Drug Interactions and Factors Modifying Drug Action PDF

how body weight and body size influence drug action?  Body weight is important to calculate the dosages of the drugs. Body weight Body weight is so important to calculate the dosages of the drugs. It influence...

how body weight and body size influence drug action?  Body weight is important to calculate the dosages of the drugs. Body weight Body weight is so important to calculate the dosages of the drugs. It influences the concentration of the drug attained at the site of action. overweight patient patient who are may require an underweight increase in dosage (compared with the to attain the same general population) therapeutic respons tend to required lower as (the general dosages for the same population.) therapeutic response.  Body size *Dose is not the same* Body size is one of the factors that prescriber considered before administering the first dose of the drug as it helps in predicting the direction and extent of possible variations in responsiveness Body composition is important to understand pharmacodynamics and pharmacokinetics of drug  Factors modifying drug action how age influences drug actions. As you get older you may be faced with more health conditions that you need to treat on a regular basis. It is important to be aware that more use of medicines and normal body changes caused by aging can increase the chance of unwanted or maybe even harmful drug interactions.  Factors modifying drug action New born * Decreases acid secretion * Decreased microsomal enzymes * Decreased plasma protein binding * Decreased G.F.R Transdermal absorption: is faster because their skin is thin and more permeable Rectal absorption : is fast and more predictable in infants and young children  Factors modifying drug action Elderly * renal function progressively declines so that * GFR will be reduced. * low in liver blood flow * Low intestine motility * Low in hepatic functions.  1 Explain how food and environmental factors influence drugs actions. v Interactions between food and drugs may inadvertently reduce or increase the drug effect. v Some commonly used herbs, fruits as well as alcohol may cause failure of the therapy up a point of to Cz serious alterations of the patient’s health. v The majority of clinically relevant food-drug interactions are caused by food-induced changes in the bioavailability of the drug.  Food/Nutrient effects on drug action Among all fruit juices, The juice modifies the E.g. inhibition of grape fruit juice (GFJ) body’s way of cilostazol metabolism possesses high metabolizing the by components of interaction with almost medication, affecting grapefruit juice all types of drugs. the liver’s ability to work the drug through a person’s system.  Warfarin v Warfarin is commonly used to treat or prevent thromboembolic events. v Patients taking warfarin are at particular risk of interactions with dietary supplements. v There is a possible interaction between warfarin and a high-protein diet. v Some vegetables (broccoli, Brussels sprouts, kale, parsley, spinach, and others) are high in vitamin K. Eating large quantities or making sudden changes in the amounts eaten of these vegetables, interferes with the effectiveness and safety of warfarin therapy v Eating charbroiled food may decrease warfarin activity, while eating cooked onions may increase warfarin activity Environmental factors that effects drug actions v Exposure to insecticides v Carcinogens v tobacco smoke. v consumption of charcoal broiled meat are well known to induce drug metabolism. v set up in which drug is taken e.g hypnotics work better when taken at night in quiet surroundings  Genetic factors The dose of a drug to produce the same effect may vary by 4–6 fold among different individuals. All key determinants of drug response, viz. transporters, metabolizing enzymes, ion channels, receptors with their couplers and effectors are controlled genetically. Lead to -different rate of metabolism: due to difference in the amount and isoform pattern of drug metabolizing enzymes which is genetically controlled. - Differences in target organ sensitivity: e.g, low activity of CYP2C9 variants metabolize warfarin at a slow rate and are at higher risk of bleeding.  Note! some people process Other people metabolize (metabolize) drugs drugs so quickly, drug slowly. result, a drug levels in the blood never may accumulate in the become high enough for body, causing toxicity the drug to be effective  Some specific Gentics effects 1-Atypical pseudocholinesterase results in prolonged succinylcholine apnoea. 2-The low activity CYP2C9 variants metabolize warfarin at a slow rate and are at higher risk of bleeding 3-CYP2D6 abnormality causes poor metoprolol/ debrisoquin metabolizer status. Since several antidepressants and antipsychotics also are substrates of CYP2D6, deficient patients are more likely to experience their toxicity. Codeine fails to produce analgesia in CYP2D6 deficient, because this enzyme generates morphine from codeine. 4-Polymorphism of N-acetyl transferase 2 (NAT2) gene results in rapid and slow acetylator status. Isoniazid neuropathy, procainamide and hydralazine induced lupus occurs mainly in slow acetylators.  5- EXPLAIN HOW FOOD AND ENVIRONMENTAL FACTORS INFLUENCE DRUG ACTIONS. The diet and nutritional status of the individuals are important determinants. As altered drug-metabolizing enzyme activities can influence the intensity and duration of drug action Drugs are better absorbed in empty stomach. To prevent gastric irritation most drugs are taken after or between foods, which affects the outcomes.  5- EXPLAIN HOW FOOD AND ENVIRONMENTAL FACTORS INFLUENCE DRUG ACTIONS. charcoal broiled food or vegetables induce the metabolism of many xenobiotics volume of neutral liquids, like water, enhances the dissolution of tablets and capsules in the gastrointestinal tract (stomach and intestine). For some drugs such as digoxin and paracetamol, the rate but not the extent of absorption is reduced.  