Therapeutics and Clinical Pharmacy-1 PDF

Therapeutics and Clinical Pharmacy-1  Course no. 0201531  3 credit hours  Prerequisite/*Co-requisite: Pharmacology (3), Biopharmacy and Pharmacokinetics and Clinical Biochemistry  Course instructors: Dr. Alaa Hammad Dr. Ameerah Hasan Ibrahim  It presents the principles of th...

Therapeutics and Clinical Pharmacy-1  Course no. 0201531  3 credit hours  Prerequisite/*Co-requisite: Pharmacology (3), Biopharmacy and Pharmacokinetics and Clinical Biochemistry  Course instructors: Dr. Alaa Hammad Dr. Ameerah Hasan Ibrahim  It presents the principles of therapeutics and the patient's factors that may affect drug selection and dose determination. Course It also teaches the treatment of the most common diseases and the follow up of the Description patient. It also deals with how to maximize the benefits and minimize the risks of treatment and the skills of using drugs.  The Associated Program No. Course Learning Outcomes Learning Output Code Course Knowledge The student should be able to: K1 Identify patients’ individual factors that may affect treatment MK3 Learning Recognize the relationship of the above factors to the disease and K2 MK3 drug factors. Describe and evaluate therapeutic regimens which are used in the K3 MK3 management of the diseases covered in this course Outcomes K4 Recognizing conventional pharmacological approaches to the therapeutic management and/ or prophylaxis of these conditions. Skills MK3 The student should be able to: S1 Apply pharmaco-therapeutic principles to real patients’ cases MS1 MS1 Determine the most appropriate therapy for patients according to S2 patients’, disease, and drug factors in order to maximize benefits and minimize risk of therapy Evaluate and interpret evidence from disease management MS1 S3 guidelines Competencies The student should be able to: Relate pharmacology, pharmacokinetic and therapeutic principles C1 to come up with best therapeutic plan for a specific patient with MC1, MS1 specific conditions  Introduction-Therapeutics General principles Drug interaction Ischemic heart disease Course Hypertension Contents Heart failure Dyslipidemia Osteoporosis Rheumatoid Arthritis osteoarthritis  1. Pharmacotherapy-A Pathophysiologic Approach, by Joseph DiPiro, 11th edition 2. Pharmacotherapy-Principles and Practice, by Marie A. Chishol-Burns, 5th edition 3. Applied Therapeutics: The Clinical Use of Drugs by Koda-Kimble, 10th edition Textbooks 4. Clinical Pharmacy and Therapeutics, by Roger Walker and Clive Edwards, 3rd edition. Recommended reference: 1. Clinical Pharmacology by P.N. Bennett and M.J. Brown, 11th edition. 2. Disease management guidelines General Principles in Therapeutics Definition of Therapeutics It is the art of pharmacotherapy of diseases. It is the practice of patient treatment. Skills of using drugs. Maximizing benefits and minimizing risks of drug therapy. General Principles in Therapeutics Treatment of a patient needs a therapist who is aware of three aspects of therapy. He should have good knowledge of: Triad of therapy Disease Factors Etiology Pathology and Pathophysiology Severity Onset (acute, subacute, chronic) Natural History Symptom and Signs Complications Patient Factors Genetic Buildup Age Gender Physiological condition (pregnancy, lactation) Associated Diseases Drug Factors Pharmacodynamic Properties Pharmacokinetic Properties Adverse Effects Drug Interaction  I. Pharmacogenetics and pharmacogenomics Patient Pharmacogenetics is the study of all genetic Individual determinants of drug's action: Cellular levels Factors Subcellular levels (receptor and cellular signal transduction) Final response affecting the body. Genetic determinants of the drug pharmacokinetics which affect absorption, metabolism, distribution and elimination of the drug. Patient Pharmacogenomics is the study of how the variation in organization Individual and function of drug related genetic materials of an individual produce Factors variation in body's response to drug. Patient Factors Genetic Buildup Age Gender Physiological condition (pregnancy, lactation) Associated Diseases Inheritable conditions causing individual variation in drug response Examples on Inheritable conditions causing individual variation in drug response Glucose-6- Variation in phosphate Warfarin cytochrome p450 dehydrogenase resistance activity deficiency  -These enzymes exhibit great genetic polymorphisms. -Genetic polymorphism affects body clearance of the drugs, and hence plasma 1. Variation in half time, blood level and consequently side effects and doses. cytochrome -Significance is greater with drugs of low P450 activity therapeutic index /narrow therapeutic window. -According to