A - GENERAL PHARMACOLOGY

A - General pharmacology (part one)

ABSORPTION 1 T is the transfer from the site of administration to the blood stream 1 F is the transfer across the blood-brain barrier 1 T from the gut can be influenced by food 1 T is reduced by severe diarrhea 1 F can be speeded by coadministration of atropine Absorption is the transfer from the site of administration to the bood stream. Absorption does not equal the penetration of drug across the blood-brain barrier. After oral administration, the presence of food dilutes (absorbs) the drug and slows gastric emptying- therefore a drug taken with a meal is absorbed from the gut more slowly. Diarrhea decreases contact time: absorption of drugs is diminished. Atropine prolongs gastric emptying and drug absorption. Enteral routes of drug administration involve as follows: 1 T oral 1 F i.m. 1 T sublingual 1 T rectal 1 F inhalation Oral. Sublingual. Rectal. Parenteral routes of drug administration involve as follows: 1 T intramuscular 1 T intravenous 1 F oral 1 T subcutaneous 1 F rectal Intramuscular, intravenous, subcutaneous. The mode of transport of a drug across biomembranes is also: 1 T done by passive diffusion 1 T done by active transport 1 T effectuated by filtration 1 T limited by energy supply if active transport takes place 1 F not determined by pH at the passage site in the case of passive diffusion of weak acids and bases Passive diffusion. Active transport. Filtration. Active transport is limited by energy supply. In ewak acids and bases passive diffusion is determined by pH at the passage site. Passive diffusion (absorption) A. is characterized by: 1 T the driving force given by the concentration gradient across a membrane separating two body compartm 1 F involves a carrier 1 F lipid-soluble drugs do not move readily in this way 1 F water-soluble drugs often penetrate by this way 1 T shows a low structural specificity The driving force for passive diffusion is the concentration gradient across a membrane. The drug moves from a region of high concentration to a region of low concentration. Passive diffusion does not involve a carrier, shows a low structural specificity. Lipid- soluble drugs readily move across most biological membranes, while water-soluble drugs penetrate the cell membrane through aqueous channels - by filtration. Active transport 1 T involves specific carriers 1 T shows saturation kinetics 1 T is energy dependent 1 T is driven by energy from ATP

1 T is capable of moving against a concentration gradient All answers are true. Transdermal route of administration 1 F is mainly used for a local effect 1 T is used for systemic effects 1 T means application of the drug to the skin via a transdermal patch 1 T is often used for the sustained delivery of drugs 1 F is quite safe (without side effects) This route of administration achives systemic effects by application of drugs to the skin, usually via a transdermal patch. This route is most often used for the sustained delivery of drugs. Is not free of side effects. Inhalation 1 F provides the slow delivery of a drug across the large surface area of the alveolar membrane 1 T can produce systemic actions almost as rapidly as IV injection 1 T is used for drugs that can be dispersed in an aerosol 1 T is used for drugs that vaporize easily 1 T is used for both systemic and local effects Inhalation provides the rapid delivery of a drug across the surface area of the alveolar membrane and can produce actions almost as rapidly as IV injections. I. is used for drugs that can be dispersed in an aerosol or that vaporize easily. I. is used for both systemic and local effects (narcotics and antiasthmatics, resp). A drug tends to pass through membranes 1 F if it is charged 1 T if it is uncharged 1 T for a weak acid and base according to the pH at the absorption site 1 T for a weak acid and base in relation to pKa 1 T in relation to relative concentrations of the charged and uncharged form A drug tends to pass through membranes if it is uncharged. The effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is determined by the pH at the site of absorption and by pKa. Which of the following statements are correct? 1 T weak acids are absorbed easily across the epithelial cells of the stomach 1 T aspirin (pKa = 3.5) is in its lipid soluble protonated form at pH = 2.5 1 T absorption of a weak basic drug is likely to occur faster from the intestine than from the stomach 1 F the basic drug promethazine (pHa = 9.1) is more ionized at pH = 7.4 than at pH = 2 1 T alkalinization of urine accelerates the renal excretion of barbiturates (weak acids) Weak acids are absorbed easily from the stomach because of higher lipid-solubility (protonated forms predominate). Aspirin obeys the same rule. On the other hand, weak basic drugs are more lipid-soluble because of a higher deprotonated form presented in the pH of the intestines in comparison to the stomach. Promethazine is more ionized at pH 2. Alkalinization of urine accelerates the renal excretion of barbiturates because of their higher ionization (conversion to deprotonated forms) and less reabsorption to blood vessels of the distal tubuli. Bioavailability A) is the extent ... B) is expressed... C) is determined 1 T A. of absorption of a drug following its administration by routes other than IV or i.a. injection in % 1 F B. as the fraction of administered drug that reaches the systemic circulation as a metabolite 1 T B. as the fraction of administered drug that reaches the systemic circulation in unchanged form 1 T C. by comparing AUC after a particular drug administr. To that after IV drug administration 1 F C. by comparing AUC after IV administration to that after a particular route of drug administration Bioavailability is the extent of absorption of a drug following its administration by routes other than its direct administration into the blood stream (IV of i.a.) . B. is expressed as the fraction of administered drug that reaches the systemic circulation in an uncharged (nonmetabolized) form. C. is determined by comparing the area under the curve after a particular drug administration to that after IV drug administration. The area under the curve (AUC) 2 F doez not reflect the extent of absorption of the drug