FOOD/NUTRIENT EFFECTS ON DRUG ACTION: WARFARIN Warfarin (anticoagulant) acts by preventing the conversion of vitamin K to a usable form. Ingestion of vitamin K in usable form will allow production of more clotting factors, making the drug less effective Some vegetables (broccoli, Brussels sprouts, kale, parsley, spinach, and others) are high in vitamin K. Eating large quantities or making sudden changes in the amounts eaten of these vegetables, interferes with the effectiveness and safety of warfarin therapy. 6- Describe the impact of genetic factors on drug action. Genetic abnormalities influence the dose of a drug and response to drugs. It affects the drug response in individuals at 2 levels. -At the level of receptors -and at the level of drugs metabolizing enzyme. All individuals do not respond in similar way to same drug. 6- DESCRIBE THE IMPACT OF GENETIC FACTORS ON DRUG ACTION. Idiosyncrasy Idiosyncrasy is the abnormal drug reaction due to genetic disorder. It is the unpredictable response seen on first dose of drug on hereditary basis. This may be due to Acetylation. Oxidation Succinylcholine apnea Glucose 6-phosphate dehydrogenase deficiency. 6- DESCRIBE THE IMPACT OF GENETIC FACTORS ON DRUG ACTION. Oxidation Polymorphism In case of Debrisoquine Poor metabolizers (PM) – need smaller dose. Extensive metabolizers (EM) need larger dose. Deficiency of Glucose-6 phosphate dehydrogenase (G-6-PD) G-6-PD Deficiency in RBCs leads to haemolytic anaemia upon exposure to some oxidizing agents like Antimalarial drug, primaquine Long acting sulphonamides  kidney diseases: Renal Failure is a medical condition of impaired kidney function in which the kidneys fail to adequately filter metabolic wastes from the blood. 05  RENAL FAILURE how kidney diseases like renal failure influence drug action ? Renal excretion plays an important role in eliminating unchanged drugs or their metabolites into urine in renal failure the metabolism of several drugs is reduced Plasma proteins mainly albumin are often low or altered instructure effect involves functional or morphological modifications of the drug 06 receptors  Liver disease "cirrhosis" Cirrhosis is a late stage of fibrosis of the liver caused by many forms of liver diseases and conditions. 08  Liver disease "cirrhosis " Liver disease (especially cirrhosis)can influence drug disposition in several ways: Increase Bioavailability of drugs having high first pass metabolism due to loss of hepatocellular function Reduce protein binding of acidic drugs ( warfarin ) present in the free form due to reduce Serum albumin Decreased Metabolism & elimination of some drugs ( morphine) oral drugs that metabolized in liver must be given in reduced dose. because they 09 distributed directly into circulation. Liver disease The liver is known for its vital role in the processing of xenobiotics, including drugs and toxic compounds. liver diseases, affect drugs eliminated via the liver. v The capacity of the liver to metabolise drugs depends on hepatic blood flow and liver enzyme activity, both of which can be affected by liver disease. v liver failure can influence the binding of a drug to plasma proteins. v Decreased Metabolism and elimination of some drugs like morphine v many drugs are altered by liver disease to an extent that requires dosage adjustment; the problem is to quantify the required changes. Cirrhosis Cirrhosis is a late stage of scarring (fibrosis) of the liver caused by many forms of liver diseases and conditions Because the liver is the primary site of drug metabolism, the pharmacokinetic profiles of drugs can be altered in patients with cirrhosis. Approximately 30% of patients with cirrhosis experience adverse drug reactions. Cirrhosis causes changes in the architecture of the liver leading to changes in v blood flow v protein binding v drug metabolizing enzymes. Ø Drug metabolizing enzymes are primarily decreased due to loss of liver tissue. Effects of Ø reduce the plasma clearance of a number Cirrhosis of drugs eliminated by biotransformation and/or biliary excretion on Ø affect plasma protein binding which in pharmaco turn could influence the processes of distribution and elimination kinetics Ø reduced liver blood flow in patients with chronic liver disease will decrease the systemic clearance of flow limited (high extraction) drugs Kidney disease and drug action Kidney disease is an increasingly common comorbidity that alters the pharmacokinetics of many drugs. Patients with renal insufficiency often react abnormally to a number of drugs. Small doses that are safe under normal conditions may cause severe and even fatal side-effects.  Renal failure and drug pharmacokinetics A condition in which the kidneys stop working and are not able to remove waste and extra water from the blood or keep body chemicals in balance. Ø Can reduce renal function, hindering drug excretion. As kidney function declines with age, drug excretion becomes less efficient, and dosing adjustments may be needed. Ø Drug distribution may be altered in renal insufficiency due to pH- dependent protein binding and reduced protein (primarily albumin) levels. Ø Plasma protein binding of many drugs is impaired in patients with renal disease. Ø Renal failure alter the hepatic microsomal mixed-function (oxidase) system of drug metabolizing enzymes.  liver and kidney diseases considered pathological factors in their effect on drugs Liver disease influence the action of the drug, “liver failure can influence the binding of a drug to plasma proteins” Kidney disease influence the action of the drug, “Plasma Summary protein binding of many drugs is impaired in patients with renal disease”  Factors modifying drug action What are drug interactions? Anytime you take more than one medication, or even mix it with certain foods or beverages, you are at risk of a drug interaction. Most drug interactions are not serious, but because a few are, it is important to understand the possible outcome before you take your medications.  