Drugs Affecting The Cardiovascular System Lecture PDF

DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM Mona Hany Badr, PhD Professor of Medicinal Chemistry  Antihypertensives Antianginal agents Antiarrhythmic drugs Cardiovascular drugs Agents for heart failure...

DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM Mona Hany Badr, PhD Professor of Medicinal Chemistry  Antihypertensives Antianginal agents Antiarrhythmic drugs Cardiovascular drugs Agents for heart failure Antihyperlipidemic drugs Anticoagulants, antiplatelets and thrombolytic drugs 2  Intended Learning Outcomes (ILOs) Lecture Objectives: What is Hypertension? Examples on frequently prescribed drugs in each pharmacological class. Mechanism of action of these drugs. SAR (if any). Limitations of their use (if any). Management of hypertension. 4 Blood pressure is a function of the amount of blood pumped by the heart and the ease with which the blood flows through peripheral vasculature. Arterial Blood Cardiac Peripheral Pressure = Output X Resistance Blood output – the volume of blood pumped from each Volume Cardiac Filling ventricle per minute: Heart Arteriolar Pressure Cardiac output Rate = stroke volume X heartVolume rate Venous Tone (ml/minute) Contractility (ml/beat) (beats/min) Major factors influencing blood pressure 5 Response mediated by the sympathetic nervous system Activation of Cardiac β1–ARs on output Sympathetic heart activity Activation of α1- Peripheral ARs on smooth resistance Decrease in BP muscle Increase in BP Renal Angiotensin blood Renin II flow Aldosterone Sodium & Blood Water volume retention 6 Response mediated by the renin-angiotensin-aldosterone system Classes of Antihypertensive drugs Diuretics Thiazide (HCT, Metolazone) Loop (Furosemide, Ethacrynic acid) Sympatholytics K-sparing Depleting NE stores Vasodilators Spironolactone & Eplerenone Triamterene (Na) Reserpine CCBs Guanethidine 1,4-DHP Centrally acting Verapamil ACEIs Clonidine Captopril (SH) Diltiazem Methyl dopa K-channel openers RAAS inhibitors Enalapril (COOH) Peripherally acting Fosinopril Minoxidil α-blockers Others ARBs β-blockers Losartan Hydralazine Mixed α- & β-blockers Nitroprusside Renin inhibitor Aliskiren 7 Sympatholytics 1) Agents Depleting NE Stores ✓ They interfere with NE reuptake and storage within the vesicles of the sympathetic neurons, leading to its depletion (via inhibition of catecholamine transporters). ✓ Reserpine is an indole alkaloid isolated from the roots of Rauwolfia serpentina. ✓ Reserpine can also deplete NE in the CNS and may depress the mood and should be avoided with patients with history of depression. ✓ It has been used in the treatment of mild to moderate hypertension, but because of its significant CNS adverse effects, it is rarely used. Reserpine Guanethidine It lacks the CNS effects of Reserpine because it is highly polar (can not pass BBB). 8  2) Centrally-acting Adrenergic agents α2-Agonist They are used as a step 2 agents in patients who fail to respond to therapy with a stage 1 drug (e.g., diuretics, calcium channel blockers, ACE inhibitors, or angiotensin II blockers). H Cl H H Cl Cl N O NH N NH2 N N N N NH NH H Cl Cl H Cl Clonidine, α2-Agonist ❑ Transdermal clonidine has also been successfully substituted for oral clonidine in some patients with mild to moderate hypertension whose compliance with a daily dosing regimen can be a problem. ❑ Adverse effects include sedation, dry mouth, and constipation. ❑ Rebound hypertension occurs following abrupt withdrawal of clonidine. The drug should, 9 therefore, be withdrawn slowly if discontinuation is required.  Drugs Affecting Adrenergics Biosynthesis Methyldopa (Aldomet ®) Its use is limited for the management of hypertension in late pregnancy (pregnancy- induced hypertension). HO NH2 decarboxylase β-hydroxylase COOH HO Methyldopa (Aldomet ®) It is a prodrug α-Methyldopamine is a false precursor to NE, which inturn reduces synthesis of NE in the vesicles. α-Methyl NE is a false neurotransmitter (a weaker agonist at the postsynaptic ARs). α-Methyl NE is a strong α2-agonist. 