PHARMACOLOGY CVS block- Drugs summary lectures 1,2 : adrenergic blockers

Adrenergic neuron blockers

Adrenergic neuron blockers

• formation of false transmitters (methyl norepinephrine) • stimulation of presynaptic α2 receptors to α-methyl dopa inhibit NE release (as clonidine) • acts centrally • Drug of choice in: hypertension in pregnancy (pre-eclampsia - gestational hypertension)

• depletion of storage sites Reserpine reserpine = depletes reserves

• inhibtion of release and enhance uptake Guanethidine

• stimulation of presynaptic α2 receptors to inhibit NE release (as α-methyl dopa) • acts centrally (on the brain) Clonidine • little used as antihypertensive agent due to rebound hypertension upon abrupt withdrawal. This can be treated with labetalol.

•used in open angle glaucoma. Acts by Apraclonidine decreasing aqueous humor formation.

α adrenergic antagonists

Drug Receptor action: Therapeutic use selectivity Phenoxybenzamine  Postural hypotension Used Before surgical (irreversible-long Non-selective  Decrease peripheral removal of (α1 – α2) vascular resistance Pheochromocytoma acting 24h)  Increase cardiac output to protect against Phentolamine (α2 block) hypertensive crisis. (reversible-short  Precipitate in Contraindicated in: acting 4h) arrhythmias Patient with and angina decreased coronary perfusion Prazosin α1 selective • Vasodilatation due to 1-Benign prostatic (short half-life) blockers relaxation of arterial and hyperplasia venous smooth muscles Doxazosin  Fall in arterial pressure 2-Hypertension with (long half-life) with less tachycardia prostate enlargement Terazosin than with non-selective α blockers 3-Reynaud’s disease (long half-life)

Tamsulosin α1A  Relaxation of smooth (present in muscles of bladder neck prostate) and prostate → improve Benign prostatic urine flow hypertrophy (BPH)  Minimal effect on blood pressure Yohimbine α2 ↑nitric oxide in corpus Aphrodisiac in cavernosum → vasodilatation erectile dysfunction → erectile process Adverse effects* of non-selective α blockers (phenoxybenzamine – phentolamine):

 Postural hypotension *α1 antagonists have  Tachycardia the same adverse effects  Headache but to a lesser degree.  Nasal stuffiness and congestion  Vertigo and drowsiness  Male sexual dysfunction (inhibits ejaculation)

- Adrenoceptors blockers

DISEASE DRUG (s) mechanism of action • ↓ cardiac output • ↓ renin and RASS system Labetalol (by injection) • Inhibition of presynaptic NE release Atenolol, Bisoprolol > Hypertension • Inhibition of sympathetic outflow in CNS Metoprolol, Propranolol • Treatment of hypertensive pregnant & hypertensive crisis

Esmolol (ultra-short • Propranolol: Membrane stabilization (block Na ퟏ channel local anesthetic effect/ antiarrhythmic acting, T = ퟏퟎ 풎풊풏), Cardiac ퟐ effect: ↓ excitability, ↓automaticity , ↓ Arrhythmias Atenolol, Propranolol conductivity) (Bisoprolol and • treatment of supraventricular & ventricular

CVS carvedilol are preferred) arrhythmias

Beta blockers • anti -ischemic action : ↓heart rate, ↓ cardiac work & Angina pectoris e.g. propranolol oxygen demand, ↓the frequency of angina episodes. Carvedilol (antioxidant Congestive • Decrease myocardial remodeling action) Heart Failure • decrease risk of sudden death. Bisoprolol, Metoprolol • Have cardio-protective effect: ↓ infarct size ,↓ Myocardial Atenolol, Metoprolol, morbidity & mortality ,↓ myocardial O2 demand. Infarction Propranolol • Anti-arrhythmic action (Quinidine-like action) • Decrease the incidence of sudden death . Timolol (eye drop) , ↓aqueous humor production from ciliary body Chronic Glaucoma propranolol ↓intraocular pressure (IOP) • Protect the heart against sympathetic Hyperthyroidism Beta blockers overstimulation (thyrotoxicosis) (e.g. Propranolol) • Controls symptoms; tachycardia, tremors, sweating. • Propranolol is Lipid soluble , thus has CNS effect Anxiety (Social and Propranolol (orally or sedative action  Control anxiety symptoms performance type) parenteral) (tachycardia, tremors, sweating) reduce episodes of chronic migraine Migraine (prophylaxis) propranolol catecholamine-induced vasodilatation in the brain vasculature (antagonize the sympathetic effect)

Labetalol (has to be Hypertensive crisis of -blockers lower the elevated blood pressure. combined with  Pheochromocytoma -blockers protect the heart from NE. blockers)

- Adrenoceptors blockers

-

• Most of them are lipid soluble (Metoprolol, propranolol, timolol, labetalol, carvedilol), these are well absorbed orally, rapidly distributed, cross readily BBB & Have CNS depressant actions

kinetis • Most of them have a half-life from 3-10 hrs except Esmolol (10 min. given by I.V.).