Factors modifying drug action How do drug interactions occur? Drug interactions can occur in several ways: A pharmacodynamic interaction occurs when two drugs given together act at the same or similar receptor site and lead to a greater (synergistic) effect or a decreased (antagonist) effect. A pharmacokinetic interaction may occur if one drug affects another drug's absorption, distribution, metabolism, or excretion.  Factors modifying drug action Drug synergism / When the combined effect of two or more drugs is greater than that predicted by their individual potencies, It can be : Additive A + B = drug A effect + drug B effect. Potentiation ( Supraadditive ) effect of A + B > effect of A + effect of B 1+1= > 2  Factors modifying drug action Drug antagonism / Is less An interaction between two or more drugs that have opposite effects on the body. Drug antagonism may block or reduce the effectiveness of one or more of the drugs. Depending on the mechanism involved antagonism may be : 1-Physical antagonism. 2-Chemical antagonism. 3-Physiological antagonism. 4-Receptor antagonism 1+1 = < 2  PBL 1.what do you mean by contraceptive pills ? what is their composition? Oral contraceptive pills are mainly combined estrogen and progestin pills. They are the most effective and reversible method of contraception. Their composition is ethinyl cstradioI (Estrogen) with a progesterone like Norethindrone or Ievonorgestrel 2. Why her fever and cough did not respond to routine antibiotics ? Tuberculosis doesn't respond to routine antibiotics like penicillins, cephalosporins etc. This is because tuberculous bacilli cell wall is made up of mycolipids which Is impermeable to routine antibiotics.also it has abundant efflux pumps which can throw the antibiotic out of the bacteria once they gain entry into tubercular bacilli. So special antibiotics like rifampicin etc shoud be used. This is the example of natural resistance. 3. What is the reason for loss of appetite and weight in this patient? These are the consequence of.tuberculosis 4. What is rifampicin? Which other antitubercular drugs might have been given in this patient? Rifampicin is an antitubercular drug which acts by inhibiting the DNA dependent RNA polymerase , It is one most effective drugs for treatment of tuberculosis. The other antitubercular drugs given in this patient would have been the first line antitubercular drugs like isoniazid ,pyrazinamide, ethambutol and streptomycin. Initially 3 or 4 or 5 of these drugs are given in combination during intensive phase for 2 to 3 months depending on the category of tuberculosis and later two drugs generally isoniazid and rifampicin are given in combination for 4 to 6 months known as maintainence phase. 5. Was the Physician justified in giving rifampicin? The physician was justified in giving rifampicin as the patient had tuberculosis but he ignored the fact that patient is on oral contraceptive pills and rifampicin can lead to contraceptive failure. He may have missed taking the history properly He could have taken consultation of gynaecologist and changed the method of contraception (e.g barrier method, or copper T etc). 6. Inspite of taking oral contraceptive drug how did the woman become pregnant? Rifampicin the antitubcrcular drug caused induction of Cytochrome P450 (Increase in function of these enzymes) OCPs are metabolized by this group of enzymes mainly estrogen so due to induction their metabolism increased leading to failure of their action of preventing pregnancy and the lady conceived once again. The physician could have prevented this by either increasing the dose of estrogen component of OCP or advising some other method of contraception. 7. What do you mean by enzyme induction & enzyme inhibition ? how does it occur Enzyme induction: Repeated administration of certain drugs increases the synthesis of microsomal enzymes. This is known as enzyme induction and the drug is referred to as enzyme inducer. E.g rifampicin, phenytoin, barbiturates, carbarnazepine etc. Enzyme inhibition: certain drugs inhibit the activity of drug metabolizing enzymes and are known as enzyme inhibitors. Enzyme inhibition is a rapid processas compared to enzyme induction. e.g chloramphenicol, erythroniyr.in 8. What is role of microsomal enzymes in enzyme induction? Microsomal enzymes are drug metabolizing enzymes which are located primarily on smooth surfaced endoplasmic reticulum of liver. The principal enzymes are mixed function oxidases or Cytochrome P450 (These are hemoproteinsaiid are so named because in their reduced form they can combine with carbon monoxide giving a product whose absorption peak is at 450cm-1. Microsomal enzymes are nonspecific in action, can be induced or activated and can metabolize only lipid soluble drugs.Microsomal enzymes are concerned primarily with Phase -1 reaction -oxidation, reduction and hydrolysis and also in phase 2 glucuronyl conjugations. Non microsomal enzymes catalyze all phase 2 reactions except glucuronide conjugation and they are non-inducible. but they can be inhibited and show genetic variation. Examples of non microsomal enzymes are monoamine-- oxidases, esterases, amidases 9. What is the clinical significance of this phenomenon Clinical importance of enzyme induction: 1- enzyme induction may accelerate the metabolism of drugs and thus reduce the duration and intensity of drug action leading to therapeutic failure 1- autoinduction may lead to development of drug tolerance e.g carbamazepine hepatotoxicity with paracetamol in alcoholicsis due to overproduction of toxic metabolite. 4- Enzyme induction can also be beneficial e.g phenobarbitone in neonatal jaundice- phenobarbitone induces glucuronyl transferase enzyme hence bilirubin is conjugated and jaundice is resolved 10. What are the other factors which may influence the metabolism of drugs? 1. age : neonates and elderly metabolize some drugs to lesser extent than adults. In both the cases, the impairment is due to diminished activity of hepatic microsomal enzymes 2. diet: protein Deficiency impairs drug metabolism. Protein rich food promote the metabolism of theophyllines and caffeine 3. Diseases; chronic diseases of liver may affect hepatic metabolism of some drugs, e.g increased duration of action of diazepam in patients of cirrhosis. 