2 T can be measured by plotting plasma concentrations of the drug versus time 2 T by definition is 100% for drugs administered IV 2 F is not influenced by drug passage through the liver 2 T is characterized also by C max and t max AUC reflects the extent of absorption of the drug. AUC can be measured by plotting plasma concentrations of the drug versus time. By definition this is 100% for drugs administered IV. If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased, and AUC is diminished. AUC is characterized also by the maximal concentration (Cmax) and time for Cmax (t max). Two related drugs are bioequivalent if they have comparable 2 T bioavailability, Cmax, tmax 2 F efficacy 2 F safety 2 F molecular weight 2 F pathways of metabolism catalyzed by CYP 450. If they have comparable bioavailability. Comparable efficacy and safety is characteristic for therapeutic bioequivalence. Drug DISTRIBUTION depends on 1 T blood flow 1 T capillary structure 1 T chemical nature of the drug 1 T binding to plasma proteins 1 T binding to tissue proteins All answers are true. The basement membrane of capillaries is exposed by slit junctions between endothelial cells predominantly in 1 F the brain 1 F the liver and spleen 1 T the most peripheral capillaries 1 F cells membranes 1 T renal glomeruli Slit junctions predominate in the renal glomeruli and in the majority of peripheral capillaries. The capillaries in the brain contain tight junctions. The liver and spleen have large discontinuous capillaries. Cell membranes involve smaller channels. Solubility of drugs. For a drug to be readily absorbed (by passive difussion) is important 1 F only high lipid solubility 1 F only high water solubility 1 T large liposolubility and some solubility in aqueous solutions (in nonionized form in the case of weak acids and bases) 1 F solubility is not important but carrier system predominates 1 F ATP is the most important Drugs with high lipid solubility cannot gain access to the surface of cells (they are totally insoluble in the aqueous body fluids). Drugs with high water solubility are unable to cross the lipid-rich cell membranes. Large lipid solubility with some solubility in aqueous solutions (in nonioonized form in the case of weak acids and bases) is necessary. Carrier system and ATP take place in active transport that is less frequent in processes of absorption. Drug bioavailability depends on 1 F bioequivalence 1 T solubility of the drug 1 T chemical stability (the pH of gastric juice contents) 1 T nature of the drug formulation (particle size, salt form) 1 T first pass metabolism Solubility of drugs. Chemical stability. Nature of the drug formulation. First pass metabolism. Bioequivalence means that two related drugs show comparable bioavailability, Cmax and tmax. Volume of distribution (Vd) and its importance: 3 T to compare the distribution of a drug with the volumes of the water compartments of the body 3 T can be used to calculate the amount of drug needed to achieve a desired plasma concentration

3 T a large Vd has an important influence on the half-life of a drug 3 F is a real physiological volume 3 F can be used to calculate the amount of the maintained dose of the drug Once a drug enters the body, it has the potential to distribute into any one of three functionally distinct compartments of body water (intravascular- extracelullar - total body water). Comparison with Vd is very useful. The additional dosage needed equals Vd(C1-C2) where Vd.C1 is the amount of drug initially in the body and Vd.C2 is the amount needed to achieve the desired plasma concentration. If the Vd for a drug is large, most of the drug is in extraplasmic space and is unavailable to the excretory organs. Therefore, any factor that increases the volume of distribution can lead to an increase in the half-life. Vd is a hypothetical volume which reflects the ratio of the drug in the extraplasmic spaces relative to the plasma space.Maintained dose of the drug depends on body clearance. Binding of drugs to plasma proteins 1 T is reversible 1 T may show high or low capacity 1 T has varying affinities 1 T is competitive 1 F is covalent Is reversible.May show high or low capacity. Has varying affinities. Is competitive. Cannot be covalent, covalent binding is strong, thus forming residua. Alpha1 acid glycoprotein and lipoprotein in plasma have the strongest binding affinity for: 1 T cationic drugs (weak bases) 1 F anionic drugs (weak acids) 1 F hydrophilic drugs 1 T hydrophobic drugs 1 F neutral drugs Cationic and hydrophobic drugs. Vd of the drug in adults presents approx. 42 liters. This drug is diluted in 1 F the plasma volume 1 F the interstitial volume 1 F the extracellular volume 1 F the intracellular volume 1 T the total body water The total body water. Albumin has the strongest affinity for 1 F cationic drugs 1 T anionic drugs (weak acids) 1 F hydrophilic drugs 1 T hydrophobic drugs 1 F neutral drugs Anionic drugs (weak acids). Hydrophobic drugs. The addition of glucuronic acid to a drug 1 F decreases its water solubility 1 T leads in the most cases to inactivation of the drug 1 F is an example of a phase I reaction 1 F is an important pathway in the newborn 1 F is catalyzed by cytochrome P-450 Usually leads to inactivation of the drug.