Pharmaco • Most of them metabolized in liver & excreted in urine. selective β1-blockers (Due to blockade of 1- receptor): Bradycardia, hypotension, heart failure Since there is NO change in lipid or glucose & NO bronchoconstriction, they’re SAFE FOR: • Asthma & COPD • Raynaud’s phenomenon and PVD • Diabetics/ Dyslipidemias • Variant Angina Note: Selectively present in low doses, Lost in high doses

Non selective β-blockers (Due to blockade of 2- receptor):

• Depression + Hallucinations • GI disturbances ( Intestinal motility) • Bronchoconstriction, specially in susceptible patients • Sodium retention 2ndry to BP renal perfusion • hypoglycemia,  Lipolysis , ↑TG (hyperglyceridemia)

•  peripheral resistance (PR) by blocking vasodilatory effect  Vasoconstriction  blood Adverse Adverse Effects: flow to organs except brain  cold extremities & intermittent claudication (2) • Erectile dysfunction & impotence • Coronary spasm (in variant angina patients) Mixed alpha & beta receptor blockers: • Carvedilol: Edema • Labetalol (membrane stabilizing effect with ISA): Orthostatic hypotension, Sedation and dizziness All β-blockers: • Masked hypoglycemic manifestations i.e. tachycardia, sweating… Coma • Heart Block (because beta blockers can precipitate heart block). • Bronchial Asthma, emphysyma & Peripheral vascular disease (safer with cardio-selective - 1 blockers). • Diabetic patients  Masking of hypoglycaemia / must be GIVEN CAUSIOUSLY

• Hypotension Contra

indications • Alone in pheochromocytoma (must be given with -blockers).

• peripheral diseases like Reynaud's disease

Sudden stoppage will give rise to a withdrawal syndrome: Rebound angina, arrhythmia, myocardial infarction & Hypertension WHY ? Due to Up-regulation of -receptors (increase number of -receptors) To prevent withdrawal manifestations  drug withdrawn gradually.

Precautions

Mind map- lectures 3,4: Antiarrhythmic Drugs

Note: Class 5 aren’t Calcium channel blockers. Class 4 are. For a better version, click here Drugs summaryANTIARRHYTHMIC- lectures 3, DRUGS4: Antiarrhythmic Drugs

Uses: Mechanism of action: -atrial flutter & fibrillation (common use). Cardiac ( Direct): -Can be used in ventricular tachycardia. (Membrane stabilizing effect)

-maintaining sinus rhythm after D.C. cardio - Block K+ channel

version. - Prolong PR & QT intervals - Widens QRS complex. Action: ADRs: -Prolong - quinidine syncope due to torsades de ANS ( Indirect):

pointes Quinidine action orally) (Given -Anticholinergic effect (Increase IA potential - Dry mouth. conduction through the A.V. - Blurred vision. duration by: node) - Urinary retention. Slow phase 0. - Constipation. *α-adrenergic blocking effect - Hypotension. - Slow

conduction Similar to quinidine except : ADRs:

- less toxic on the heart. - More effective in ventricular than in - Lupus erythematosus-like atrial arrhythmia. syndrome ( in long term

therapy). - No anticholinergic or α-blocking actions - Hypotension . - Torsades de pointes.

(Can beIV) given(Can - Hallucination & psychosis .

Procainamide

Uses: ADRs: Treatment of emergency ventricular -Hypotension arrhythmia (e.g. during surgery, following -Similar to other local anesthetics.

acute myocardial infarction). CNS adverse effects: -paresthesia.

(Na+ channel channel (Na+ blockers) Not effective in: - Oral administration. - tremor. Action: infusion) - In atrial arrhythmia. - Dysarthria. Lidocaine - Decrease T1/2: - tinnitus. action - confusion. IB slow or bolus IV (given 2 hours

potential - Convulsion. CLASS CLASS I duration by ADRs: shortening Uses: - Ventricular arrhythmia. - Nausea phase 3 - Vomiting (repolarizatio - Digitalis-induced arrhythmia. - Tremor n) - Drowsiness T1/2: - Diplopia - 10 hours - Arrhythmia

- Hypotension Mexiletine

( effective( orally)

Action: Uses: ADRs:

- Slow phase 0 - Supraventricular arrhythmia. - Proarrhythmia. (depolarization - Wolff-Parkinson-White syndrome - Heart failure due to -ne IC - No effect on - Very effective in ventricular inotropic effect. action potential arrhythmia. - CNS adverse effects: duration. - Should be reserved for ventricular Dizziness, tremor, blurred

Flecainide arrhythmia. vision, abnormal taste sensation, paraesthesia. CLASS III CLASS II (β- ADRENOCEPTOR BLOCKERS) by prolongphase potentialduration Prolongthe action Action: period of AV node. and ectopic pacemaker. automaticity of SAnode c effect on the heart. b the heart. a Action: - - -

2 1 Block Block Reduce sympathetic - - prolong prolong refractory decrease decrease

β Drugs summary Drugs 1

receptor receptor in

3 .