4. Genetic factors: students can quote some of the examples here like fast acetylators, slow acetylators, succinyl choline apnoea and G6PD deficiency. 11. How drugs are metabolized? Discuss the phases of metabolism chemical alteration of the drug in a living organism is known as. biotransformation or drug metabolism. the metabolism of drug usually converts the lipid soluble and unioinized compounds into water soluble and ionized compounds. They are not reabsorbed in renal tubules and are excreted. Sites : liver is the main site of drug metabolism; other sites are Gl-tract, kidney. lungs, blood, skin and placenta. The end result of drug metabolism is inactivation but sometimes a compound with pharmacological activity may be formed. Pathways of drug metabolism : drug metabolism reactions are grouped in two phases. Phase 1 non-synthetic reactions & Phase 2 or synthetic reactions Phase I reactions are Oxidation, reduction, hydrolysis and at end of phase 1 the metabolite may be active or Inactive. Phase II reactions are conjugation reactions Ike glucuronide conjugation, acetylatiqn, glycine conjugation, sulfate conjugation, glutathione conjugation etc. Drug Metabolizing enzymes They are broadly divided into two groups Microsomal and nonmicrosomal a. Microsomal enzymes; they are mainly present in endoplasmic reticulum of cells and they catalyze most of the Phase 1 reactions and Phase II glucuronide conjugation. They include cytochrome P450, glucuronyl transferse etc. Microsomal enzymes are inducible. b. Non-Microsomal enzymes: They are found in cytoplasm, mitocondreia of liver cells and in plasma,,they catalyze all Phase II reactions except Glucuxonide coniugation. Some of the oxidative reactions, most of reduction and hydrolytic reactions are also carried out by non=microsomal enzymes. These enzymes usually show genetic polymorphism and are not inducible. 12. Was physician justified in giving oral iron along with oral calcium?Why ? No because iron absorption is hindered by presence of calcium. The patient should have been given instruction to take calcium and iron tablets at different times 13. What arc the factors which effect the absorption of drugs ? 1. Physiochemical properties of the drug like a. Physical state: liquids' better absorbs than solid b. lipid soluble drugs better absorbed c. Particle size: drugs with smaller particle size absorbed better d. Disintegration time: time taken by the tablet or capsule to break up into small particles e. Dissolution time: time taken by particles to go into solution. Shorter the time, better is absorption f. Formulations: Pharmacologically inert substance like lactose , starch calcium etc may interfere with absorption 2. Route oF drug adminstration 3. pH and ionization 4. Food. 5. presence of other drugs 6.pharmacogentic factors. 7.area of absorbing surface 8. gastrointestinal and other diseases 14. Why did the doctor ask patient to take iron along with lemon juice? Because lemon juice contains ascorbic acid which can facilitate the conversion of. Ferric form of iron to ferrous form. Non heme iron is mostly absorbed in ferrous form Fe2+. 15.What are the various mechanisms by which a drug is absorbed? 1. Passive diffusion 2. Filtration 3. Active transport 4. Facilatcd diffusion 16. What do you mean by drug interaction? What type of drug interaction is involved in this case? Alteration in the effectiveness or toxicity of on drug due to another simultaneously administered drug is known as drug-drug interaction. The drug interaction involved in this case is pharmacokinetic mainly related to metabolism and enzyme induction, i.e between OCPs and rifampicin. The second drug interaction is at absorption level i.e between iron and calcium and iron and vitamin C. 17. What are the various measures undertaken to avoid drug interactions 1. Switching one of the potential interacting drugs 2. Allowing an interval of 2-3 hours between administration of interacting drugs this may be beneficial for drugs interacting at absorption level 3. Altering the dose of one of the interacting drugs for example reducing the dose of the drug which is likely to have enhanced effect as a result of interaction, in this case the dose is generally reduced by one third or half with subsequent monitoring for toxic effects either clinically or by therapeutic drug monitoring. Conversely if the drug is likely to have reduced effects as a result of interaction the patient should be monitored similarly for therapeutic failure and the dose increased if necessary. 4. Advising patients to seek guidance about their medication if they plan to stop smoking, or start a herbal remedy, as they may need close monitoring during the transition. 5. Overall it is important to anticipate when a potential drug interaction might have clinically significant consequences for a patient. In these situations advice should be given on how to minimize the risk of harm, for example by recommending an alternative treatment to avoid the combination of risk by making dose adjustment or by monitoring the patient closely 1 8. Discuss the ethical issues involved in this case Ethical issues related to contraception Ethical issues related to Medical termination of pregnancy Ethical issues related to the physician, is this a case of He didn’t take the history of medical negligence if so what are the consequences. Thisthe patient session can be utilized for an effective debate among students.  