First-order kinetics means that 1 F a constant amount of drug is metabolized per unit time 1 T the rate of drug metabolism is directly proportional to the drug concentration 1 T a constant percent of drug is metabolized per unit time

1 T the actual concentration of the drug in plasma is much less than the Michaelis constant, Km 1 F the enzyme is saturated by high free-drug concentration and the rate of metabolism remains constant The rate of drug metabolism is directly proportional to the drug concentration. A constant percent of drug is metabolized per unit time. The concentration of the drug is much less than the Michaelis constant, Km. Drugs may be absorbed from the small intestine by: 1 T passive diffusion 1 T fitration (through the pores) 1 T active transport 1 F exocytosis 1 F binding to plasma proteins Passive diffusion is the main mechanism for the absorption of most drugs from all gut areas. Active transport is involved in the absorption of drugs which are structural analogues of natural metabolites e.g. 5-fluorouracil. Exocytosis refers to "bulk" removal of material from cells e.g. transmitter release. Pinocytosis (the reverse) is involved in the absorption of compounds of high MW. Protein binding is not involved with the mechanism for absorption, but may facilitate the diffusion of some highly bound drugs. The apparent volume of distribution is: 1 T defined as the fluid volume in which the drugs seems to be dissolved 1 T given the symbol V 1 F regarded as a particular physiological space within the body 1 F never greater than total body water 1 T the hypothetical volume The apparent volume of distribution (Vd) is defined as the hypothetical fluid volume in which the drug appears to be dissolved. For drugs with extensive tissue distribution, the Vd is ofter greater than the total body water. Enteral routes of drug administration 1 T are very convenient 1 F bypass the gastrointestinal tract 1 F always involve solid dosage forms 1 T include sublingual administration 1 F include subcutaneous injection Enteral routes include buccal, sublingual, rectal and oral administration. In the latter case the drug is placed into a gastrointestinal tract. Drugs are frequently given as solid dosage forms, because they are convenient for self-administration, but solutions and suspensions are also used, particularly in paediatric medicine. Subcutaneous injection is a particular route. Biological membranes: 1 T have a phospholipid bilayer with a "fluid hydrophobic" core 1 F possess pores through which any water soluble material can pass 1 T contain drug receptors 1 F will permit the passage of large ionic molecules 1 T can contain carrier systems Biomembranes contain protein and phospholipids arranged in a "fluid mosaic". The phosholipids are oriented to form a bilayer with their polar heads projecting into the aqueous medium and their apolar "tails" forming a fluid hydrophobic core. These membranes allow the passage of small (MW higher than 100) water soluble molecules, which suggests the presence of pores. Large ionic molecules (e.g. proteins) will not usually cross these membranes as they are too large to pass through pores and not sufficiently lipid soluble to dissolve in the lipid core. Biomembranes can contain carrier systems. Glomerular filtration of drugs 1 F does not occur when the drugs MW is higher than 400 daltons 1 F is not restricted by plasma protein binding 1 F occurs only for the non-ionized form of the drug 1 F takes place in the distal tubule 1 T produces an ultrafiltrate in which the concentration of free drug is the same as that in the plasma water Filtration occurs at the glomerulus. The pores in the glomerular membrane are large and allow passage of substances up to MW 66 000. Both ionized and nonionized drugs are filtered. Filtration is restricted by high protein binding as the bound drug is not filtered but the concentration of unbound (free) drug is the same in plasma and filtrate.