Ibutilide Propranolol Amiodarone Atenolol Esmolol Metoprolol -

lectures version version rhythm after D.C. cardio 2 arrhythmias resistant ventricular 1 Therapeutic uses: blocking effects ) and its calcium channel adrenoceptor ( due to its α - effects - Main effect ) prolongs refractory period ( duration and therefore - pharmacological actions: ventricular arrhythmias. sudden reduceof incidence myocardialinfarction used inpatients hadwho flutterfibrillation).or ofventricular rate( atrial Given IV frorapid control life= Veryactingshort (half • •Causes QTinterval prolongation. rhythm. •Used for the acute conversion of atrial flutter or fibrillation normal to sinus • arrhythmias ( e.g. WPW ). supraventricular 3

Given Given by rapid I.V. infusion. May cause torsades de pointes. vasodilating vasodilating effects additional class Ia, II & IV prolongs action potential - - -

maintenance of sinus main use serious : resistant

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& β blocking blocking effects , 4

due to due -

: Antiarrhythmic: Drugs

to -

- - - - Adverse effects: - - - Uses: breast milk breast milk and appear in - metabolism hepatic primarily by - and CYP P n desethylamiodaro N metabolite its major active - 103 - Pharmacokinetics: ------( patients should avoid exposure to the sun)

photodermatitis & skin deposits hyper pulmonary fibrosis bradycardia & heart block, heart failure peripheral neuropathy hepatocellular necrosis corneal micro deposits constipation CNS: tremor, headache, ataxia, paresthesia may cause bluish discoloration of the skin. cross placenta eliminated 4503 - metabolized to long t - e by cytochrome Digitalis WBW. emotion. Atrial days) - A 1

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procaiamide,flecainide quinidine, warfarin, of several drugs e.g. 3 e.g. : Rifampin of amiodarone serum concentration enzymes will decrease inducers of these 2 juice. Cimetidine, Grapefruit Ritonavir, Trazodone, e.g. : Loratadine, of amiodarone serum concentration enzymes will increase that inhibit these drugs (or substances) CYP metabolized by 1 Drug Interactions:

- - -

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CLASS V (MISCELLENIOUS Class IV ANTIARRHYTHMIC DRUGS) Drugs: refractoryperiod - - node S.A & node. Action Digitalis Adenosine cause: main site actionof is A.V calcium channel blockers.

prolongation of effective slowing of conduction

Drugs summary Drugs

:

( ( negative potential ( SAnode). 3 dromotropic mainly at AV node. ( negative 2 (hyperpolarization). 1 actions: A - Adenosine) of action : (of Mechanism inhibits inhibits - 1 - -

inhibiting inhibiting phase

- decreasing decreasing conduction velocity Opening of potassium channels receptors, causing the following

Diltiazem Verapamil lectures

cAMP chronotropic 3 2 1 Therapeutic uses :

effect effect ) - - -

NOTeffective inventricular arrhythmias re atrialarrhythmias by binding by binding to adenosine - entry supraventricular arrhythmias. e.g. WPW 4

3 pacemaker pacemaker action

,

4 effect effect ). : Antiarrhythmic: Drugs

and does not depress contractility ■ paroxysmal supraventricular tachycardia ■ ■ Therapeutic uses : (of Adenosine) block) block) ■ of patients ( bronchospasm ) 10 ■ ■ Adverse effects: (of Adenosine)

preferred oververapamil drug of choice for acute management of half brief brief AV block ( contraindicated in heart shortness of breath and chest burning in flushing in about %

-

life life = less than 20

10 % of patients sec. sec.

–

safer safer

Drugs summary

mind map- lectures 5,6: treatment of heart failure

For a more detailed mind map (therapeutic use), click here. Drugs summary- lectures 5,6: Treatment of heart failure

Veno- Aldosterone Arterio- Group Diuretics dialators antagonists dialators

Decrease Action Decrease preload afterload

• reduce salt and water retention dilate arterial Dilate venous antagonist of Mechan • which decrease ventricular blood vessels to blood vessels aldosterone ism of preload and venous pressure ↓ peripheral and ↓ receptor • reduction of cardiac size vascular action preload • Improvement of cardiac resistance performance

