions, the sodium channels are predominantly in the Resting state and are nonconducting

76 When the membrane is depolarized, the sodium channels Open and conduct sodium, resulting in the inward sodium current that makes the major contribution to phase 0 of the action potential

77 The inward sodium current rapidly decays as channels move to the Inactive state
The return of the Inactive channel to the Resting state is termed reactivation and is voltage- and time-dependent

78 The theory assumes that channel blocker drugs bind different channel states with different affinities and that drug binding alters the transition rates between different states Drug binding results in transitions to R*, O*, and I* , channel states which have different transition rates between states than the normal channel states The most clinically useful drugs would have affinity for the Open and/or Inactive state, and thereby exhibit use-dependent blockade

79 Drugs with high affinity for the Resting state would be toxic
Additive and synergistic interactions between drugs that prolong action potential duration and those that have high affinity for the Inactive state have been predicted

80 e.g.- lidocaine and quinidine
combination therapy in experimental settings using low doses of each drug has indicated greater efficacy and fewer side effects than high doses of the individual drugs

81 Guarded Receptor Theory
An alternative theory for channel blockers is termed the "guarded receptor" model and it assumes that drug binding to different channel states is regulated by access of drug to drug binding sites on the channel

82 This theory may be more useful in analyzing the properties of ionizable channel blockers whose access to the intracellular drug-binding sites is pH-dependent Other potentially useful models to predict the actions of channel blockers are based on the size, ph, and solubility of drugs

83 Examples of Channel Blockers Showing Use-Dependent Blockade
Quinidine, procainamide, and disopyramide preferentially bind to the Active state of the sodium channel Amiodarone binds almost exclusively to the Inactive state of the sodium channel

84 Lidocaine binds Active and Inactive states of the sodium channel
Verapamil and diltiazem bind Active and Inactive states of the calcium channel Quinidine, bretylium, and sotalol show reverse use-dependence towards potassium channel blockade

85 Sodium Channel Blockers (Class I)
* Class IA - quinidine (Quinidex) - procainamide (Pronestyl) - disopyramide (Norpace)

86 flecainide (Tambocor) -
* Class IB - lidocaine (Xylocain) tocainide (Tonocard)) - - mexiletine (Mexitil) * Class IC - encainide (Enkaid) flecainide (Tambocor) -

87 - Acebutolol (Sectral) - Esmolol (Brevibloc) - sotalol (Betapace)
Beta-Adrenergic Blockers (Class II) - propranolol (Inderal) - Acebutolol (Sectral) - Esmolol (Brevibloc) - sotalol (Betapace)

88 Drugs that Prolong Repolarization (Class III)
sotalol (Betapace) amiodarone (Cordarone) Calcium Channel Blockers (Class IV) verapamil (Calan, Isoptin) diltiazem (Cardizem) mebefradil (Posicor)

89 Miscellaneous - adenosine (Adenocard) - digoxin (Lanoxin)

90 Sodium Channel Blockade
> Sodium channels are responsible for the initial rapid (Phase 0) depolarization of atrial, Purkinje, and ventricular cells. > Sodium channel activation (opening) is voltage-dependent >The sodium current entering the cell during phase 0 depolarization is very intense, but brief > Activation (opening) and inactivation (closing) of cardiac sodium channels is very rapid

91 Blockade of sodium channels *
Slows the rate and amplitude of phase 0 depolarization Reduces cell excitability Reduces conduction velocity SA and AV nodal cells have relatively few sodium channels and therefore lack a rapid phase 0 depolarization

92 Calcium Channel (L-type) Blockade
> Calcium channels (L-type) are responsible for the prolonged plateau phase (Phase 2) seen in the action potential of atrial, Purkinje, and ventricular cells > L-type calcium channel opening is voltage-dependent, but requires a more positive membrane potential than cardiac sodium channels .