Prodrug has a modified molecule chemically to form a compound that is 1 F easily extracted by the liver (undergoes first pass effect) 1 F more rapidly excreted by the kidneys 1 T better absorbed and distributed 1 T useful for sustained release 1 F topically used especially for large areas Better absorbed and distributed. Can be used for sustained release of the active compound Sustained release preparations 2 T can have a symbol "retard" 2 T can be various pharmaceutical means of slowing absorption of rapidly eliminated drugs 2 T release a steady "infusion" of drug into the gut lumen for absorption during transit time 2 T reduce adverse effects due to high plasma concentrations 2 F are very cheap Are very expensive. Other answers are true. Advantages associated with slow release preparations: 1 F transit time through the small intestine approx. 6 hours 1 F there is no danger of high local drug concentrations causing mucosal damage 1 F overdose is easy to treat 1 F useful flexibility of dosing (tablets can be easily divided) 1 T improved compliance Transit time through the small intestine is only 6 h, prolongation of dosage interval from 12 to 24 hours is not reliably achieved. In slow transit time (elderly) there is a danger of high local drug concentrations. Overdosage is difficult to treat. Reduced flexibility of dosing, since sustained release preparations are difficult to treat because large amounts of drug continue to be absorbed after tablets have remind in the GIT. Compliance is improved. Advantages of the rectal route of administration: 1 T exposure to the acidity of gastric juice and to digestive enzymes is avoided 1 T the portal circulation is partly bypassed (50%) 1 T convenable in patients unable to swallow or who are vomiting 1 T useful both for local and systemic effects 1 F can cause severe local irritation Severe local irritation is a disadvantage of the rectal route. Other answers are true. Factors effecting percutaneous drug absorption are: 1 T age 1 T region 1 T hydration 1 T vehicle 1 T physical properties of drugs Age : infant skin is more permeable. Region and surface area. Hydration: under plastic-film occlusion the stratum corneum accepts water (up to 50%) with increased permeability. Vehicle. Physical properties (liposolubility ) of drugs. Which one region of skin is the most permeable for drugs? 2 F plantar 2 F anterior forearm 2 F scalp 2 F scrotum 2 T posterior auricular skin Posterior auricular skin. Transdermal patches are recommended 1 T for some instances of poor compliance 1 T to apply each dose to the same general anatomical area 1 T to a different spot for succesive patches to minimize local irritation

1 T for bypassing presystemic metabolism 1 T for local effects All responses are O.K. Intranasal administration 1 T can be used both for local and systemic effects 1 T has valuable absorptive properties 3 T is useful because of high intranasal ability to absorb complex peptides 3 T is convenable for desmopressin (an analog of antidiuretic homone) administration 1 T bypasses the portal circulation All answers are true. Inhalation is suitable for 1 T aerosols 1 T nebulized particles 1 T large absorptive surface area 1 T gases 1 F compounds more polar i.e. water-soluble that are better absorbed. The total respiratory surface area is about 60 m2. Systemic absorption of inhaled drugs is better in lipid-soluble compounds. After intramuscular injection 1 T lipid-soluble drugs diffuse freely through capillary walls 1 F water-soluble drugs of small molecular weight are not transported accross the capillary walls 1 T water-soluble drugs of high molecular weight are absorbed slowly via the lymphatics 1 F drug absorption is increased by shock, heart failure 1 T depot intramuscular injections are used to improve compliance of patients Shock and heart failure decrease drug absorption. Water-soluble drugs of small molecular weight are transported rapidly via the pores. Disadvantages of i.m. injections: 1 T Sciatic nerve palsy following injection into the buttock 1 T Elevated serum creatine phosphokinase due to enzyme release from muscle 1 T Severe allergic reaction 1 T Hematoma formation 1 T Pain Sciatic nerve palsy is avoided by injection into the upper outer gluteal quadrant. Elevated CPK can cause diagnostic confusion. Allergic reaction can be protracted because there is no way of stopping absorption of the drug. Hematoma formation can occur especially after fibrinolytic therapy. Muscle is poorly innervated but distension with large volumes in painful. Injected volume should usually be no greater than 5 ml. Characteristics of subcutaneous administration 2 T (versus i.m.) absorption is slower because of lower cutaneous blood flow 2 F absorption can be increased by adrenaline 2 F absorption is enhanced by immobilization and reduction of blood flow 2 T compressed pellets can be administered 2 T inj. with Insulin zinc suspension (amorphous) and insulin zinc suspension (crystalline) are used Compressed pellets can be used for example estrogen or testosterone for hormone replacement therapy. Absorption can be reduced by vasoconstriction (using adrenaline), by immobilization and reduction of blood flow (by a tourniquet and local cooling).

A - General pharmacology (part two)

Pharmacokinetics describe 1 F the changes of plasma drug concentrations in relation to effects 1 F the changes of drug effects in relation to pathological states influencing mechanisms of elimination 1 F toxicity of drugs 1 T the time-dependent changes of the total amount of drug in the body following various routes of admin