10  3) Peripherally-acting Adrenergic agents Adrenergic Receptor Blockers Mixed α and β– α–blockers β–blockers Antagonists Non-selective Non-selective α1 β1 11 3) Peripherally-acting Adrenergic agents Adrenergic Receptor Blockers 𝛂1-Blockers are effective agents for the initial management α–Blockers of hypertension and are especially advantageous for older men who also suffer from symptomatic benign prostatic hyperplasia. O Quinazoline Acyl moiety Non-selective N R O N N N Piperazine O NH2 α1-Selective General Structure Prazocin 12  3) Peripherally-acting Adrenergic agents Adrenergic Receptor Blockers Aryloxypropanolamines β–blockers Non-selective Propranolol (Non-selective) β1 Atenolol Metoprolol β1-blocker β1-blocker 13  β–blockers Some Notes: β-blockers reduce blood pressure primarily by competitive inhibition of cardiac (β1) thereby reducing the contractility of the myocardium (negative inotropic) and decreasing heart rate (negative chronotropic). They may also inhibit the release of renin from the kidney, thus decreasing the formation of angiotensin II and secretion of aldosterone. Non-selective β-blockers (block both 𝛃1- and 𝛃2-adrenoceptors), are contraindicated in patients with asthma and diabetes (suppress insulin release). β1-blockers are more cardioselective. Note that this relative selectivity can be lost at higher drug doses, adversely affecting asthma, peripheral vascular disease, and diabetes. CNS side effects (dizziness & sedation) associated with lipophilic drugs (propranolol), as it can cross the BBB. These side effects can be avoided with the use of hydrophilic drugs, such as atenolol. 14 Mixed α and β–Antagonists ▪ It is a non selective β-blocker/ α1-blocker. ▪ Vasodilation occurs via α1-blockade while the β-blocker helps avoid reflex tachycardia. ▪ S-carvedilol has α- and β-blocking activity while the R-isomer exhibits α1-blocking activity. ▪ Selection of mixed α/β-blockers are recommended for management of more severe hypertension. Carvedilol 15  Renin-Angiotensin- Aldosterone System (RAAS) Renin is substrate-specific and the rate limiting step in the formation of angiotensin II. ACE degrades bradykinin (inflammatory mediator) which is: I. Vasodilator, II. Bronchoconstrictor, III. Stimulates natriuresis, IV. Stimulates prostaglandin synthesis 16  1) Angiotensin Converting Enzyme Inhibitors MOA: (ACEIs) They block ACE resulting in: Suppression of angiotensin II. Accumulation of bradykinin (stimulate vasodilatation & diuresis). Decrease the secretion of aldosterone, resulting in decreased sodium and water retention. They are of particular value in treating hypertensive patients with coexisting heart failure or myocardial infarction. Side effects: Dry irritating cough and angioedema (bradykinin). May cause skin rashes and abnormal metallic taste (only captopril). Hyperkalemia (↓aldosterone). Can not be used during pregnancy (increase risk of fetal renal damage & fetal malformations 17 ). ▪ ACE is a membrane-bound enzyme which converts angiotensin I to angiotensin II. ▪ It is a member of a group of enzymes called the zinc metalloproteinases. Captopril The catalytic site of this enzyme was found to comprise: ✓ Arginine residue which provides a cationic site that attracts a carboxylate ion. ✓ A zinc ion binding site. ✓ Two hydrophobic pockets lie between these groups. ✓ A hydrogen binding site that forms a AgI hydrogen bond with an amide carbonyl. 18  SAR of ACEIs The N-ring portion must contain a carboxylic acid for binding to the cationic site in ACE to mimic the C-terminal carboxylate of ACE substrate. Large hydrophobic heterocyclic rings (i.e. the N-ring) increase potency. The zinc binding group can be: (A) sulfhydryl, (B) carboxylate, or (C) phosphinate. -SH group shows superior binding to Zn2+. Sulfhydryl containing compounds can form disulfides (dimers) which may shorten the duration of action. X is usually a methyl group. Esterification of the carboxylate or phosphinate produces orally bioavailable prodrugs. 19 Nomenclature is designated as …pril (ester prodrug) versus …prilat (active drug). Thiol containing ACEIs Captopril (Capoten ®) Non-thiol containing ACEIs Carboxylate ester Phosphinate ester 20 Fosinopril Fosinoprilat Fosinoprilat 21 Lisinopril Lisinopril exhibits good oral bioavailability even though it is the most hydrophilic, because in the duodenum, lisinopril most likely exists as a di-zwitterion in which the ionized groups are internally bound to one another. In this manner, lisinopril may be able to pass through the lipid bilayer with an overall net neutral charge. N.B: Lisinopril and captopril are the only ACE inhibitors which are not prodrugs. 