93 >The calcium current entering the cell during phase 2 is intense and prolonged
> Blockade of calcium channels reduces the amplitude and length (time) of phase 2 in atrial, Purkinje, and ventricular cells > In SA and AV nodal cells, calcium entry through L-type channels represents the major ion flux during depolarization

94 Potassium Channel Blockade
> are activated during the repolarization (Phase 3) of the action potential > Blockade of potassium channels prolongs action potential duration >Prolongation of action potential duration usually results in an increase in effective refractory period

95 ** An ideal antiarrhythmic drug should target ectopic pacemakers and rapidly depolarizing tissue to a greater extent than normal tissues of the heart ** Many of the sodium (Class I) and calcium (Class IV) channel blockers have this property because they preferentially block sodium and calcium channels in depolarized tissues

96 ** Therapeutics > It is often problematic to determine the best drug for a given patient due to: - the unknown etiology of many arrhythmias, - patient-to-patient variability, - the multiple actions of many antiarrhythmic drugs. ** Three trial-and-error approaches are widely used:

97 > Serial drug testing guided by electrophysiologic testing
>Empiric depends upon the past experience > Serial drug testing guided by electrophysiologic testing > Drug testing guided by electrocardiographic monitoring (Holter monitoring).

98 Before beginning therapy:
Any factor that might predispose a patient to arrhythmias (electrolyte abnormalities, hypoxia, proarrhythmic drugs, underlying disease states) should be eliminated A firm diagnosis should be made before beginning therapy and a baseline ECG should be established to monitor the efficacy of treatment

99 Monitoring during therapy should include:
Continuous and careful monitoring for efficacy and adverse effects

100 Monitoring of the plasma concentration of the drug ( the free & protien bound )
This is important due to the narrow therapeutic levels & the variation index of activity

101 Proarrhythmias ** Proarrhythmias are drug-induced arrhythmias.
Two recently recognized ventricular proarrhythmias seen with antiarrhythmic drugs:

102 1- Torsades de pointes > Polymorphic arrhythmia that can rapidly develop into ventricular fibrillation > Associated with drugs that have Class III actions (potassium channel blockers) > Also seen with other drugs such as terfenadine under certain circumstances

103 > Potentiated by bradycardia
> Usually occurs within the first week of therapy > Preexisting prolonged QT intervals may be indicator of susceptibility > Potentiated by bradycardia > Often associated with concurrent electrolyte disturbances (hypokalemia, hypomagnesemia

104 2-CAST proarrhythmia > Monomorphic, sustained ventricular tachycardia first recognized in CAST trials with encainide and flecainide > Patients with underlying sustained VT, CAD, and poor LV function (LV ejection fraction < 40%) are at greater risk to develop this form of proarrhythmia

105 Antihypertensive Agents

106 Diuretics ** Primary Mechanisms of Action: deplete sodium and reduce blood volume; also causes persistent decrease in total peripheral resistance; ** Efficacy of up to mm Hg when administered alone and perhaps more when used in combination with other agents

107 Loop Diuretics – > shorter duration of action than thiazide-type diuretics; > reserved for use in subjects refractory to thiazides > e.g >> furosemide (lasix) * Side Effects: dehydration, most metabolic effects as thiazides (i.e., hypokalemia, impaired diabetes control, increased LDL/HDL) * Selected Drug Interactions - digitalis - lithium

108 Potassium-Sparing Diuretics - often used:
1) in combination with other diuretics (i.e., thiazides) to prevent or correct hypokalemia; 2) to avoid potassium depletion in patients taking digitalis **>> spironolactone (Aldactone) - antagonizes effect of aldosterone Side Effects: hyperkalemia, gynecomastia

109 ** Triamterene (Dyrenium)
- weak antihypertensive activity . - Side Effects: hyperkalemia, gastrointestinal disturbances - Selected Drug Interactions > Lithium > NSAIDs > ACE inhibitors

110 ** Therapeutic Notes: > Thiazide diuretics are available as fixed-dose combinations with potassium-sparing or other antihypertensive drugs > Often used in combination with antihypertensive agents that impair vascular responsiveness (i.e., vasodilators) since blood pressure can become very sensitive to blood volume in the presence of these agents

111 > Potassium supplements can be prescribed to compensate for hypokalemia
> The thiazides are not useful in patients with renal insufficiency (glomerular filtration rate < 40 ml/min)

112 Calcium Channel Blockers
* Primary Mechanisms of Action: >> inhibit Ca++ influx into vascular smooth muscle; >> relax peripheral arteriole smooth muscle and thereby decrease total peripheral resistance; >> interfere with both angiotensin II and alpha2-mediated vasocontriction,>>> and perhaps alpha1-mediated vasoconstriction

113 * Pharmacology of Ca++ Channel Blockers
- Effects on Vascular Smooth Muscle - L-type Ca++ channel blockers inhibit L-type voltage-dependent Ca channels -T-type Ca++ channel blockers inhibit T-type voltage-dependent Ca channels