CD CD1 A 28-year-old male (58kg) presented to the emergency department with increasing pain and swelling and slight discharge in his left forearm and some decreased range of motion and tenderness in his right shoulder. During the visit, he was diagnosed with left upper extremity cellulitis and an empirical prescription of tablet Cephalexin 500 mg, tid, was given him. A swab was also taken from the left forearm for microbiological analysis. He was instructed to review with the consulting physician after three days. By the third day the swelling of his left forearm had increased, with increasing quantity of purulent discharge. He also complained of significant pain in the affected area and had a measured oral temperature of 390C. Treatment given based on experience, without precise 1. What is an Empirical Prescription? knowledge of the cause or nature of a disorder. medical treatment or therapy based on experience and, more specifically, therapy begun on the basis of a clinical "educated guess" in the absence of complete or perfect information. By the third day the results of the microbiology study of the swab taken from the affected arm were available. They showed the presence of Gram-positive bacteria in clusters, which on antibiotic sensitivity testing were Methicillin resistant. Considering this finding the consulting physician decided to prescribe the antibiotic Vancomycin intravenously, while discontinuing the oral cephalexin. The recommended dose for this patient is 15mg/kg every 12 hourly. 2. Calculate the required dose to be given IV in 24 hours to this pt. É 24hours/12hours=2 15mg/kg x 2=30mg/kg The half-life (t1/2) of Vancomycin is 3.5 hours, while the clearance (CL) in a young healthy adult is 7L/hr. 3. Considering the above parameters calculate the Volume of Distribution (Vd) of Vancomycin in this patient. =35.35L  4. What other equations can be used to calculate Vd? Vd = dose / plasma concentration It can be expressed as litres, or indexed to body mass in L/kg. Plasma concentration can be observed at different times, giving rise to several different possible strategies of calculating the volume of distribution. Vinitial = Vd of the central compartment (from the rapid distribution phase) Vextrap = Vd of the tissue compartment (from the elimination phase) Varea = Vd extrapolated from the AUC of the concentration curve Vss = Vd in a "steady state" model, the most useful in calculating the loading dose A Medical student present in the clinic questions the physician about the Vd and what it represents? The physician says that the Vd is just an apparent volume. He uses the example of Digoxin, a drug used in treatment of heart failure, whose Vd approaches 400 L. 5. What does he mean by this apparent volume? The volume that would accommodate all the drugs in the body, if the The apparent volume of distribution (Vd) for a drug is defined as the hypothetical fluid volume concentration wasthethe through which same drug as in plasma is dispersed. It is calculated by dividing the total amount of drug given by the concentration of drug in plasma Surprised at being told that the Vd of Digoxin can approach 400 L, the student tries to find out the reason for this. How can the drug be distributed in 400 L of fluid in a 60 kg man? 6. What are the possible explanations for this phenomenon? What does it mean when drugs have a very high or a very low Vd? Part 1 Volume of distribution may be increased by kidney failure (due to fluid retention) and liver failure (due to altered body fluid and plasma protein binding). Conversely it may be decreased in dehydration. Part 2 The volume of distribution (Vd) is a pharmacokinetic parameter representing an individual drug’s propensity to either remain in the plasma or redistribute to other tissue compartments. By definition, Vd is a proportionality constant that relates the total amount of drug in the body to the plasma concentration of the drug at a given time. The following equation can represent Vd: Volume of Distribution (L) = Amount of drug in the body (mg) / Plasma concentration of drug (mg/L) Based on the above equation: A drug with a high Vd has a propensity to leave the plasma and enter the extravascular compartments of the body, meaning that a higher dose of a drug is required to achieve a given e plasma concentration. (High Vd -> More distribution to other tissue) Conversely, a drug with a low Vd has a propensity to remain in the plasma meaning a lower dose of a drug is required to achieve a given plasma concentration. (Low Vd -> Less distribution to other tissue) On further reading the medical student finds that Vd is a primary pharmacokinetic parameter and is influenced by a variety of factors dependent on the drug, patient’s physiology, and pathology, etc. 7. What are the possible factors that influence the Volume of Distribution? 1. Age 2. Lipid solubility 3. Degree of plasma protein binding 4. pKa value of the drug 5. Affinity of different tissue After extensive reading the medical student is now well versed with the concept of Vd and the factors that affect it. At the next clinic the physician introduces him to a patient who has been prescribed the drug Amiodarone. The physician questions the medical student about the loading dose for Amiodarone and why it is needed. 8. Based on your understanding of Vd, what do you think is a loading dose and why is it needed? Is loading dose needed for all drugs? Part 1 Loading Dose: This is a single or few quickly repeated doses given in the beginning to attain target concentration rapidly. A loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. Part 2 No  9. What are the characteristics of drugs for which loading dose is needed? How do you calculate the loading dose? Part 1 A loading dose is most useful for drugs that are eliminated from the body relatively slowly, i.e., have a long systemic half-life. Such drugs need only a low maintenance dose in order to keep the amount of the drug in the body at the appropriate therapeutic level, but this also means that, without an initial higher dose, it would take a long time for the amount of the drug in the body to reach that level. Drugs which may be started with an initial loading dose include digoxin, teicoplanin, voriconazole, procainamide and fulvestrant. One or series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly. Part 2 A loading dose is typically calculated through the following formula: LD=(Volume of Distribution X Concentration Steady State)/Bioavailability E The Physician explains to the student that the half-life (t1/2) of Amiodarone is 90 days, and, in his patient, he wants to achieve a steady state concentration (Css) of 2mg/l, while giving the drug orally. 