1-Spironolactone 1- Chlorothiazide • nonselective first-line agent in heart antagonist of failure therapy Nitroglyceri aldosterone used in volume overload receptor ne (pulmonary and/ or • a potassium & Isosorbide peripheral edema) sparing diuretic Hydralazine dinitrate used in mild congestive used in Used when heart failure used I.V. for congestive the main Drugs 2- Furosemide severe heart heart failure symptom is a potent diuretic used for failure when • improves Rapid fatigue immediate reduction of the main survival in due low pulmonary congestion & symptom is advanced heart cardiac output severe edema associated dyspnea due failure with : to pulmonary 2- Eplerenone - acute heart failure congestion a new selective - moderate and severe aldosterone chronic failure receptor antagonists

Drugs summary- lectures 5,6: Treatment of heart failure

Angiotensin converting Angiotensin α-adrenoceptor Direct Group enzyme inhibitors receptor blockers blockers vasodilators Action Decrease both ( preload and after load ) 1st line for hypertension & chronic heart failure therapy Blocks AT1 receptors along with diuretics. decrease the action of Mechanism inhibit ACE  reduce synthesis block α- receptors in AgII of AgII  activation of of action (more potent effect arterioles and venules Bradykinin system which is a than ACE) potent vasodilator. ↓ preload and afterload

1-Decrease peripheral resistance (Afterload ) reduce blood pressure by Useful 2-Decrease Venous return (Preload) decreasing both afterload Effects 3- Decrease sympathetic activity & preload which help 4- Inhibit cardiac and vascular remodeling heart failure patients

Losartan, Valsartan, Sodium Captopril Enalapril Rampril Irbesartan Prazosin nitroprusside Rapidly absorbed from GIT after oral administration Food reduce their bioavailability - I.V acute or Prodrugs converted severe Short to their active refractory HF duration Drugs metabolites in the of action liver -Acts Not a Long T1/2 immediately prodrug (given once daily) - Effect lasts Enalaprilat 1 – 5 min (active metabolite of Enalapril ) Used I.V in hypertensive emergency

1- acute renal failure 2- hyperkalemia 3-hypotension in hypovolemic Adverse patients effect 4- Dry cough 5- angioneurotic edema 6-Dysgeusia

• during the second and third Contra- trimesters of pregnancy indications • renal artery stenosis Drugs summary- lectures 5,6: Treatment of heart failure

β – adrenocepters Group Cardiac glycosides (Digitalis) Phosphodiesterase-III inhibitors agonists action Increase contractility (+ve inotropic) Amrinone / Milirone Dobutamine Drugs Digoxin Enoximone / vesnarinone (new drugs) (selective β1 agonist)

Inhibit Phosphodiesterase isoenzyme Inhibit NA/K ATPase enzyme (the 3 in cardiac and blood vessels to Sodium pump) inhibit cAMP degradation (↑cAMP) 1- inhibit Na/K pump directly

Mechanis 2- indirect inhibition of Na/Ca exchange 1- in heart: ↑ Ca which ↑ 3- facilitate Ca influx m of action contraction 4- ↑ Ca release from ER & T tubules 2- in peripheral vessels dilatation of Net result : increase the intracellular arteries and veins (reduction of Calcium preload and afterload)

1- increase the force of myocardial Pharmacol contraction to increase cardiac output - ogical ( +ve inotropic effect ) action 2- slow heart rate by vagal stimulation (-ve chronotropic effect)

- narrow therapeutic index Pharmaco- - 40-80 % absorbed orally (variable kinetics bioavailability) - 85% excreted unchanged in urine

Milrinone : Acute heart failure - congestive heart failure Treatment of acute - Atrial arrhythmias: (intravenously), not safe nor effective Therapeuti heart failure in • Atrial flutter in the longer treatment (> 48hours) c uses Cardiogenic shock • Atrial fibrillation Amrinone not used now because it • Supraventricular tachycardia (I.V in severe cases) causes thrombocytopenia

1) digitalis-induced arrhythmias (any type of arrhythmias for example bigeminal rhythm ) 2) GIT side effects (The earliest signs of 1) GIT upsets (Nausea ,vomiting) toxicity) 2) thrombocytopenia Adverse 3) live toxicity 3) CNS side effects especially in old age effects (Milrinone has LESS hepatotoxic and Factors that increase toxicity: less bone marrow depression than - Renal diseases amrinone) - Hypokalemia - Hypomagnesemia - Hypercalemia Drugs summary- lectures 5,6: Treatment of heart failure

Group β-adrenoceptor blockers Natriuretic Peptides

Second generation: Bisoprolol, Metoprolol β1 receptors blockers (cardio selective) Drugs Nesiritide Third generation: Carvedilol , Nebivolol have vasodilator actions ( α- blocking)

Nesiritide is a purified preparation of human β-blockers: BNP (which is normally secreted by the 1- attenuate cardiac remodeling ventricular myocardium in response to stretch) (cardiac dilatation & hypertrophy) manufactured by recombinant DNA Mechanism of 2- slow heart rate, which allows the left technology. action ventricle to fill more completely It increases cyclic-GMP in vascular smooth 3- decrease renin release muscle, leading to smooth muscle relaxation reduce mortality and morbidity of and reduction of preload and afterload patients with HF

indicated for the treatment of patients with Therapeutic reduce the progression of chronic heart acutely decompensated heart failure who have uses failure, not used in acute heart failure dyspnea at rest or with minimal activity

