PHARMACOLOGY II Dr A.SHYAM SUNDAR.,M.Pharm.,Ph.D Associate Professor in Pharmacology, University of Nizwa, Sultanate of Oman

What is Pharmacology? Pharmacology is the science that deals with drugs. It explains what drugs do,and how they do it. A knowledge of Pharmacology is essential for using drugs effectively in treatment.

Drugs... Drug is a substance used to cure,diagnose or prevent the disease. WHO defines drug as product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of recipient. Drugs are intended to have a selective action,but this ideal is seldom achieved There is always a risk of adverse effects as well as a benefit connected with using any drug.

Pharmacokinetics... ‘Kinesis’ means ‘movement’,hence pharmacokinetics means “how drugs move inside the body”. It deals with Absorption, distribution and metabolism and excretion of drugs. Simply it gives details regarding “what the body does to the drug.

Pharmacodynamics... ‘Dynamics’ means ‘power’,hence Pharmacodynamics detail about the power the drug. Pharmacodynamics is the study of drug effects. Simply it deals with what the drug does to the body.

Drug names... Chemical name explains the drug’s chemical composition and molecular structure. ex.( +/- ) – 2 – ( p-isobutylphenyl ) proponic acid. Generic Name ( Nonproprietary name ) name given by the United States Adopted Name Council.Universally accepted. ex.ibuprofen. Trade Name ( Brand name/ Proprietary name) the drug has a registered trademark ; use of the name restricted by the drug’s owner ex. Motrin

Receptors Receptors are proteins in nature. They may be located inside the cell or on the cell’s surface. Most of the drugs and endogenous substance binds with receptors and then produce Biological actions.

Agonists and Antagonists... Agonists are the drugs that bind to receptors and stimulate/ enhance a response ex. Insulin, isoproterenol – stimulate beta 1 receptor. Antagonists are the drugs that bind to receptors and block a response ex. cimetidine – blocks H2 receptor. Agonists and Antagonists can preferably defined with the terms Affinity and Intrinsic activity. Affinity is the tendency of the drug to bind with the receptor. Intrinsic activity is the capacity of the drug to produce biological action after binding with the receptor.

Sources of drugs... From plants (eg, morphine). From animals (eg, insulin). From minerals (eg, iron). From synthetic chemical compounds manufactured in laboratories. (Eg, adding, deleting, or altering a side-chain). From micro organisms (eg, many antibiotics). From biotechnology origin: this process involves manipulating Deoxyribonucleic acid (dna) and ribonucleic acid (rna)

Types of drugs... Prescription drugs. Non-Prescription drugs. Controlled drugs

Prescription Drugs Prescription drugs are drugs that the government has designated to be potentially harmful unless their use is supervised by a licensed health care provider. Although these drugs have been tested for safety and therapeutic effect, prescription drugs may cause different reactions in some individuals. Prescription drugs, also called legend drugs, are the largest category of drugs. Prescription drugs are prescribed by a licensed health care provider. The prescription (see Fig) contains the name of the drug, the dosage, the method and times of administration, and the signature of the licensed health care provider prescribing the drug.

Non-Prescription drugs Declared by the FDA to be safe (if taken as directed) and obtained without a prescription. These drugs are also referred to as over-the-counter (OTC) drugs and may be purchased in a variety of settings, such as a pharmacy, drugstore, or in the local supermarket. OTC drugs include those given for symptoms of the common cold, headaches, constipation, diarrhea, and upset stomach. These drugs are not without risk and may produce adverse reactions. For example, acetylsalicylic acid, commonly known as aspirin, is potentially harmful and can cause gastrointestinal bleeding and salicylism . Labeling requirements give the consumer important information regarding the drug, dosage, contraindications,precautions, and adverse reactions. Consumers are urged to read the directions carefully before taking OTC drugs.

Controlled Substances... Controlled substances are the most carefully monitored of all drugs. These drugs have a high potential for abuse and may cause physical or psychological dependence. Prescriptions for controlled substances must be written in ink and include the name and address of the patient and the Drug Enforcement Agency number of the primary health care provider.

Drug use in Pregnancy... Drugs administered to pregnant women, particularly during the first trimester (3 months), may cause teratogenic effects. A teratogen is any substance that causes abnormal development of the fetus leading to a severely deformed fetus. Drugs are one type of teratogen. In an effort to prevent teratogenic effects, the FDA has established five categories suggesting the potential of a drug for causing birth defects.