22  2) Angiotensin II Receptor Blockers (ARBs) Angiotensin II produces its biological effects by interacting with two receptor subtypes; AT1 and AT2. AT1 effects include vasoconstriction, aldosterone secretion, sodium reabsorption, and catechol release. All currently available ARBs selectively block the AT1 receptors, decreasing the activation of AT1 receptors by angiotensin II. They are biphenyl methyl derivatives that possess certain acidic moieties (e.g. COOH or tetrazole). 23 For clarification only  The tetrazole and carboxylate groups must be in the ortho position for optimal activity (the tetrazole group is superior in terms of metabolic stability, lipophilicity, and oral bioavailability). They do not cause dry cough or angioedema (side effect of ACEIs), but they are still contraindicated with pregnancy. Losartan (Cozarr®) Losartan is metabolized by CYP450 enzymes to an active metabolite which is more active than the parent drug and both contribute to total antihypertensive effects, that is, losartan is not a prodrug. Active metabolite 24  3) Renin Inhibitor (Aliskiren) Renin is a very specific enzyme that recognizes the peptide sequence of angiotensinogen. Aliskiren is a selective orally active non-peptide renin inhibitor for the treatment of hypertension. Aliskiren directly inhibits renin and, thus, acts earlier in the RAAS than ACEIs or ARBs. It is contraindicated during pregnancy (as all drugs affecting RAAS). 25  Vasodilators (direct-acting) They produce their effect directly on the vasculature. Their most characteristic side effects are due to the increase in sympathetic reflex activity which leads to: Reflex tachycardia, which can be controlled by the use of a β-blocker. Stimulating renin release, leading to sodium and water retention, which can be controlled by co-administration of a diuretic. Direct acting vasodilators include: ✓ Calcium channel blockers. ✓ Potassium channel openers. ✓ Hydralazine. ✓ Sodium nitroprusside. 26  1) Calcium Channels Blockers (CCBs) CCBs block the inward movement of Ca2+ by binding to the L-type Ca2+ channels. This causes muscle relaxation and suppresses cardiac or blood vessels activity (i.e.: negative inotropic effect on the heart and vasodilating effect on vascular smooth muscle Three different chemical classes: 1. Phenylalkylamines (Verapamil). 2. Benzothiazepines (Diltiazem). 3. Dihydropyridines (Nifedipine). CCBs have an intrinsic natriuretic effect; therefore, they do not usually require the addition of a diuretic. CCBs are contraindicated in pregnancy as they induce abortion due to relaxation of cervical muscle. CCBs, verapamil and diltiazem, should generally be avoided in patients with CHF, due to their negative inotropic. 27  Phenylalkylamine and Benzothiazepine Dihydropyridine At physiologic pH, verapamil and diltiazem are At physiologic pH, they are primarily unionized primarily ionized Have vasodilating and cardiodepressant actions. Dihydropyridines are primary vasodilators. Not associated with reflex tachycardia, due to Reflex tachycardia as a result of sympathetic their ability to block AV nodal conductance. They responses to the vasodilatory effects of this should not be used in combination with β- class. The use of β-blocker can minimize this blockers. effect. They have antiarrhythmic, antianginal and They are particularly attractive in treating antihypertensive activity. hypertension and angina. O S * NO2 CN O MeOOC COOMe O N O * * N electrons are involved in O O resonance (delocalization) O O N 28 Verapamil and are much less N Diltiazem available for protonation H (Isoptin®) (Cardizem®) Hence, less basic Nifedipine (Aldalat®)  1,4-Dihydropyridines Position 4 requires an aromatic substitution possessing an electron- withdrawing group (Cl or NO2) in the SAR ortho and/or meta position. The importance of the ortho and meta Positions 2 and 6 are substituted with substituents is to provide sufficient bulk an alkyl group that may play a role in to “lock” the conformation of the 1,4- the agent's duration of action (with the DHP such that the C4 aromatic ring is exception of amlodipine, all perpendicular to the 1,4-DHP ring. This dihydropyridines have C2 and C6 perpendicular conformation has been methyl groups). proposed to be essential for the activity of the 1,4-DHPs. Cl Positions 3 and 5 are carboxylic MeOOC COOEt groups that must be protected with N O NH2 an ester functional group. H Amlodipine (Norvasc®) 1,4-Dihydropyridine ring is essential for activity. Substitution at the N1 position or the use of Greater selectivity for vascular smooth muscle than oxidized (piperidine) or reduced (pyridine) ring 29 systems greatly decreases or abolishes activity. myocardial tissue and a longer half-life than nifedipine.  