114 - Little or no effect of Ca++ channel blockers on receptor-operated channels or on release of Ca++ from SR “ - Vascular selectivity" is seen with the Ca++ channel blockers

115 Pharmacokinetics > All clinically-approved compounds are available for oral administration > Verapamil is also available for i.v. administration for interrupting supraventricular arrhythmias

116 > Absorption is nearly complete after oral administration
> Bioavailability is reduced because of first-pass hepatic metabolism >There is significant binding of all channel blockers to plasma proteins (70-99%) >Therapeutic effects are evident within min after oral dose; peak effects within 15 min i.v

117 > Typical plasma half-life is 1
> Typical plasma half-life is 1.5 to 6 hours (24-40 hours for bepridil, some of the newer dihydropyridines, and mibefradil) > Half-lifes may increase with repeated oral dose due to hepatic saturation > Longer half-lifes for elderly patients and patients with hepatic cirrhosis or renal insufficiency

118 > Metabolism of verapamil, diltiazem, and nifedipine is inducible
> Verapamil, diltiazem, and possibly nicardipine inhibit hepatic enzymes > Metabolism of verapamil, diltiazem, and nifedipine is inducible > Diltiazem and verapamil have vasodilatory metabolites; dihydropyridines do not

119 Therapeutic Uses of Ca++-Channel blockers
The primary indications for the Ca++-channel blockers are angina, arrhythmias, and hypertension - Angina - Variant (vasospastic, Prinzmetal's) angina: This syndrome is a direct result of reduction in coronary flow, not an increase in myocardial oxygen demand Verapamil, nifedipine, nicardipine, bepridil, and diltiazem are all effective

120 - Arrhythmias: >> i.v. verapamil (followed by oral administration) is a drug of choice for interrupting and controlling paroxysysmal supraventricular tachycardias))

121 * The calcium channel blockers are generally safe and are as effective as beta-adrenergic blockers or diuretics in the treatment of mild to moderate hypertension * Calcium channel blockers are especially effective in treating low-renin hypertension (common in blacks and the elderly)

122 Less Common of Calcium Antagonists:
> Subarachnoid hemorrhage > Treatment of migraine > Raynaud's phenomenon > Posthemorrhagic cerebral vasospasm > Inhibition of platelet aggregation >To slow development of atherosclerosis > Hypertrophic cardiomyopathy > Postinfarct tissue preservation

123 Nifedipine (Procardia) –
>> a dihydropyridine; relatively selective vasodilator and less cardiac depression than verapamil or diltiazem >> Side Effects: tachycardia, headache, peripheral edema, flushing

124 Diltiazem (Cardizem) - >> intermediate action on heart and blood vessels
>> Side Effects: dizziness, headache, edema, bradycardia

125 Verapamil (Calan) - >>greatest effect on heart
>>Side Effects: dizziness, headache, edema, constipation, bradycardia

126 **Therapeutic Notes > Ca++ channel blockers are only rarely associated with abnormalities in electrolyte, carbohydrate, or lipid metabolism. The drugs do not alter plasma concentrations of uric acid . > Ca++ channel blockers are useful in hypertensive patients with a wide variety of concomitant illnesses including CAD, COLD, DM and variant angina. "

127 ** Sympatholytic Drugs
Primary Mechanisms of Action: reduce sympathetic activity to heart and/or blood vessels thereby decreasing cardiac output and/or total peripheral resistance

128 ** Centrally Acting Agents - reduce sympathetic output from vasopressor centers in brainstem
>> Clonidine (Catapres) – alpha2 agonist at medullary cardiovascular regulatory centers; decreases sympathetic outflow from CNS

129 Side Effects: sedation (12-35% patients) and dry mouth (25-40% patients), marked bradycardia is rare, Selected Drug Interactions: may potentiate actions of other CNS depressants

130 Therapeutic Notes: Must be withdrown slowly

131 Methyldopa (Aldomet) > acts on central alpha2 receptors to decrease BP chiefly by decreasing sympathetic outflow from CNS Side Effects: > sedation, nightmares, movement disorders, hyperprolactinemia; rarely hypersensitivity of skin and liver, anemia (1-5%)

132 *Therapeutic Notes Selected Drug Interactions - MAOIs - levodopa
- probably the most extensively used hypotensive agent in pregnancy