PHARMACIST...

PHARMACIST...

CARDIOVASCULAR PHARMACOLOGY

4 BASIC POINTS & 4 MAIN DISEASES Heart Failure is a condition in which the heart is unable to meet the metabolic demands of the body. Hypertension is a condition in which the pressure at which heart ejects its blood into the arteries persistently increases abnormally. Cardiac Arrhythmias, a group of disorders in which there will be abnormality either in the impulse generation or impulse conduction. Angina is the hearts way of signaling that it doesn't receive sufficient blood supply and Myocardial Infarction occurs when oxygen deprived myocardial cells start dying. James Olson, Clinical Pharmacology Made Ridiculously Simple, Second Edition, MedMaster Series,

ANS AND CVS When sympathetic nervous system is stimulated... When parasympathetic nervous system is stimulated... β1 receptors activated and causes Increase in heart rate, Increase in conduction velocity and Increase in force of contraction M2 receptors activated and causes Decrease in heart rate, Decrease in conduction velocity and Decrease in force of contraction α1 receptors activated and causes vasoconstriction Secretion of Catacholamines and α1and β1 actions occur.

UNIT 1: CONGESTIVE HEART FAILURE UNIT INSTRUCTIONAL OUTCOMES: At the end of this unit, the student should be able to, Differentiate the types of heart failure List compensatory mechanisms of heart failure Describe the physiology of cardiac contraction and ionic movement during cardiac contraction List the classes of drugs used to treat cardiac failure and their mechanism of action Recall vital informations about the drugs used in CHF. Apply pharmacological knowledge gained in the clinical scenario.

Types of heart failure... Low-output heart failure vs High-output heart failure In LOHF, the metabolic demands of the body is normal and heart will not be able to supply the normal demand. In HOHF, the metabolic demands may be very high (due to anemia or hyperthyroidism),and the heart will not be able to supply blood to meet this increase in demand. Left sided heart failure vs Right sided heart failure LSHF leads to pulmonary edema and RSHF leads to systemic edema Systolic Failure vs Diastolic Failure Systolic failure : Abnormality in cardiac contraction (As seen in IHD and Cardiomyopathy) Diastolic failure: Abnormality in Ventricular relaxation (As seen in HTN and Cardiomyopathy)

COMPENSATORY MECHANISMS OF HEART FAILURE Increased sympathetic activity. Retention of sodium and water. Myocardial hypertrophy. Lippincott's Illustrated Reviews: Pharmacology, 4th Edition.

Physiology of cardiac contraction Actin and myosin Tropomyosin Troponin complex Ca++ Ions

Ionic Movement during cardiac contraction Lippincott's Illustrated Reviews: Pharmacology, 4th Edition.

Therapeutic Goals in CHF Acute/Decompensated Heart Failure: Decrease congestive symptoms (Diuretics) Increase Myocardial Contractility (Inotropes) Chronic/Compensated Heart Failure: Decrease Workload of Heart (Vasodialators) Decrease mortality by reversing cardiac remodeling (Aldosterone Antagonists)

Classification of drugs Review Questions: 1. What are the therapeutic goals for a CHF patient? 2. List the rationale why the above mentioned drugs are used in CHF Lippincott's Illustrated Reviews: Pharmacology, 4th Edition.

MOA OF CARDIAC GLYCOSIDES Lippincott's Illustrated Reviews: Pharmacology, 4th Edition.

Cardiac Glycosides Examples: Digoxin, Digitoxin, Strophanthin and Ouabain Used for acute treatment of CHF, Atrial Fibrillation, Atrial Flutter and Supraventricular tachycardia. Used for acute treatment CHF ( Digoxin is an exception which is given orally as maintenance) MOA in CHF: Inhibition of Na+-K+ ATPase. MOA in Atrial Flutter: Vagomimitic action (AV conduction rate is decreased) Unlike other inotropes, CG’s do not increase heart rate and Oxygen consumption. (Rather O2 consumption and HR decreases)

Cardiac Glycosides- Adverse Effects and Toxicity First symptoms are Nausea and Vomitting Causes visual disturbances and Gynacomastia. Mild toxicity can be treated with KCl( KCl is contraindicated in severe toxicity) Digitalis induced vetricular Arrhythmias can be treated with Lignocaine(DOC)/ Phenytoin. Digitalis induced Atrial Tachycardia can be treated with propanolol Digibind (Digoxin antibody) is preferred in case of severe toxicity