2) Potassium Channel Openers/Agonists These agents activate (open) the ATP-sensitive potassium channels, leading to relaxation and vasodilatation. They are contraindicated in diabetic patients (decrease insulin release). NH2 NH2 - N N O Sulfotransferase N N OSO3 N N NH2 NH2 Minoxidil (prodrug) Minoxidil Sulfate It is the only direct-acting vasodilator that requires metabolic activation to produce its antihypertensive effect. Minoxidil topical solution is used to treat alopecia (hair loss) due to its ability to 30 stimulate hair growth.  3) Other Vasodilators It has been used to treat moderate to severe hypertension, the exact H NH2 mechanism is not completely clear. N It is usually used orally in combination with β-blockers and diuretics. N It is also used to control high BP during pregnancy or in emergency N situations. 1-Hydrazinophthalazine Together the three drugs decrease cardiac output, plasma volume Hydralazine and peripheral vascular resistance. It is commonly used in the management of hypertensive emergencies because it effectively reduces the patient’s blood pressure to a safe level. Sodium Nitroprusside Na2[Fe(CN)5NO] It produces vasodilation by the release of NO. It is administered by intravenous infusion and has a short half-life. 31  Diuretics Diuretics are defined as chemicals that increase the rate of urine formation (diuresis). The primary target organ for diuretics is the kidney, where these drugs interfere with the reabsorption of sodium and other ions at different sites in the nephron (the functional unit of the kidney). 32  Diuretic Classes Site-1 diuretics: carbonic anhydrase inhibitors. Site-2 diuretics: high ceiling or loop diuretics. Most commonly used Site-3 diuretics: thiazide and thiazide-like diuretics. diuretics for treatment of hypertension Site-4 diuretics: potassium sparing diuretics. In addition to agents that enhance water excretion: ▪ Non-site specific diuretics: Osmotic diuretics. ▪ Antidiuretic hormone (ADH) receptor antagonist: Aquaretics. Bowan's cap. Distal tubule (3) Glomerulus ascending Proximal tubule limb Collecting duct (1) (2) (4) 33 Loop of Henle  Site-2 Diuretics: High Ceiling or Loop Diuretics These drugs inhibit the luminal Na+/K+/2Cl− symporter Site-2: Thick ascending limb a protein located in the cell apical membrane. of loop of Henle The result is a significant Na+ and Cl− loss along with Ca2+ and Mg2+ loss, together with K+ loss. Loop diuretics are characterized by a fast onset and short duration of action They are the most powerful of all diuretics (Why?) because the ascending limb accounts for the absorption of 25-30% of the filtered load of Na+ (and Cl-), hence the name high-ceiling diuretics. They are more similar pharmacologically than chemically. 34 1) Phenoxy acetic acids These compounds act via inhibition of sulfhydryl-containing receptor in the renal tissue Ethacrynic acid (Edecrin®) Cl Cl O COOH H3C Cl O COOH H3C Cl RSH H H H S Ethacrynic acid is the only loop diuretic H O R H O that is not a sulfonamide derivative and may be useful in patients who are allergic to sulfonamides. SAR (or CH3) Cl H3C Cl 32 1 O COOH α,β-unsaturated 4 H carbonyl group is important for H O 35 activity 2) 5-Sulfamoyl-2(or 3)-aminobenzoic acid derivatives SAR 1. The substituent at the 1-position must be acidic. 3 H 2. A sulfamoyl group in the 5-position is essential for X 2 N R optimal high-ceiling diuretic activity. H2N OH S 3. The activating group (X) (good leaving group) in O O O the 4-position can be Cl, CF3, phenoxy, alkoxy, benzyl, or benzoyl group. Furosemide (Lasix®) 4. Substitution in the 2-and 3-position (R) H Cl N R= CH2 > CH2 > CH2 S O O H2 N OH S O O O 36 Therapeutic Applications 1. Edema associated with congestive heart failure, liver cirrhosis and nephrotic syndrome. 2. Hypertension. Adverse effects 1. Hypokalemia (particularly dangerous if patient is on digitalis). i.e. The patient with heart failure and treated with digoxin. (Potassium depletion can be avoided by the use of potassium sparing diuretics or dietary supplementation with K+). 