133 Adrenergic blocking agents
- reduce norepinephrine release in heart and blood vessels; decrease cardiac output and/or total peripheral resistance ** Reserpine (Serpasil) disrupts norepinephrine vesicular storage; probably both central and peripheral action;

134 Side Effects: > Sedation, diarrhea, depression, bradycardia, nasal congestion * Selected Drug Interactions > May potentiate effects of CNS depressants MAOIs

135 - prevents norepinephrine release from nerve terminals;
** Guanethidine (Ismelin) - prevents norepinephrine release from nerve terminals; - reserved for severe hypertension ** Side Effects: - marked orthostatic hypotension, diarrhea, bradycardia, impotence;

136 Alpha1 Adrenergic Antagonists
- act at post-synaptic receptors to produce arteriole and venous vasodilation ** Prazosin (Minipress) - less tachycardia than direct vasodilators Side Effects: first dose produces precipitous fall in blood pressure, dizziness , headaches , weakness

137 ** Therapeutic Notes - Drugs do not impair excercise tolerance
- Drugs decrease BP only to a certain extent, since fall is directly related to that component of vascular resistance maintained by sympathetic activation

138 ** Beta-Adrenergic Antagonists
- Mechanisms of action include: 1) decrease myocardial contractility & CO; 2) decrease renin secretion and hence decrease levels of angiotensin II * Propranolol (Inderal) - "nonselective";

139 Metoprolol (Lopressor) - beta1 "selective”
* Nadolol (Corgard) - "nonselective"; long half-life, better patient compliance * Pindolol (Visken) - "nonselective"; partial agonist (some intrinsic sympathomimetic activity); less bradycardia than other beta-blockers Metoprolol (Lopressor) - beta1 "selective” * Labetolol (Trandate, Normodyne) - ""beta / alpha";

140 beta-blockers may mask insulin- induced hypoglycemia.
* Side Effects : - mild chronic fatigue, low exercise tolerance, sedation, nightmares, increased airway resistance, bradycardia *Therapeutic Notes - beta-blockers must be withdrawn - beta-blockers are roughly equivalent in efficacy as antihypertensive agents beta-blockers may mask insulin induced hypoglycemia.

141 Vasodilators Primary Mechanism of Action: dilate small arteries thereby decreasing peripheral resistance Hydralazine (Apresoline) - orally effective, used both for treating resistant hypertension and emergencies Side Effects: tachycardia, aggravation of angina, fluid retention, nausea, vomiting, sweating, flushing, lupus-like syndrome

142 Minoxidil (Loniten) - used mainly for treating resistant hypertension
Nitroprusside (Nipride) - used to treat hypertensive emergencies; immediate onset, but brief duration, of action; also dilates veins Diazoxide (Hyperstat IV) - used to treat hypertensive emergencies; long duration of action

143 Angiotensin Converting Enzyme (ACE) Inhibitors
> Inhibit production of angiotensin II (vasoconstriction and sodium-retaining activity); decrease total peripheral resistance Captopril (Capoten) Enalapril (Vasotec) Lisinopril (Zestril, Prinivol)

144 Angiotensin II Antagonists
Action: relax smooth muscle and thereby promote vasodilation, increase salt and water excretion, decrease plasma volume Saralasin Losartan (Cozaar)

145 Side Effects of Angiotensin Antagonists: hyperkalemia
Therapeutic Notes: > angioneurotic edema and cough associated with ACE inhibitors have not been seen with this agent > contraindicated in second and third trimester of pregnancy

146 Some Considerations for Choosing Treatments

147 Pregnancy > If taken before pregnancy, most antihypertensives can be continued except ACE inhibitors and angiotensin II receptor blockers > Methyldopa is most widely used when hypertension is detected during pregnancy > Beta-Blockers are not recommended early in pregnancy

148 African Americans > Diuretics have been demonstrated to decrease morbidity and mortality, and hence should be first choice. > Ca++ blockers and alpha/beta blockers are effective. > Patients may not respond well to monotherapy with beta-blockers or ACE inhibitors.

149 Elderly > Smaller doses, slower incremental increases in dosing, and simple regimens should be used > Close monitoring for side effects (i.e., deficits in cognition after methyldopa; postural hypotension after prazosin) is appropriate.