Contraindications and Interactions of Digitalis METABOLIC: 1. Hypokalemia 2. Hypomagnesemia 3. Hypercalcemia DRUGS: 1. Thiazides and Furosemide: (Results in Hypokalemia and Hypomagnesemia 2. Quinidine and Ca++ channel blockers (Results in Decreased Renal Clearance and hence toxicity). DISEASES: 1. Hypothyroidism and Hyperthyroidism 2. Myocarditis 3. Digoxin precipitates toxicity in Renal Failure and Digitoxin precipitates toxicity in Hepatic Failure.

MOA OF BETA ADRENERGIC AGONISTS AND PHOSPHODIESTERASE INHIBITORS Lippincott's Illustrated Reviews: Pharmacology, 4th Edition.

DOPAMINE and DOBUTAMINE Selective Beta-1 receptor agonist. MOA: Increases cAMP Increases Cardiac Contraction Increases Cardiac Output Acts on Dopamine, Beta and Alpha receptors based on the dose administered 1-2 µg/kg/min Stimulates Dopamine receptors Increased Vasodilation. 2-10 µg/kg/min Stimulates Beta 1 receptors Increased Cardiac Contraction. >10 µg/kg/min Stimulates Alpha receptors Increased Vasoconstriction. Anand, M.D. Ramachandran, Pharmacology Recall, Second Edition, Wolters Kluwer

Inodialators Examples: Inamrinone, Milrinone and Vesnarinone. They act as Inotropes as well as Vasodilators. Acts by inhibiting the enzyme Phosphodiesterase and thereby increasing the level of cAMP in heart and blood vessels. Short term use of severe and refractory CHF. Milrinone is preferred as inamrinone causes thrombocytopenia. Both Inamrinone and Milrinone may result in arrhythmias.

Direct acting Vasodilators Vasodilators reduces both preload and afterload. Venodilation reduces preload and Arterial dilation reduces afterload. Minoxidil is used to treat male pattern bladness. Nitrates Hydralazine Anand, M.D. Ramachandran, Pharmacology Recall, Second Edition, Wolters Kluwer

MOA OF ACE INHIBITORS CONTRAINDICATED IN PREGNANCY Lippincott's Illustrated Reviews: Pharmacology, 4th Edition.

BETA-BLOCKERS IN CHF β-blockers decrease sympathetic activity by blocking the β-receptors on the excitable cells in the myocardium and blood vessels. A blockade of these receptors results in decreased cardiac contractile activity and heart rate, decreased blood pressure, and decreased peripheral circulation. All these effects reduce the oxygen demand of myocytes. β-blockers such as bisoprolol, carvedilol, metoprolol are used in treatment of heart failure in addition to the treatment of diuretics and ACE-inhibitors

DIURETICS IN CHF Diuretics increase excretion of Na+ ions from the kidney. As a result water is excreted as well, which lowers plasma volume, extra cellular fluid, cardiac output and ultimately relieve edema and dyspnea. Two classes of diuretics are applied in the treatment of the symptoms of heart failure. Loop diuretics act in the ascending loop of Henle. Example: Furosemide. Thiazide diurietics act in the distal tubule. Example: Hydrochlorothiazide. Spironolactone is also used in maintenance of severe heart failure since it slows down the remodeling of the heart by antagonising the aldosterone receptors of the heart.

CHF- Updates Vasopeptidase Inhibitors: Examples: Omapatrilat and Sampatrilat These drugs inhibit ACE and NEP(Neutral Endo Peptidase) Orally administered for the treatment of chronic CHF. Same properties as ACE inhibitors PLUS natriuresis. Angioedema is the major adverse effect.

CHF- Updates Levosimenden is an agent that sensitizes the myocardium to Ca++ apart from inhibiting phosphodiesterase. Nesiritide: Is an rBNP (Brain Derived Natriuretic Peptide) Increases cGNP and causes vasodilation Treatment acute CHF associated with dyspnea at rest.

CONGESTIVE HEART FAILURE - Summary Therapeutic goals: 1)Reduce workload of the heart 2)Improve myocardial contractility James Olson, Clinical Pharmacology Made Ridiculously Simple, Second Edition, MedMaster Series,