extent of contribution to drug metabolism and clinical importance, the most important enzymes are CYP3A4/5, CYP2D6, and CYP2C9/19. Substrates of CYP3A4 in Groups Calcium channel blockers Benzodiazepines Ethinylestradiol Diltiazem Midazolam Paracetamol Nifedipine Alprazolam Felodipine Omeprazole Triazolam Verapamil Glibenclamide Clonazepam Azole antifungals Theophylline SSRIs Citalopram Ketoconazole Antipsychotics Fluoxetine Itraconazole Aripiprazole Sertraline Risperidone Clotrimazole Statins Ziprasidone Atorvastatin Tricyclic antidepressants Lovastatin Amitriptyline haloperidole Simvastatin Imipramine Clomipramine Amiodarone PDE5 inhibitors Antiepileptics Sildenafil Macrolide Erythromycin Phenobarbital Clarithromycin Carbamazepine Valproate Substrates of CYP2D6 in Groups Beta-blockers Antipsychotics Metoprolol Haloperidol Carvedilol Risperidone Timolol Perphenazine Alprenolol Thioridazine Class I antiarrhythmics Zuclopenthixol Flecainide Aripiprazole Lidocaine Others: Propafenone chlorphenarmine Encainide metoclopramide Mexiletine tamoxifen All tricyclic antidepressants Most SSRIs Fluoxetine Paroxetine Substrates of CYP2C9 Phenytoin S-warfarin Tolbutamide Losartan Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, diclofenac, piroxicam, tenoxicam, mefenamic acid) acid) Substrates of CYP2C19 S-mephenytoin Omeprazole and other proton-pump inhibitors Diazepam Propranolol Imipramine (TCA) Amitriptyline )  -There are several polymorphic forms. 2. Glucose-6- -It is sex-linked disorder. phosphate -It affects Africans, Mediterraneans, Middle East, and South East people. dehydrogenase deficiency -A hemolytic episode may be triggered by eating broad beans (favism) or by administration of some drugs. -It is not necessary for a drug to cause hemolysis in all patients with glucose-6- phosphate dehydrogenase deficiency.  Antimalarial: pamaquin, pentaquine, primaquine, 2. Glucose-6- quinocide, mepacrine phosphate (quinacrine), chloroquine and dehydrogenase quinine. deficiency Sulphonamides: sulpacetamide, sulphamethoxypyridazine, sulphapyridine, sulfafurazole, sulphasalazine.  Sulphones: Dapsone, Sulfoxone. Nitrofurans: Nitrofurantoin, 2. Glucose-6- furazolidone. phosphate Other anti-infective drugs: Quinolones, Sulfonamides, para- dehydrogenase aminosalicylic acid, chloramphenicol, deficiency streptomycin, NSAIDs: Aspirin, Amidopyrine, antipyrine, acetanilide, phenacetin.  Vitamin K analogues: Acetomenaphthone (Menadiol 2. Glucose-6- Diacetate), Menophthone (menadione), Menadiol sodium phosphate diphosphate, Menaphthone sodium bisulphite. dehydrogenase Miscellaneous drugs and chemicals: deficiency Dimercaprol, Methylene blue, Naphthalene, Quinidine.  -This condition is autosomal dominant. -Patients with warfarin resistance 3. Warfarin have variant form of epoxide reductase. (VKOR) resistance -In this condition, warfarin has low affinity to the enzyme. -Inhibition of this enzyme, which is responsible for regeneration of active vitamin K, needs very large dose of warfarin. Patient Factors Genetic Buildup Age Gender Physiological condition (pregnancy, lactation) Associated Diseases  Drug treatment in the extremes of age differs in many aspects from prescription in young adults. Age Handling of drugs by the body, and body response to drugs differ in the extremes of age due to differences in the anatomy, physiology, and pathophysiology in babies and elderly. This leads to change in pharmacokinetics and pharmacodynamics of administered drugs.  When drug treatment is considered for elderly, factors which should be taken in consideration are: -The drug to be chosen. Drug -The dose to be given. treatment -Dosage regimen to be determined. in elderly -Pharmaceutical formulation to be used.  These factors depend on understanding the changes in drug's pharmacodynamics and pharmacokinetics (1. absorption, 2. Drug distribution, 3. metabolism, and 4. treatment elimination) in elderly people. in elderly Changes in the pharmacokinetics of drugs in elderly 1. Absorption in elderly Drug absorption is generally slightly slower in elderly than in young adults. This is due to: - Higher pH - Slower gastric emptying. - Reduced blood flow to the gastrointestinal tract. Changes in the pharmacokinetics of drugs in elderly 2. Distribution in elderly Drug distribution in elderly is influenced by the following factors: -Lean body mass -Total body water -Body fat -Plasma proteins a. Plasma albumin b. Orosomucoid (alpha1-acid glycoprotein) Changes in the pharmacokinetics of drugs in elderly 3. Drug metabolism in elderly There are some clinically important changes in elderly that may affect drug metabolism. These include: 1. Decrease in phase I metabolism 2. Decrease of 1st pass metabolism 3. Capacity for hepatic enzyme induction is lessened 4. Slow recovery of the liver from recent injury Changes in the pharmacokinetics of drugs in elderly Examples of drugs which metabolism is affected in elderly are:  Benzodiazepines: alprazolam, chlordiazepoxide, diazepam, flurazepam. Lorazepam and oxazepam are only slightly affected.  