Mind map – drugs for heart failure

mind map- lectures 7,8: Antihypertensive Drugs Antihypertensive Drugs DIURETICS Potassium-sparing diuretics Loop diuretics Thiazides Amiloride as well as Furosemide spironolactone Hydrochlorothiazide -Sever & Moderate hypertension - Not potent antihypertensive, In Mild hypertension -Sever heart failure mainly used in Heart failure)

β- Adrenoceptor monotherapy in mild to moderate hypertension, In Blockers severe cases used in combination with other drugs. non cardio selective(β1 & β2) cardio selective(β1) α–β adrenergic blockers

Propranolol Bisoprolol Labetalol Nadolol Atenolol carvidalol metoprolol contraindicated in asthmatic patients

α1-Adrenoceptor •Added to β- blockers for treatment of blockers hypertension of pheochromocytoma

Prazosin & Terazosin Doxazosin

Due to the postural hypotension, α1-adrenoceptor blockers are not commonly used for Rx of HTN ++ Treatment of chronic hypertension with oral preparation Ca CHANNEL •Nifedipine used for Raynaud’s phenomena •Nicardipine can be given by I.V. route & used in hypertensive BLOCKERS emergency

Dihydropyridine Verapamil Diltiazem It is more selective as vasodilator than a It is more effective as cardiac Intermediate action. Used cardiac depressant. This group is depressant , therefore mainly for angina pectoris specifically used for treatment of commonly used as hypertension. antiarrhythmic . e.g. Nifedipine, Nicradipine, Amlodipin (Ankmlor)

mind map- lectures 7,8: Antihypertensive Drugs Antihypertensive Drugs Centrally acting α methyl dopa sympatholytic drugs

Clonidine Indirect α 2 agonist Direct α2-agonist Safely used in hypertensive pregnant women Sudden withdrawal causes rebound hypertension

Minoxidil K- channel opener, Arteriodilator Vasodilators 1.severe hypertension 2.correction of baldness (by Hypertrichosis)

Na nitropruside Hydralazine Diazoxide Release of (NO), Arterio & venodilator Direct , Arteriodilator 1.Hpertensive 1.Hpertensive emergency 1.Moderate -severe hypertension. emergency 2.Severe heart failure 2.Hypertensive pregnant woman 2. Treat hypoglycemia 3. Heart failure (CHF) ADRs: cyanide toxicity, (contraindicated for diabetics methemoglobinemia Cause lupus-erythematosus-like syndrome

Note that ACE I all end with USES: ACE INHIBITORS the suffix “-pril” - Hypertension •Drugs include captopril, - Heart failure Cause Acute renal failure, lisonopril, enalapril, ramipril, - Diabetic contraindicated in renal fisonopril nephropathy artery stenosis

BLOCKERS OF AT1 Note that all end with the suffix “-sartan” Clinical Uses: RECEPTOR •Drugs include: hypertension. losartan (Especially in Adverse effects: asthmatic patients) As ACEI except cough ,wheezing, valosartan and angioedema. Because it has no irbesartan effect on bradykiniin

Drugs summary- lectures 7,8: Antihypertensive Drugs

Classification Examples Important notes

Hydrochlorothiazide, • K-sparing diuretics reduce K loss in the urine Diuretics Furosemide ,potassium • Hydrochlorothiazide & Furosemide sparing diuretics decrease the B.P by decreasing (Amiloride, & volume of blood & cardiac output spironolactone) • Furosemide is indicated for hypertension with renal impairment captopril, lisonopril, • Cause and increase the risk of renal failure ACE Inhibitor enalapril, ramipril,& thus contradiction in patient with renal fisonopril diseases & Pregnant women Angiotensin Losartan, valosartan, & Same ADRs & contraindications as ACEI, except receptor Blockers irbesartan for cough and angioedema, thus indicated for asthmatic hypertensive patients. • Treat chronic hypertension Calcium channel Verapamil, Diltiazem, • Nicardipine is used in hypertensive blockers Nicardipine & emergency Nifedipine • side effects : Verapamil  Constipation Nifedipine  reflex tachycardia. • Hydralazine used in Hypertensive pregnant

woman. ADRs: lupus erythematous like syndrome. Hydralazine, Minoxidil, Vasodilators • Minoxidil Cause: (Hypertrichosisis) Diazoxide, & Na increase hair growth, That’s why it is nitropruside contradicted in female. • Na nitropruside Cause: Cyanide toxicity & used in hypertensive emergency Nadolol, Bisoprolol, • In severe cases used in combination with β- Adrenoceptor Atenolol, metoprolol, other drugs. Blockers Labetalol, & carvidalol • They decrease cardiac output & renin release • Mask the symptoms of Hypoglycemia in diabetic patients. • Prazosin is short-acting, causes first dose α- Adrenoceptor Prazosin, Doxazosin & hypotension & postural hypotension Blockers Terazosin • Doxazosin is Preferred, because of its long half- life clonidine can lead to rebound hypertension Centrally acting Clonidine & α methyl α methyl dopa : Safe in Pregnant woman sympatholytic dopa