10. What do you mean by the term half-life (t1/2 )? How is it defined? Time in which amount of drug or plasma conc. (Cp) is reduced to 50% It is the time taken for the plasma concentration or amount of the drug present in the body to reduce to 50% of previous level Clinically t ½ that is calculated from BETA ELIMINATION PHASE is considered as t ½ of drug. 11. How can you calculate t1/2? What are the primary determinants of t1/2? Part 1 T1/2 can be determined if the clearance (Cl) and volume of distribution (Vd) is known. Cl is the ratio of the rate of elimination of a drug to the concentration in the plasma (rate of elimination/plasma drug concentration). The Vd is the ratio of the amount of drug in the body to the drug concentration in the plasma (amount of drug in body/plasma drug concentration). The half-life of a drug can be determined using the following equation: t1/2 = (0.7 times Vd) / Cl 50.643 part 2 1-The volume of distribution 2-The clearance 12. What does the physician mean by the term steady state concentration (Css)? Steady-state concentration (Css) occurs when the amount of a drug being absorbed is the same amount that’s being cleared from the body when the drug is given continuously or repeatedly. Steady-state concentration is the time during which the concentration of the drug in the body stays consistent. The Physician informs you that the patient is also on an oral anticoagulant drug called Warfarin. He has been on Warfarin for two years now and his International Normalized Ratio (INR) – a lab measurement for assessing the effectiveness of Warfarin – is within normal range. He has been complaining of severe upper respiratory tract symptoms and the physician has decided to prescribe a course of oral Ciprofloxacin tablets, tid, for five days to the patient. On the third day the patient comes to the emergency with multiple ecchymoses all over his legs and lower back. He is also bleeding from his gums. The physician reviews the prescription and immediately spots a prescribing error. He explains to the patient about a drug interaction between Warfarin and Ciprofloxacin, involving his plasma proteins and liver enzymes. He instructs you to read up on the subject. 13. Is the drug interaction that has happened a pharmacokinetic or a pharmacodynamic interaction? Both ‫الدكتورة قالت‬ Pharmacokinetic 14. What are plasma proteins? What is their role or function in pharmacotherapeutics? Part 1 Blood proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood proteins act as enzymes, complement components, protease inhibitors or kinin precursors. Contrary to popular belief, haemoglobin is not a blood protein, as it is carried within red blood cells, rather than in the blood serum. Serum albumin accounts for 55% of blood proteins, is a major contributor to maintaining the oncotic pressure of plasma and assists, as a carrier, in the transport of lipids and steroid hormones. Globulins make up 38% of blood proteins and transport ions, hormones, and lipids assisting in immune function. Fibrinogencomprises 7% of blood proteins; conversion of fibrinogen to insoluble fibrin is essential for blood clotting. The remainder of the plasma proteins (1%) are regulatory proteins, such as enzymes, proenzymes, and hormones. All blood proteins are synthesized in liver except for the gamma globulins. Part 2 Plasma protein binding plays a key role in drug therapy that affects pharmacokinetics and pharmacodynamics of drugs and may affect the metabolism of drugs 15.Can you give some more examples of drug-drug interactions arising out of displacement of drug from plasma proteins. A Learning Objectives 1. Define apparent volume of distribution and discuss its clinical significance of volume Apparent volume of distribution: Fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. Clinical Significance -Dialysis is not very useful for drugs with high Vd e.g digoxin, imipramine -It helps in estimating the total amount of drug at any time -amount of drug = Vd X plasma conc of drug at certain time -Vd is important to determine the loading dose Loading dose = Vd X desired concentration 2. Discuss the factors affecting volume of distribution Physico-chemical properties of drug: lipid soluble and unionized form of drugs readily cross cell membrane and are widely distribute, e.glignocaine, propranolol. Drugs such as heparin is confined only to intravascular compartment as it exists in ionized form. degree of plasma protein binding: drugs that are highly bound to plasma proteins have a low volume of distribution Tissue storage: certain drugs can get sequestrated in some tissues. Such drugs have large vd e.g. digoxin Disease states: the volume of distribution of drugs can be altered in certain diseases e g CCF, uremia etc. Fat: lean body mass ratio, highly lipid soluble drugs get distributed to the adipose tissue. If the ratio is high, the volume of distribution for such drug will be higher and fat acts as a reservoir for such drugs.  3. Define plasma half-life and discuss factors affecting it Half life Time in which amount of drug or plasma conc. (Cp) is reduced to 50% – Plasma t1/2 for most drugs – Biological t 1⁄2for stored drugs – Biological effect/ therapeutic t1⁄2 for Hit & Run drugs In first order kinetics ln (Dt/D0) = -ke.t To find time taken for 100 mg to reduce to 50 mg ln (50/100) = -ke.t1/2 ln 0.5 = -ke.t1/2 0.693 = ke.t1/2 ke.t1/2 = 0.693 t1/2 = 0.693/ke ke = 0.693/t1/2 t1/2 is constant in 1st order variable in zero order Clinical importance of plasma half life – It helps to Determine duration of action of drug Determine frequency of drug administration Estimate time required to reach the steady state Factors affecting Half Life: 1. Plasma protein binding: Drugs having plasma protein binding have longer half life ( directly proportional). Acidic drugs bind albumin while basic drugs mostly bind globulins. 