Barbiturates  Tricyclic antidepressants: imipramine, nortriptyline  Beta-blockers: propranolol  Others: quinidine, theophylline, thioridazine. Changes in the pharmacokinetics of drugs in elderly 4.Drug elimination in elderly - There is a decrease in the renal functions after the age of 55 years. - This is important for drugs that eliminated mainly by the kidney particularly drugs with low therapeutic index. - Aminoglycosides t1/2 may be doubled in elderly. The least affected aminoglycoside is tobramycin. - Digoxin dose is usually halved in elderly. - The elimination of lithium and chlorpropamide is greatly affected. Changes in the pharmacodynamic of drugs in elderly The main reported pharmacodynamic changes are: 1. Decreased sensitivity to the short-term treatment by verapamil on cardiac conduction. 2. Attenuated action of angiotensin converting enzyme inhibitors in elderly due to low plasma level of renin. Changes in the pharmacodynamic of drugs in elderly 3. Decreased action of the antimuscarinic drugs on the heart due to attenuation of its parasympathetic innervation. 4. Drugs act on CNS produce an exaggerated response in relation to that expected from the plasma concentration. e. g. sedative hypnotic drugs may have pronounced hangover effect and ataxia. These drugs are also more likely to depress respiration because of decrease in pulmonary function Changes in the pharmacodynamic of drugs in elderly 5. Responses to β-adrenoceptor agonists and antagonists are blunted. 6. Reduced sensitivity of baroreceptors leads to postural hypotention with drugs that reduce blood pressure e.g. prazosin, chlorpromazine. 7. Decreased production of vitamin K-dependent clotting factors with comparable warfarin concentration.  Changes in the pharmacodynamic of drugs in elderly 8. Drugs are more liable to produce condition accompanying aging e.g. -mental confusion due to sedatives, -parkinsonism due to neuroleptics, -glaucoma and urine retention due to drugs with anticholinergic effect.  The incidence of drug side effects is higher in elderly. The factors that increase this incidence include: Adverse 1. Increasing number of drugs that they need due to multiple diseases. This reactions of increases the side effects and drug-drug interactions.—polypharmacy drugs and elderly 2. Poor compliance with dosing regimens 3. Body changes of aging that require modification of dosage forms Drugs with special cautions in elderly Drug Comment Long-acting benzodiazepines These agents have very long half-lives, cause prolonged sedation and increase the risk of falls and fractures. If benzodiazepine therapy Chlordiazepoxide (Librium) is unavoidable, use short-acting agents. Diazepam (Valium) Chlorazepate (Tranxene) Flurazepam (Dalmane) Meprobamate (Miltown) It is highly sedating and addictive. All use should be avoided except in individuals who are already physically dependent. Amitriptyline (Elavil), Because amitriptyline and doxepin are very sedating and anticholinergic, their use should be avoided. Doxepin (Sinequan) Methyldopa (Aldomet) Avoided. Methyldopa causes bradycardia and can exacerbate depression in the elderly. Safer antihypertensives are available. Indomethacin Avoided. Other NSAIDs cause CNS toxic reactions less often Chlorpropamide Avoided. Other oral hypoglycemics have shorter half-lives and do not cause SIADH. Diphenhydramine Use only in the smallest effective dose and only for emergency treatment of allergic reactions. Causes confusion and sedation. Orphenadrine (Norflex) Causes more sedation and anticholinergic effects than its alternatives do. Nitrofurantoin Potential for renal impairment; safer alternatives exist. Thioridazine (Mellaril) Greater potential for CNS and extrapyramidal side effects. Mineral oil Potential for aspiration and adverse effects. Safer alternatives are available. Drugs with special cautions in elderly Anticholinergics and Antihistamines All nonprescription and many prescription antihistamines can have potent Chlorpheniramine anticholinergic effects and cause confusion and sedation. To treat allergic reactions, use non-anticholinergic antihistamines rather than these agents. Diphenhydramine Hydroxyzine Cyproheptadine (Periactin) Promethazine (Phenergan) Tripelennamine Hyoscyamine (Levsin) Propantheline (Pro-Banthine) Dicyclomine (Bentyl) Disopyramide (Norpace) Strong anticholinergic and negative