Drugs summary – lectures 9,10: Antihyperlipidemic drugs

1. Drugs targeting exogenous pathways Ezetimibe Bile acid sequestrants (resins) Drug Cholestyramine, Colesevelam and Colestipol Selectively inhibits absorption of dietary and (Bind bile acids [BA]preventing their Mechanis biliary cholesterol in the small intestine  pool enterohepatic recycling &  fecal excretion m of cholesterol available to the liver upregulate LDL (10 folds). that will hepatic C uptake & receptor. plasma & tissue C . Pharmaco- LDL 20% LDL 15-30%  TG 8%  HDL 3-5% logical  HDL 1-4%  TG & VLDL action As Monotherapy, Primary prevention of low risk As Monotherapy: rarely, if statin is of CHD , contraindicated Indications As Combination Therapy; is safe (With statinsOr As combination with statins in type IIa With other lipid lowering drugs As fibrates ). Hyperlipoproteinemia • GIT disturbance, headache, fatigue, • clinically safe as they are not systemically • artheralgia and myalgia. absorbed, but May  absorption of fat ADRs & soluble vitamins ( A, D, E, K) Interaction • They also  absorption of some drugs, except for Colesevelam Contra- • Biliary obstruction • Chronic constipation indications • Severe hypertriglyceridemia Adjuvants in Hyperlipidemia Omega -3-FA β---Sitosterol (found in fish oils containing The adjuvant (found in plants with structure similar to highly unsaturated FA) cholesterol)

Mechanism & decreases TG & gives Some Compete with dietary & biliary cholesterol vascular protection Absorption. Effect decrease LDL levels +10% treatment of very high TGs Given as food supplement before meal in Indication Hypercholesterolemia

Antihyperlipidemic drugs Combinations

Synergistic combination Contraindicated combination Should be taken with breaks in between. Statin & ezetimibe. Statins & Fibrates, because the Resins: decreases the absorption incidence of myopathy may of statins and ezetimibe. increase

Drugs summary – lectures 9,10: Antihyperlipidemic drugs

2. Drugs targeting endogenous pathways Statins Fibrates

Drug Simvastatin- Lovastatin Niacin (Nicotinic Acid) Clofibrate, Fenofibrat, Atorvastatin - Pravastatin Gemfibrozil Rosuvastatin competitive inhibitors of HMG- promotes hepatic apoA-I They increase gene CoA reductase, which catalyzes a production and slows transcription for Mechanism rate-limiting step in de novo hepatic clearance of lipoprotein lipase (LPL) → hepatic cholesterol synthesis apoA-I and HDL ↑catabolism of TG

LDL 18-55% LDL (15-30), LDL (5-20), Pharmaco-  HDL (15-35) HDL (10-20) logical  HDL 5-10%   action Triglyceride (20-50) Triglyceride (20-50)  TG & VLDL 10-30% first-line drugs when LDL-lowering • Type llA 1st-line defense for: drugs are indicated, as they have hypercholestrolemia – • Mixed dyslipidemia additional Pleiotropic effects. Type llB (i.e. raised serum TG  Monotherapy : hypercholesterolemia and C ) 1. Type IIa Hyperlipoprotinemia. & any combined • Patients with low HDL If there is no control, hyperlipidemia and high risk of combine (sequestrants / • Patient with atheromatous disease Indications ezatimibe, niacine,.. ) to hypertriglyceridemia & ( often type 2 diabetic decrease cholesterol . low HDL-C. patients ) 2. In all ischemic insults • Hyperchylomicronemia. • Patients with severe  Combination therapy • mixed dyslipidemia resistant dyslipidemia 1. Mixed dyslipidemias ( combination with 2. In diabetics and patients with other lipid lowering insulin resistance drugs ).