2. Calcium and magnesium depletion. 3. Hyperuricemia (increase serum uric acid), so cautions should be taken in patients with gout.). 37  Site-3 Diuretics: Thiazide and Thiazide Like Diuretics The thiazides/thiazide-like agents compete for the Cl− binding site of the Na+/Cl− symporter in DCT cells inhibiting the absorption of Na+ and Cl− thus increasing their excretion. For this reason, they are referred to as saluretics. They also inhibit the reabsorption of potassium, but to a lesser degree. 38  5 4 SAR X 6 N 3 R Benzothiadiazine H2N 1 NH derivative S 7 S 8 O O O O X = Cl, Br, CF3, NO2 An electron-withdrawing group is necessary at C6 (e.g., Cl, CF3) for diuretic activity (electron-donating groups, such as methyl or methoxy, reduce the diuretic activity). The CF3-substituted diuretics are more lipid soluble and have a longer duration of action than their Cl-substituted analogs. The unsubstituted sulfonamide group at C7 is essential for activity. Saturation at C3-C4 results in a 10-fold increase in activity. Substitution with a lipophilic group at C3 markedly increases diuretic potency and duration of action. Alkyl substitution on the N at 2 position decreases polarity, so increasing the 39 duration of action.  Thiazide Diuretics Hydrothiazide Diuretics Members Chlorothiazide Hydrochlorothiazide H Cl N Cl N H2N NH H2N NH S S S S O O O O O O O O Thiazide like diuretics Metolazone Difference between the thiazide and thiazide-like diuretics is the replacement of a “sulfonamide” by an “amide.” 40  Therapeutic Applications This is the most commonly prescribed class of diuretics. 1. Edema secondary to congestive heart failure, liver cirrhosis and nephrotic syndrome. 2. Hypertension. Adverse effects 1. Hypersensitivity reactions (due to sulphonamide group). 2. Hypokalemia, so care should be taken with digitalized patients. (Potassium depletion can be avoided by the use of potassium sparing diuretics or dietary supplementation with K+). 3. Hyperuricemia (increase serum uric acid), so cautions should be taken in patients with gout. 41  Site-4 Diuretics: Potassium Sparing Diuretics They act at the collecting duct and often given in combination with diuretics act at site 2 or 3 in an attempt to avoid hypokalemia that accompanies the latter diuretics. O a) Aldosterone receptor antagonists: Spironolactone (Aldactone®) O 17 Spironolactone is a competitive antagonist to H aldosterone (main endogenous mineralocorticoid H H MR) for its receptor site. 7 O S MR antagonists require: O The presence of a γ-lactone ring at C17. A substituent on C7 (the unhindered C7 position is required for aldosterone binding to MR). 42  Spironolactone might cause hyperkalemia. It might cause impotence related to nonselective binding of spironolactone to the androgen (AR), glucocorticoid (GR), and progesterone receptors (PR). 9𝛂,11𝛂 -epoxy group While eplerenone may also lead to potential toxic hyperkalemia most other adverse effects are minor since eplerenone exhibits specificity for MR without action on other steroid receptors. 43 b) Sodium channel blockers They block Na-channels in the luminal membrane thus preventing Na+-K+ exchange. Triametrene (Dyrenium®) Triaminophenyl pteridine NH2 N N H2N N N NH2 44  MANAGEMENT OF HYPERTENSION In some patients with mild hypertension, life-style modification (exercise, weight loss, stress management and low sodium diet) can reduce the elevated blood pressure, but usually drug treatment is required. American and European hypertension guidelines recommend initial BP treatment based on four major classes of pharmacotherapies including: ACE inhibitors (ACEi), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide/thiazide‐like diuretics. β‐blockers are recommended in selected patients, such as those with heart failure or myocardial infarction. Combination therapy is recommended by both guidelines for stage 2 hypertension. By combining different antihypertensive drug classes in low doses, their different mechanisms of action result in synergistic BP lowering with minimum adverse effects. For example, the addition of low dose thiazide diuretic dramatically increases the 45 response to ACEIs and β–blockers without producing the undesirable side effects.