1 T the time-dependent changes of plasma drug concentrations The time-dependent changes of total amount of drug in the body following various routes of administration. The timedependent changes of plasma drug concentrations. KINETICS OF IV INFUSION: which statement is true? 1 T with a continuous IV infusion, the rate of drug entry into the body is constant 1 F the rate of drug exit from the body is always constant as well 1 F at any point in time the rate of drug exit is not related to the plasma concentration of the drug 1 T the rate of drug exit = Ke.C (C=plasma conc. of drug, Ke=first-order rate const. for drug removal) 1 F after the start of IV infusion the plasma concentration of the drug rises until the end of the admin The rate of drug exit from the body increases proportionaly as the plasma concentration rises. At every point in time the rate of drug exit is proportional to the plasma concentration of the drug. After the start of an IV infusion, the plasma concentration of the drug rises until the rate of drug eliminated from the body precisely balances the input rate. A steady state plasma concentration of the drug is achieved 1 T because the drug accumulates until the rate of drug loss exactly balances the rate of drug administr 1 T when the rate of drug elimination is equal to the rate of administration 1 T in 4-5 times t 1/2 1 F in t 1/2 1 T by a first-order process in its fractional approach Because the drug accumulates until the rate of drug loss exactly balances the rate of drug administration. It is achieved when the rate of drug eliminations is equal to the rate of administration. It is achieved in 4-5 times t 1/2. After t equals t 1/2, then the 50% of the final steady-state concentration is achieved. Its fractional rate of approach is achieved by a first-order process. Is it true? 2 T C ss = R / Ke Vd 2 F C ss = R . Cltot 2 T where C ss = the steady state concentration and R is the infusion rate ( e.g. mg/min) 2 T where Vd = volume of distribution and Cltot = total body clearance 2 T where ke = first order rate constant for drug elimination from the total body C ss = R/ Cltot...if Cltot = Ke Vd. During an IV inf. at the same rate, drug A with double t 1/2 is compared to B: 2 F Css of drug A is achieved twice as fast 2 T Css of drug A is achieved in double the time 2 T Css of drug A is twice as high (mg/ml) 2 F Css of drug A is twice as low (mg/ml) 2 F Css of drugs A and B give the same values Css of drug A is achieved twice as slowly. Css of drug A is twice as high as that of drug B (Vd of drugs A and B are the same). Ke is twice as high in drug B (Css = R/Ke. Vd) t 1/2 (the half-life) is the time required for the drug 1 T concentration in Cmax to change by 50% (the plasma concentration decreases from C to 1/2 C) 1 F dose to be given by 50% 1 F absorption to reach 50% of the administered dose 1 F metabolite to take 50% of the paternal drug 1 F cost to fall by 50% It is the time required for the drug Cmax concentration to change by 50%.

The rate of an IV inf.of drug C is double that of D (t1/2 and Vd are equal), then 2 F Css of drug C is achieved at double the time 2 F Css of drug C is achieved twice as slowly 2 T Css of drug C is achieved at the same time as that required for drug D 2 T Css of drug C is doubled if compared with drug D 2 F Css of drug C reaches the half value of that for drug D Although increasing the rate of infusion of the drug increases the rate at which any given concentration of drug in the plasma is

achieved, it does not influence the time required to reach the ultimately steady-state concentration. On the other hand, Css of drug C is double. Which factors are determinant of the rate of approach to steady-state? 1 T t 1/2 (the half-life) 1 F the rate of an IV infusion 1 T only factors that affect t 1/2 1 F the dose 1 F the duration of an IV infusion T 1/2 and factors influencing this parameter. Loading dose (followed by an infusion to maintain Css) 2 T can be injected as a single dose to achieve the desired plasma level rapidly 2 T can be administered as an IV inf. with the faster rate to achieve the desired plasma level rapidly 2 T depends on Vd 2 F depends on Cltot 2 T = Vd x desired steady-state plasma concentration It can be administered as a single dose or as an IV infusion with the faster rate to achieve the resired plasma level rapidly. Its value depends on Vd and can be calculated as follows: loading dose = Vd x desired steady-state plasma concentration When of the infusion is stopped, the plasma concentration declines to zero with the 1 F a higher time course than that observed in approaching the steady state 1 T the same time course observed in approaching the steady state 1 F a reduced time course than that observed in approaching the steady state 1 T a time course which can be influenced by the pathological state 1 T a time course determined by Ke It declines to zero with the same time course observed in approaching the steady-state and a time course which is determined by Ke and can be influenced by the pathological state. Kinetics of fixed doses. In multiple intravenous injections: 1 T they result in time-dependent fluctuations in the circulating level of drugs 1 T plasma concentration of the drug oscillates between Cmac and Cmin 1 T the mean plasma concentration increases until a steady state is achieved 1 F t 1/2 depends on the dose of the drug (in the first-order process) 1 T using smaller doses at shorter intervals reduces the amplitude of the swings in drug concentrations T 1/2 does not depend on the dose of the drug (in the first-order process). Kinetics of fixed doses.Plasma concentr. of orally administr. drugs is influenced 1 F only by the rate of absorption 1 F only by the rate of drug elimination 1 T by both the rate of absorption and the rate of drug elimination 1 F only by t 1/2 1 F only by the drug metabolism It is by both the rate of absorption and the rate of drug elimination (e.g. metabolism and excretion). Total body CLEARANCE 1 T is expressed as the volume of plasma from which all drug is removed in a given time (ml/min) 1 T equals dose/AUC (after IV administration) 1 F is not constant over time 1 T is the sum of the clearances from the various drug-eliminating organs 1 T determines the maintenance dose It is constant over time. Note that the clearance has units of volume/unit time. Renal clearance (Clren) 1 T equals the amount of the renal plasma flow multiplied by the extraction ratio 1 F of a drug eliminated only by glomerular filtration obviously exceeds 125 ml/min 1 T 480 ml/min of benzylpenicilin involves tubular secretion