2. Pharmacokinetic pattern: Especially metabolism and elimination Zero order kinetics reach half time early 3. Renal/hepatic diseases Half life increase in renal diseases b/c the elimination is less Increase in hepatic diseases b/c the metabolism not taking a place 4. Active metabolites: Drug that need to be converted to active metabolism have longer half life 5. Enterohepatic circulation Some drugs are metabolized in the liver. They are conjugated with glucuronic acid and excreted into the bile. In the intestines, the conjugate is broken down by the bacteria and enzymes. The active drug is released and is reabsorbed. These drugs have a longer half life. Examples include rifampicin, doxycycline, spironolactone and digitoxin. 6. Volume of Distribution Greater the volume of distribution, more is the half life. Drugs having half life less than two hours: Aspirin, ACTH, cephalosporins, chlorthiazide, heparin, lignocaine, methyl dopa, naloxone, penicillin G (30min), dobutamine (I min), esmolol Drugs having half life between two to five hours Atropine, cimetidine, indomethacin, paracetamol Drugs having half life between ten to twenty four hours Amitriptyline, imipramine, practolol, theophylline Drugs having half life greater than thirty six hours Diazepam, digoxin, phenobarbitone, thyroxin, warfarin, piroxicam (48 hrs). 4. Describe the method of calculation of volume of distribution and plasma half life 5. Discuss plasma protein binding and its significance Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. Reversible (weak finding force) Lipid soluble drugs are mainly protein-bound Common blood proteins that drug bind to are human serum albumin, lipoprotein, glycoprotein, and α, β‚ and γ globulins. Acidic drugs find to albumin Basics drugs bind to glycoproteins Significance: Prolonged duration of drug action Pharmalogically inactive Non-diffusible A fixed distribution (lower volume of distribution) 6. Discuss the concept of drug interactions occurring due to plasma protein binding Highly plasma protein bound drugs are largely restricted to vascular compartment because protein bound drug does not cross the membranes except through the large paracellular spaces, such as in capillary, they tend to have smaller volume of distribution and less plasma concentration. Drug with high affinity to plasma protein like albumin can displace drug with low affinity from the bound site (As one drug can bind to many sites on protein molecule and conversely more than one drug can bind can bind to same site). Review Questions 1. Half-life (t 1⁄2) doesn’t depend on: a) Biotransformation b) Time of drug absorption c) Concentration of a drug in plasma d) Rate of drug elimination 2. Systemic clearance (CL) is related with: a) Only the concentration of substances in plasma b) Only the elimination rate constant c) Volume of distribution, half life and elimination rate constant d) Bioavailability and half life 3. A drug is given at a dose of 50 mg/kg to a 70 kg man. The plasma concentration after giving it is 10 mg/ml. The half-life is 8 hours. Clearance would be: a) 30.3 ml/hr b) 300.3 ml/hr c) 3 ml/hr d) 0.3 ml/hr 4. Define; a) Loading dose : This is a single or few quickly repeated doses given in the beginning to attain target concentration rapidly. b) Maintenance dose : This dose is the one that is to be repeated at specified intervals after the attainment of desire plasma concentration of the drug. c) Clearance : Theoretical volume of plasma from which the drug is removed in unit time. d) Half-life : It is the time taken for the plasma concentration or amount of the drug present in the body to reduce to 50% of previous level. e) Bioavailability : It is a measure of the fraction of administered dose of a drug that reaches the systemic circulation in the unchanged form. f) Therapeutic window : For every drug, there exists some concentration which is just barely effective (the Effective Concentration) and some dose which is just barely toxic/the Toxic Concentration. Between them is the therapeutic window where most safe and effective treatment will occur. ‫هم مخرجًا‪ ،‬اللهم إني أسألك‬ ‫اللهم إني أسألك أن تشرح لي صدري‪ ،‬وأن تيسر لي أمري‪ ،‬وأن تجعل لي من كل ضيق فرجًا‪ ،‬ومن كل ٍّ‬ ‫أن توفقني في دراستي‪ ،‬وأن تجعلها من أحب األعمال إليك‪ ،‬اللهم إني أسألك أن تبارك لي في وقتي‪ ،‬وأن تجعله في طاعة لك‪،‬‬ ‫ومرضاة لك‪.‬‬ ‫ال تنسوننا من دعواتكم‬ Basic Therapiutic Module First quiz-Batch10: 1. At 6 h after IV administration of bolus dose , the plasm level of a drug is 3/mg/L if the Vd=10L and the elimination half life = 3 h, what was the dose administered? A. 100 mg B. 120 mg C. 180 mg D. 200 mg 2. Which of the following is true regarding drug handling by the newborn? A. The newborn has higher GFR B. Glomerular Filtration reaches adult rates by 5 years of age C. Tubular secretion takes about 7 years to mature in newborn D. Hepatic drug metabolizing system is in adequate in newborns E. Blood- brain barrier is less permeable to drugs 3. Which of the following is true regarding physiological changes during pregnancy, especially in the third trimester, which can alter drug disposition? A. Gastrointestinal motility is reduced delayed absorption of oral drug. B. Extracellular fluid volume expands, so volume of drug distribution may increase. C. Plasma albumin level rises, so the unbound fraction of acidic drugs decreases. D. Renal blood flow decreases markedly- non-polar drugs are eliminated faster. E. Hepatic microsomal enzymes undergo inhibition-many drugs are metabolized slower. 4. Which of the following statement is FALSE regarding influence of liver / disease on drug deposition and action? A. Bioavailability is increased due to decreased first pass metabolism in liver disease. B. Serum albumin is increased, so bound form of drug is increased in liver disease. C. Clearance of drugs that are primarily excreted unchanged is reduced in kidney disease. D. Decreased drug absorption from GIT due to mucosal edema in congestive heart failure. 