• Hepatotoxicity, raised • Sensation of warmth & • Myositis: concentrations of liver cutaneous flushing (can Rhabdomyolysis Acute renal failure, enzymes ( serum be avoided by low dose especially in alcholics & aminotransferases) of Aspirin). patients with renal ADRs • Teratogenicity, statins should • reactivation of peptic impairment. • Gallstones, especially be avoided during pregnancy ulcer Clofibrate • Myalgia & Myopathy ( • hepatotoxicity. Creatine kinase) • Hyperglycemia • ↑ uric acid. Pravastatin and fluvastatin are the - increase risk of statins of choice in patients taking myopathy when Drug other drugs metabolized by combined with statins interaction cytochrome 3A4 system. - Displace drugs from plasma proteins

Drugs summary – lecture 11: Thrombolytic drugs

Thrombolytic drugs (plasminogen activators) Types Fibrin Specific Non fibrin-specific AKA: Tissue plasminogen Activators (t-PA) Action They activate mainly plasminogen bound to Activate both plasminogen bound to clot clot surface (non-circulating plasminogen in surface and circulating plasminogen in tissue). blood. Examples Alteplase Reteplase Tenectepla Streptokinas Anistrepla Urokinase se e (SK) se Origin A modified recombinant Streptokinas acylated Human Recombinant human t-PA e is a plasminog enzyme Form Of Prepared By Recombinant Bacterial en obtained Human tPA. Technology protein. combined from urine with SK or kidney 5 Min 15 Min. 30 Min <20 minutes 70-120 IV infusion. T1/2 min administr IV Bolus Two I.V. Bolus Single IV I.V infusion bolus I.V. 12-20 min Followed By Injections Bolus. injection ation An Infusion. Price - the cheapest more Very expensive Expensive ADRs • Less risk of bleeding than Non fibrin- Antigenicity More No specific thrombolytics , because of Allergy effective anaphylaxi selectivity to fibrin (no systemic Bleeding. and has s (not plasminogen activation) less ADRs antigenic) • Not antigenic: Can be used in patients than SK with antistreptococcal antibodies (due to either recent infection or use of SK). Uses • ST-elevation Myocardial approved Venous or lyses of Infarction (STEMI) for Acute arterial acute • Pulmonary Embolism Myocardial thrombosis massive Infarction pulmonar (AMI) y emboli Contraind Absolute contraindications include: Relative contraindications  Active internal bleeding include: ications  Cerebral hemorrhagic stroke Active peptic ulcer  Recent intracranial trauma or neoplasm Severe uncontrolled  Major surgery within two weeks hypertension. Antidote Fibrinolytic Inhibitors (Antiplasmins) inhibit plasminogen activation and promote clot stabilization. E.g. Aminocaproic Acid & tranexamic acid & Aprotinin

Drugs summary – lectures 12,13: Antianginal drugs:

Antianginal drugs Agents that improve symptoms and ischemia Agents that improve prognosis 1. Organic nitrates • Short acting nitrates 1. Aspirin / Other antiplatelets • Long - acting nitrates. 2. Statins 2. Calcium channel blockers 3. ACE Inhibitors 3. Potassium channel openers 4. -AD blockers 4. -adrenoceptor blockers 5. Metabolically acting agents *They help in 6. Others (Ivabradine) 1.Halt progression * All used for Prophylactic therapy to Halt 2.Prevent acute insult progression, Prevent acute insults (ACSs), Improve 3.Improve survival survival. except for Short acting nitrates which are indicated for attacks & situational prophylaxis

For a better version, click here

lectures 12,13: Antianginal drugs:

1. Organic nitrates

Types Short acting Long acting

Drugs Nitroglycerine [GTN] Isosorbide mono & dinitrate

• Sublingual tablets or spray for variant angina - Acute symptom relief of stable • For long-term Persistent prophylaxis of angina - Situational prophylaxis “as stable angina. Indications before exercise” • CHF  Isosorbide mononitrate + • I.V. Preparations: in unstable angina, hydralazine [if contraindication to ACEIs] refractory AHF, AMI

1. Nitric oxide binds to guanylate cyclase in vascular smooth muscle cell to form cGMP. Mechanism 2. cGMP activates PKG to produce relaxation

1. Venous vasodilation → ↓preload Hemodynam 2. Coronary vasodilation → ↑myocardial perfusion ic effect 3. Arteria vasodilatation → ↓afterload 4. Shunting of flow from normal area to ischemic area by dilating collateral vessel

Loss of vasodilator response of nitrates on use of long-acting preparations (oral, transdermal) or continuous intravenous infusions, for more than a few hours without interruption. Mechanism: NIRATE 1-Compensatory neurohormonal counter-regulation TOLERANCE 2-Depletion of free-SH groups Nitrate tolerance can be overcome by: 1.Smaller doses at increasing intervals (Nitrate free periods twice a day). 2.Giving drugs that maintain tissue SH group like Captopril.