1 T is reduced by renal insufficiency in drugs excreted in a nonmetabolized form mainly by the kidney 1 T can be increased by an increase in pH of urine in weak acids (barbiturates, salicylates). It equals the amount of the renal plasma flow multiplied by the extraction ratio. Clren of a drug eliminated by glomerular filtration obviously cannot exceed 125 ml/min. Clcr, the creatinine clearance, 1 T takes 120 ml/min or 1.33-3 ml/sec in a healthy subject 1 T is a measure of removal of endogenous creatinine from the plasma 1 T takes 20-30 ml/min in renal failure 1 T describes mainly glomerular filtration 1 F is not very often used to characterize the state of a patient It takes 120 ml/min or 1.33-3 ml/sec approx. in a healthy subject. It describes mainly the process of glomerular filtration. Its value falls to 70 ml/min in renal insufficiency and to 20-30 ml/min in renal failure. It is often used to characterize the state of the patient. T 1/2 (the half-life) of a drug: 2 T is directly proportional to its volume of distribution 2 T is inversely related to its clearance 2 T = 0.683 Vd/Cltot 2 T becomes longer if the volume of distribution increases 2 F the larger the volume of distribution, the more drug is available for excretion by the kidney. The larger the volume of distribution, the more drug is outside the plasma compartment and is unavailable for excretion by the kidney. Ke (the elimination rate constant) = 0.01 min-1 means that 1 F about 10% of the drug amount in the body is eliminated in 1 min 1 T about 1% of the drug amount in the body is eliminated in 1 min 1 F 10 mg of drug is eliminated in 1 min 1 F the plasma concentration is reduced by 1 mg/ml in 1 min 1 F 1 mg of drug is eliminated by the kidney in 1 min 3% of the drug amount in the body is eliminated in 1 hour. Css of the drug given by IV inf.(t 1/2=12h) is reached in? 1 F 18 hours 1 F 30 hours 1 T 48-60 hours 1 F 24 hours 1 F 120 hours In approximately 48-60 hours atfer the start of the infusion.. Which of the following results in a doubling of the Css of a drug? 2 T Doubling the rate of infusion 2 F Maintaining the infusion rate, but doubling the loading dose 2 F Doubling the rate of infusion and doubling the concentration of the infused drug 2 F Tripling the rate of infusion 2 F Quadrupling the rate of infusion Doubling the rate of infusion.

A - General pharmacology (part three)

Can disease influence the way the body handles drugs? 1 T Yes, it should be borne in mind before prescribing (a choice) of the drug 1 T Yes, therapeutic failure may be a consequence of such a possibility 1 T Yes, an alternative route of administration may be appropriate in such circumstances 1 T Yes, an individualized dose regimen is often necessary 1 T Yes, then toxicity should be avoided

All answers are true. Cardiac failure. A. Malabsorption can occur because of..... B. Absorption .......... 1 T A. mucosal edema 1 T A. reduced gastrointestinal blood flow 1 F A. splanchnic vasodilation 1 T A. changed GIT motility, secretion and pH 1 T B. of thiazide diuretics is reduced Reduced gastrointestinal blood flow due to low cardiac output can reduce drug absorption. Splanchnic vasoconstriction accompanies cardiac failure as an adaptive response redistributing blood to more vital organs, and exacerbates any problem with drug absorption. Other secondary changes in gastrointestinal motility, secretion, altered pH and so on presumably also affect drug absorption adversely. Absorption of thiazides is reduced in the extend depending on cardiac failure severity Vd of quinidine in patients with congestive failure is approx. 1/3 of normal: 2 T usual doses can therefore result in elevated plasma concentrations 2 F usual doses can therefore result in decreased plasma concentrations 2 T overdose and toxicity can be induced 2 F therapeutic failure can be observed (because of low concentrations at the receptor site) 2 F but this change has no influence on the effects of quinidine Usual doses can therefore result in elevated plasma concentrations. In this way overdose and toxicity can be induced. In cardiac failure drugs with a high extraction ratio (more than 70%): 2 T are theophyllin and lidocaine for example 2 T show perfusion limited clearance which is reduced according to lower organ blood perfusion 2 T reach the steady-state levels inversely related to cardiac output 2 F are rapidly eliminated 2 F exert shorter half-lives Decreases in elimination occur with drugs exerting high hepatic extraction ratios. Their half-lives are prolonged. For example, theophylline clearance is decreased and its half-time doubled in patients with cardiac failure and pulmonary edema. Heart failure reduces renal excretion (renal clearance) of some drugs 2 T because of reduced glomerular filtration 2 T which are eliminated by the kidney in unchanged form (and their Clren reaches more then 50% of Cl to 2 F which are eliminated by the kidney in the form of inactive metabolites 2 T e.g. aminoglycosides and dixogin 2 T and can increase their toxicity Heart failure reduces renal elimination of drugs because of reduced glomerular filtration, predisposing to toxicity from drugs such as aminoglycosides and digoxin that are eliminated by this route in unchanged form (and their Clren is higher than 50% of Cltot). In patients with renal impairment A.... A+B. to adjust the dose regimen... 2 T A...glomerular filtration (GF) and tubular secretion of drugs usually fall 2 T A...the decline in excretion of drugs eliminated mainly by Clren is directly related fo GF 3 F A+B.. we usually use the measurement of endogenous creatinine clearance 3 T A+B. ..we usually use the estimated creatinine clearance 3 F A+B.. we usually use blood urea Measuring of endogenous creatinine clearance requires accurate urine collection, which is often far from easy in ill, confused and incontinent patients. Estimated creatinine clearance based on creatininemia values (and calculated by means of the formula by Sierbaek-Nielsen or Cockcroft and Gault) is usually used to adjust the dose regimen for drugs that are eliminated mainly by renal clearance (more than 50% of total clearance). The main limitation of plasma creatinine as a means of estimating GRF is in acute renal failure. The thing is that plasma creatinine reflects renal function accurately in chronic renal failure unless severe, but only increases after an acute reduction in renal function after a lag of several days. Blood urea is almost useless as a marker of renal drug elimination since it is influenced by protein intake and metabolism, liver function, state of hydration etc. Which drugs should be avoided or used with caution in renal failure? 2 T Aminoglycosides, amphotericin B 2 T Methotrexate, azathioprin