5. Which of the following is known to inhibit the hepatic microsomal enzyme responsible for warfarin metabolism? A. Grapefruit juice B. Carbamazepine C. Phenobarbital D. Rifampin 6. In order to increase the absorption of nonheme iron on oral administration, what advice should be given to the patient? A. Not to take iron along with copper B. Not to take iron along with calcium C. Not to Take iron along with animal protein D. Not to take iron along with lemon juice 7. Which of the following statement is false? A. Loading dose id generally required for the drugs that are eliminated slowly B. Volume of distribution cannot be more than total body water C. At a steady state (Cpss), the drug entering the body equals the drug leaving the body D. Plasma protein binding makes the drug relatively shorter acting. 8. Which of the following characteristic of the drug will relatively have the highest Vd? A. Polar / water soluble drugs with large molecular weight B. Nonpolar / Lipid soluble drugs with large molecular weight C. Polar / water soluble drugs with small molecular weight D. Nonpolar / Lipid soluble drugs with small molecular weight 9. Auto-induction is characteristically seen with which of the following drugs? A. Isoniazid B. Ketoconazole C. Rifampicin D. Carbamazepine 10. Which of the following statement is False? A. Non microsomal enzymes catalyse all phase-2 reactions except glucuronide conjugation.  B. Non-Microsomal enzymes are non-inducible. C. Microsomal enzymes catalyse all phase- 1 reactions and glucuronide conjugation. D. Microsomal enzymes metabolize metabolise water soluble drugs. 11. Therapeutic failure of combined oral contraceptives can be caused by which of the following drug? A. Warfarin B. Ciprofloxacin C. Rifampicin D. Chloramphenicol Basic Therapiutic Module Second quiz-Batch10: Q1. Which of the following effects is related to direct beta1-adrenoreceptor stimulation? A. Bronchodilation B. Vasoconstriction C. Tachycardia D. Bradycardia Q2. Type of receptor present at the NM junction is? A. M1 B. M2 C. M3 D. Nm E. Nn Q3. Which of the following is an adverse effect seen with the use of Propranolol? A. Loss of appetite B. Bradycardia C. Increased libido D. Decreased bronchial secretions E. Dry mouth Q4. A 40 year old male patient, known asthmatic develops hypertension. Propranolol should not be given in this patient because it may block whorth of the following, receptor and increase the bronchospasm? A. Alpha receptor B. Beta receptor C. Muscarinic receptor D. Nicotinic receptor Q5. Which of the following routes of drug administration is the fastest route for the access to the systemic circulation? A. Oral B. Intra muscular C. Intra venous D. Subcutaneous Q6. Which of the following drug is used to decrease muscarinic symptoms of Organo-Phosphorus Poison? A. Adrenaline B. Atropine C. Ephedrine D. Physostigmine Q7. Which of the following is the example of enteral route? A. By mouth B. Intra venous C. Intra muscular D. Subcutaneous Q8. The counter regulatory hormone for insulin is? A. Epinephrine B. Norepinephrine C. Glucagon Q9. Which of the following drug causes loss of corneal reflex A. Epinephrine B. Pilocarpine C. Lignocaine Q10. A 20 years old female suffered a panic attack while giving a presentation and is breathing rapidly, what do you expect out of the followings A. Metabolic Acidosis B. Metabolic Alkalosis C. Respiratory Acidosis  D. Respiratory Alkalost Q11. A 45- year-old female with renal failure, missed her dialysis and was feeling unwell, which of the following acid base disorder can she develop? A. Metabolic Acidosis B. Metabolic Alkalosis C. Respiratory Acidosis D. Respiratory Alkalosis Basic Therapiutic Module Third quiz-Batch10: 1. Which of the following is classified as a type B adverse drug reaction? (Unpredictable adverse drug reaction)? A. Toxic effect B. Side effect C. Idiosyncrasy D. Tachyphylaxis E. Tolerance 2. Cotrimoxazole is a fixed dose combination of which of the following? A. Sulphamethoxazole & triamterene B. Sulfamethoxazole & trimethoprim C. Sulfamethoxazole & ceftriaxone D. Pyrimethamine & sulfadoxine E. Sulfadoxin & triamterene 3. Which of the following is true about the occurrence of an Adverse Drug Reaction? A. Unintended & noxious B. Intended & noxious C. Unintended& beneficial D. Intended & beneficial 4. The combination in cotrimoxazole has which of the following effect? A. Synergistic B. Additive C. Antagonistic D. Diagnostic 5. Which of the following step can lead to antibiotic resistance A. Judiciously use antibiotics only when they are essential not for every infection like viral flu B. Antimicrobial drug sensitivity test and culture can be done wherever appropriate C. Use of combination of antibacterial where ever possible like in Tuberculosis D. Treat infection with antibiotics for shorter than recommended duration 6.Penicillin acts by inhibiting which of the following mechanism? A. By inhibiting transpeptidase enzyme essential for bacterial cell wall synthesis B. By inhibiting bacterial protein synthesis C. By inhibiting dihydrofolate reductase enzyme D. By inhibiting DNA dependent RNA polymerase 7. All are consequences of non- compliance to medication EXCEPT; A. Therapeutic drug failure B. Wastage of money on drug dispensed cost C. Appearance of adverse drug reactions D. Poorly managed chronic diseases. 8. Which of the following is a consequence of polypharmacy? A. Drug interactions B. Least adverse drug reactions C. Improves compliance and adherence D. Better outcome 9. Which of the following drug acts by inhibiting cell wall synthesis? A. Cephalosporins (Ceftriaxone) B. Trimethoprim C. Sulphamethoxazole D. Tetracyclines (Doxycycline) 10. Science and activities relating to detection, assesment, understanding & prevention of adverse effects is known as? A. Pharmacovigilance B. Pharmacokinetics C. Pharmacodynamics  D. Polypharmacy 11. An undesirable effect of a drug that occurs pharmacological actions is called as at therapeutic doses and can be predicted from its A. Side effect B. Toxicity C. Idiosyncrasy D. Hypersensitivity 12. Which of the following term is defined as "the extent to which patients take medications as prescribed by their health care providers? A. Non- compliance B. Adherence C. Polypharmacy D. pharmacovigilance