• Throbbing headache • Flushing in blush area ADRs • Tachycardia & palpitation • Postural hypotension, dizziness & syncope • Rarely methemoglobinema

• Known sensitivity to organic nitrates, Uncorrected hypovolemia Contra- • Glaucoma: nitrates  aqueous humour formation indications • Head trauma or cerebral haemorrhage Increase intracranial pressure • Concomitant administration of PDE5 Inhibitors

lectures 12,13: Antianginal drugs:

2. Calcium channel blockers (CCBs) Dihydropyridines: More Selective to VSMCs Nifedipine , Nicardipine & Amlodepine Classification (Heterogeneous) Phenylalkylamines :Verapamil More selective to cardiomyocyte Benzthiazepines :Diltiazem Intermediate in action Calcium channel blockers  Bind to L Type Ca channels  decrease their frequency of Mechanism opening in response to depolarization  entry of Ca   Ca from internal stores  No Stimulus-Contraction Coupling  RELAXATION  Cardiomyocyte Contraction VSMC Contraction Coronary dilatation

Antianginal cardiac work through their –ve 1- After load  myocardial O2 supply actions inotropic & chronotropic action cardiac work  (verapamil & diltiazem)  myocardial oxygen myocardial oxygen demand demand  IN STABLE ANGINA; Regular prophylaxis  IN VARIANT ANGINA Attacks prevented Indications  IN UNSTABLE ANGINA Seldom added in refractory cases  Long acting Dihydropyridene (Amlodepine) is a useful antianginal if with CHF, because the don’t decrease cardiac contractility. • Short acting dihydropyridine (Nifedipine , Nicardipine) should be AVOIDED  BP  Precaution symathetic activation reflex tachycardia + syncope impair coronary filling ischemia ….. • nitrates + Verapamil & diltiazem Combinations • beta-adrenoceptor blockers + Long acting dihydropyrdine (amlodepine)

3. K+ CHANNEL OPENERS Drugs Nicorandil

1.Opening of KATP channels (more arteriolar 2. Acting as NO donner; as it has a dilator) nitrate moiety (more venular dilator) Mechanism On VSMCs :K+ channel opening  (dual) Hyperpolarization VASODILATATION On VSMCs : NO donner  cGMP/ PKG On Cardiomyocyte : K channel opening  VASODILATATION Repolarization  Cardiac work 1. Prophylactic 2nd line therapy in stable angina Indications 2. refractory variant angina • Flushing, headache, ADRs • Hypotension, palpitation, weakness • Mouth & peri-anal ulcers, nausea and vomiting

lectures 12,13: Antianginal drugs:

4. β1 Adrenergic Blockers β1 Blockers Atenolol, Bisoprolol, Metoprolol  Heart rate by Heart contractility by Antianginal 1- Duration of diastole 1.Workload mechanism 2- Coronary blood flow 2.O2 consumption 3-oxygen supply

1-Regular prophylaxis  Cardio-selective are better to spare b2-AR Stable 2-They are 1st choice on prolonged use   incidence of sudden death specially due to ventricular tachycardia  by their antiarrhythmic action. contraindicated  as it has no vasodilator action. They may worsen symptoms 1-Indication Variant and aggravate condition. Unstable halts progression to AMI  improve survival AMI Reduce infarct size, reduce morbidity & mortality - blockers should be withdrawn gradually. sudden stoppage  give rise to withdrawal manifestations: Rebound angina, arrhythmia, myocardial infarction & hypertension Due  Precautions Up-regulation of -receptors. Given to diabetics with ischemic heart disease if Benefits are more than hazards

5. Metabolically Acting Agents

1.O2 requirement of glucose pathway is lower than FFA pathway Mechanism 2.During ischemia, oxidized FFA levels rise, blunting the glucose pathway 3.Reduces O2 demand without altering hemodynamics

Indication Used whenever needed as add-on therapy

ADRs GIT disturbances Trimetazidine 1-Hypersensitivity reaction Contraindications

2-In pregnancy & lactation

Mechanism Inhibits the late sodium current which increases during ischemia 1-It prolongs the QT interval so not given with Class Ia & III antiarrhthmics Contraindications

2-Toxicity develops due to interaction with CYT 450 inhibitors Ranolazine

6. Others (Ivabradine)

Selectively blocks If (If is an inward Na+/K+ current that activates pacemaker cells of the Ivabradine SA node) Reduces slope of depolarization, slowing HR, reducing myocardilal work & O2 demand THANK YOU FOR CHECKING OUR WORK 435 PHARMACOLOGY TEAM عبدالرحمن السياري أحمد اليحيى لولوه الصغير شماء السعد خالد الزهراني شادن العمران رهف بن عبّاد عبدهللا الجنيدل لمى الزامل سارة الخليفة أحمد المصعبي كوثر الموسى ساره المطوع عبدالرحمن الزامل ديمه الراجحي فاطمة الدين عبدالرحمن الشمري معاذ باعشن جواهر الحربي آية غانم عبدالعزيز الشعالن دالل الحزيمي أسرار باطرفي محمد السحيباني رنيم الدبيخي نوف العبدالكريم فارس المطيري نورة الصومالي وضحى العتيبي فوزان العتيبي منيرة السلولي ريما الحيدان محمد ابونيان نورة البصيص منيرة العمري عمر القحطاني يوسف الصامل For any correction, suggestion or any useful information do not hesitate to contact us :[email protected]