2 T Digoxin, lithium, enalapril, captopril 2 F Digitoxin 2 F Opioids Digitoxin and opioids can be used because they are eliminated via the hepatic metabolic pathways and in bile mainly. Is it true? 2 T there are two ways of reducing total dose to compensate for impaired renal function 2 T either each dose can be reduced or the interval between each dose can be lengthened 3 T the prolonged interval is useful when a drug must achieve some threshold concentration 3 F therapy should be monitored by measuring Cmax (peak concentrations) only 3 T Cmin of aminoglycosides can predict ototoxicity of these antibiotics The prolonged interval is useful when a drug must achieve some threshold concentration to produce its effect, but does not need to remain at this value throughout the dose interval. Therapy with these drugs is appropriately monitored by measuring Cmax (in blood sampled at a brief interval after dosing /30 min/, sufficient to permit at least partial tissue distribution), and Cmin (trough levels) immediately before the next dose. Because of nephrotoxicity and ototoxicity related to drug plasma concentration, Cmin of amioglycosides cannot be higher than the limits recommended. Patients A. with mild renal impairment .. A+B.on non-steroidal anti-inflammatory drugs may 2 T A. depend on vasodilator prostaglandin biosynthesis (PG I2 and E2) to preserve renal blood pressure 2 T A+B. have cyclo-oxygenase and hence synthesis of vasodilator prostaglandins inhibited 2 F A+B. are quite able to preserve renal blood pressure 2 T A+B. may develop acute reversible impairment with salt and water retention 3 T A+B. sulindac is a partial exception, because it inhibits cyclo-oxygenase less in kidneys Patients with mild renal impairment on NSAID may not be able to preserve renal blood pressure. Acute reversible impairment with salt and water retention may be developed. The same is true for patients with heart failure, nephrotic syndrome, cirrhosis or ascites. Guidelines for drug prescribing for patients with renal disease: 1 T consider the possibility of renal impairment before drugs are prescribed 1 T if Clren of drug is higher than 50% of Cltot then dose reduction will probably be necessary 1 T monitor therapeutic and adverse effects 1 T when appropriate, monitor drug concentrations in plasma 1 F do not use potentially nephrotoxic drugs. They must be avoided in any case Use potentially nephrotoxic drugs with special care (non-steroid anti-inflammatory drugs, aminoglycosides, converting enzyme inhibitors). Markers of hepatic function which serve to correlate it with Clhep of drugs: 1 T serum albumin is the most useful parameter describing hepatic drug metabolizing activity 1 T prothrombin time shows moderate correlation with drug clearance by the liver 1 F indocyanine green, antipyrine and mesocaine (lignocaine) are very useful markers 1 T attempts to find them have been unsuccessful 1 F activity of CYP450 in vitro Low albumin reflects depressed synthesis of hepatic protein including those involved in drug metabolism. In neither case does prothrombin time have a continuous relationship with drug clearance and it can be used mainly to distinguish the severely affected from the milder cases. Indocyanine green, antipyrine and mesocaine have proved of little value. There is a poor correlation between microsomal enzyme activity from liver biopsy specimens in vitro and drug clearance in vivo. Conclusion: attempts to correlate changes in pharmacokinetics of drugs with test for derangement of liver function have been unsuccessful in contrast to the successful use of plasma creatinine in renal impairment. Liver disease:A. Absorption is altered because.... D.Drug metabolism ... 1 T A...portal/systemic anastomoses allow bypassing hepatic presystemic metabolism 1 F A...bioavailability of drugs with high hepatic extractions is decreased 1 T A...of mucosal edema caused by hypoalbuminemia and portal hypertension 1 T D... need not be impaired in patients with moderate to severe disease 1 F D... is very low at any phase of hepatic disease A...bioavailability of drugs with high hepatic extraction is increased. D... drug metabolism is not affected to the same extent even in very severe disease.