inotropic effects make this agent a poor antiarrhythmic choice. Long-term use of non-selective NSAIDs: Potential for renal failure, GI bleeding, hypertension and heart failure. Naproxen (Narosyn, Anaprox) Piroxicam (Feldene) Daily Fluoxetine (Prozac) Has a long half-life and can produce insomnia and agitation. Safer alternatives exist. Long-term use of stimulant laxatives: May be appropriate in the presence of opiate analgesic use. Otherwise, may Bisacodyl (Dulcolax) exacerbate bowel dysfunction. Cascara sagrada Amiodarone (Cordarone) Associated with QT prolongation and torsades de pointes. Lack of efficacy in the elderly. Rules of prescribing for elderly Below are general rules that are useful to follow in elderly: 1. Do not give unnecessary drug. 2. Avoid giving drug with major side effects. 3. Think about drug formulation and give the convenient formulation. 4. Assume any new symptoms may be due to drug side effects or drug withdrawal. Rules of prescribing for elderly 5. Think about the dose. Elderly usually need lower doses than young adults. 6. Take a careful drug history. Elderly commonly take drugs without prescription. 7. Do not use fixed drug combinations unless they are very convenient. 8. When a drug is added think about withdrawing a drug. Rules of prescribing for elderly 9. Ensure good compliance. It is necessary to explain well how to use the drug and ensure that the elderly understands you. 10. Stopping a drug is as important as starting a drug. Drug withdrawal reactions are more sever and dangerous in elderly. Drugs in premature infants, neonates and infants There are a lot of differences in body responses and handling of drugs below the age of one year. These differences are due to: 1. Body constituents of fat, water and muscle differ in babies compared to young adults. 2. A number of body functions are not completely mature soon after delivery. They need variable time for maturity. Generally, at the age of one year satisfactory maturation of the functions related to drug pharmacodynamics and pharmacokinetics is noticed. Pharmacokinetic of drugs in infants 1. Absorption in infants Factors peculiarities of absorption in infants are: - Gastric pH decreases from 6-8 to 1.3 in the 1st 24 hours in newborn. - Gastric emptying is slow in the first day of life. - Immature secretion of pancreatic lipase. Pharmacokinetic of drugs in infants - Rectal absorption is efficient. - Absorption after intramuscular injection is unpredictable - Transdermal absorption is better due to underdevelopment of skin barrier and good skin hydration. Pharmacokinetic of drugs in Age group Body ECF infants weight 2. Distribution Premature 85% 50% infant Fat and water content, and water distribution in the body Infant 78% 25-35% affect drug distribution. Variation of water distribution Adult 60% 19% according to age is as follow: Pharmacokinetic of drugs in infants These differences in body water and fat produce: Increase in the apparent volume of distribution of water- soluble drugs. Premature infant has only 1% fat of the total body weight in contrast to 15% in mature infant. Fat-soluble drugs have lower apparent volume of distribution in infants due to less fatty tissues. Pharmacokinetic of drugs in infants Additional factors that may affect distribution in infants are:  Low plasma protein binding in newborn infant because of: 1. Low plasma protein. 2. Low binding capacity. 3. Low binding affinity.  Competition by bilirubin Pharmacokinetic of drugs in infants Selected drug examples that have low plasma protein binding in newborn infant are phenobarbital, salicylate, phenytoin, theophylline, propranolol, lidocaine, penicillin, nafcillin, and chloramphenicol. 3. Metabolism It is characterized by - Low activity of cytochrome P450 Pharmacokinetic of drugs in infants Low activity of glucuronide conjugation enzymes in neonatal life Sulfation is well developed. Methylation is well developed 4- Elimination Kidney functions need 6-12 months to mature. Glomerular filtration rate is only 30-40% of the adult in the first few days of life. It increases to 50-60% of the adult at 3 week of age. Drugs need to be excreted by the kidney may be given in reduced doses e. g. aminoglycosides, penicillins and diuretics, before the age of 6 month. Pharmacodynamic of drugs in infants Body response may differ in infant due to pharmacodynamic factors of the drug. Maintenance dose of digoxin is higher in infant Propylene glycol causes hyperosmolarity in infant. Benzyl alcohol causes toxicity and death. Fluroquinolones are suspected to cause arthropathy in infant. Aminoglycosides show less toxic effect in infants. Prostaglandin analogue keeps ductus arteriosus patent in newborn