150 Diabetes mellitis > ACE inhibitors, alpha-antagonists, and calcium antagonists can be effective, and have few adverse effects on carbohydrate metabolism

151 Hyperlipidemic - Low dose diuretics have little effect on cholesterol and triglycerides - Alpha-Blockers decrease LDL/HDL ratio. - Calcium-channel blockers, ACE inhibitors, angiotensin II receptor blockers have little effect on lipid profile

152 Obstructive airway disease
Avoid beta-blockers

153 Anti-platlets & Anti-coagulants


155 Antiplatelet and Anticoagulation Therapy
Oral Antiplatelet therapy Aspirin Thienopyridines Ticlopidine Clopidogrel Heparins UFH LMWH IV Antiplatelet therapy Abciximab Eptifibatide Tirofiban

156 Anticoagulants Unfractionated Heparin (UFH)
Most widely used antithrombotic agent Recommendation is based on documented efficacy in many trials of moderate size Meta-analyses of six trials showed a 33% risk reduction in MI and death, but with a two fold increase in major bleeding

157 Unfractionated Heparin (UFH)
Disadvantages include: Poor bioavailability No inhibition of clot-bound thrombin Dependent on antithrombin III (ATIII) cofactor Frequent monitoring (aPTT) to ensure therapeutic levels Rebound ischemia after discontinuation Risk of heparin-induced thrombocytopenia (HIT)

158 Low-Molecular-Weight Heparin (LMWH)
Fraction of standard (UFH) heparin Advantages over UFH: Greater bioavailability No need to closely monitor Resistant to inhibition by activated platelets Lower incidence of HIT Enhanced anti-factor Xa activity Effective subcutaneous administration Enoxaparin, dalteparin, reviparin, nadroparin, fraxiparin

159 Platelets in Acute Coronary Syndromes
Platelets play a key role in ACS Sources of platelet activation (triggers) thromboxane A2 (TXA2) ADP epinephrine collagen thrombin

160 Complementary Mode of Action between
Clopidogrel and ASA COX, cyclooxygenase; ADP, adenosine diphosphate; TxA2, thromboxane A2

161 Anti-platelet Therapy
Aspirin Irreversible inhibition of the cyclooxygenase pathway in platelets, blocking formation of thromboxane A2 Bolus dose of mg, followed by maintenance dose of mg/d

162 Aspirin In AMI, ASA reduced the risk of death by 20-25%
In UA, ASA reduced the risk of fatal or nonfatal MI by 71% during the acute phase, 60% at 3 months, and 52% at 2 years

163 Ticlopidine Clopidogrel
Block ADP receptor resulting in inhibition of transformation of GP IIb/IIIa into its high affinity state

164 GP IIb/IIIa inhibitors
abciximab (monoclonal antibody) eptifibatide (peptide inhibitor) lamifiban and tirofiban (non-peptides)

165 Organic Nitrates (Nitrovasodilators)
* Chemistry: All these agents lead to the formation of the reactive free radical, nitric oxide (NO) - Glyceryl trinitrate (GTN, nitroglycerin, Nitro-Bid) - Isosorbide dinitrate (ISDN, Isordil) - Isosorbide-5-mononitrate (5-ISMN, Ismo) - Amyl nitrate (highly volatile liquid which is administered by inhalation) - Nicorandil (Icorel)

166 Mechanism of Action > Nitrovasodilators are enzymatically converted to NO in the target tissues > NO is an important endogenous diffusible mediator of smooth muscle contraction and neuronal transmission > NO is very short-lived (half-life of a few seconds)

167 Nicorandil - an experimental antianginal that acts by two separate mechanisms; both result in lower intracellular Ca2+ in vascular smooth muscle - Generation of NO and the subsequent stimulation of cGMP in vascular smooth muscle - Activation of the ATP-dependent potassium channel which hyperpolarizes the plasma membrane

168 Pharmacological Effects
- Peripheral vasodilation - Dilation of veins predominates over that of arterioles, resulting in a large reduction in preload and a lesser reduction in afterload - Reduction in preload and afterload decreases myocardial workload and results in decreased myocardial oxygen demand ** Nicorandil has a more pronounced effect on afterload and coronary flow than conventional nitrovasodilators

169 Routes of Administration
> Oral > Subligual > IV infusion > Transdermal

170 Tolerance and Dependence

171 Adverse Effects - Orthostatic hypotension - Tachycardia
- Severe throbbing headache - Dizziness - Flushing Syncope (fainting) - - Contraindications - Organic nitrates are contraindicated if intracranial pressure is elevated



Similar presentations

Ads by Google