Liver disease. Drug distribution is increased because : 1 F reduced plasma albumin increases plasma protein binding 1 F bilirubin accumulates and may enhance drug binding sites 1 T the free fraction of some drugs (tolbutamid, phenytoin) is increased 1 T Vd of several drugs is increased (diazepam, theophyllin) 1 T of ascites Reduced plasma albumin reduces plasma protein binding. Bilirubin and other endogenous substances accumulate and may displace drugs from the binding sites. Some guidelines for drug prescribing for patients with liver disease: 1 T If possible use drugs that are eliminated by routes other then the liver 1 T Hepatotoxins (cytostatics) should be used if necessary with close monitoring 1 T Precipitants of hepatic coma should be avoided 1 F Drugs causing sodium retention and those containing sodium are often used without caution. 1 F Drugs that interfere with hemostasis are not bearing any risk. Precipitants of hepatic coma (sedative and analgesic drugs) probably because of a combination of pharmacokinetic and pharmacodynamic alterations, should be avoided. For the same reason, potassium-spare diuretics are preferable over thiazides and loop diuretics. Fluid overload and ascites are exacerbated by drugs causing sodium retention (indomethacin, glucocorticoids) and those containing sodium (some antacids and high doses of carbenicilin). These drug should be avoided or used with caution. Drugs that interfere with hemostasis (aspirin, anticoagulants and fibrinolytics) increase the risk of bleeding, especially if varices are suspected.

A V - General pharmacology (part four). Introduction of new drugs

The tree codes of practice are: 1 F Good Marketing Practice (GMAP) 1 T Good Pharmaceutical Manufacturing Practice (GMP) 1 T Good Laboratory Practice (GLP) 1 T Good Clinical Research Practice (GCP) 1 F Good Physician Practice (GTP) Good Pharmaceutical Manufacturing Practice. Good Laboratory Practice. Good Clinical Practice. The process of developing new therapeutic agents 1 T comprizes 6 well-defined pathways 1 T is expensive 1 T is highly regulated 1 T takes approximately 12 years or even more 1 F does not concern risks of drug administration Comprizes: Discovery/design (1), Synthesis (2), Preclinical studies (3), Clinical testing (4), Regulatory approval- product licence (5), Postmarketing surveillance (6). Is very expensive. The average cost of taking a new chemical entity from the laboratory to the market place in 1990 was more than L 150 million and the process took approximately 12 years. Minimizes the risks and optimizes the benefit to society of new therapeutic agents. The manufacture of ethical pharmaceuticals (new chemical entities): 1 T can be chemical and biotechnological 1 F need not to be verified (the quality depends on the producer) 1 T must be performed according to the guidelines of GMP 1 F is not protected by the patent life 1 T the version of that drug may be made (generic drugs) once the patent life of a drug has expired Has to be verified. Is protected by the patent life. Once the patent life has expired anyone may manufacture and sell their version of that drug (generic drugs) Preclinical studies 1 F are performed using animals and humans 1 T help to predict the efficacy and toxicity of drugs that are candidates for clinical use

1 F give data easily extrapolated to clinical trials 1 T are performed using animals 1 T should be approved by the special Ethics Committee Help to predict the efficacy and toxicity. Prediction of the effects of drugs in humans by extrapolation from animal data is at best of limited value. Preclinical studies are performed using animals. Should be approved by the Ethics Committee which is specialized in this topic. Preclinical study 1 T consists of screening of specific pharmacological activity 1 F is not interested in general pharmacological profiles 1 T is focused on acute toxicity (the estimated lethal dose) 1 T concerns chronic toxicity 1 T involves specific toxicities Consists of screening of specific pharmacological activity. Gives also the general pharmacological profiles (secondary pharmacology). Is focused on acute and chronic toxicity. Involves specific toxicities. For chronic toxicity 1 T 3- 4 doses are selected 1 T doses are administered daily 1 T doses are administered to two species 1 F a placebo dose is not essential 1 F a top dose at which fatalities will occur must be excluded 3-4 doses are selected and administered daily to two species, one rodent (usually rat) and one non-rodent (usually dog). The doses selected are intended to include a "no effect" dose, low dose, mid dose and a top dose at which a fatalities can occur. A placebo dose if necessary. Chronic toxicity estimation: 1 T involves biochemical, hematological and urinalysis profiles 1 T contains a physical examination 1 T is based also on plasma concentrations of the drug 1 F is focused on histopathological examination performed only on the liver 1 T lasts according to the number of the doses to be given to humans in the next phase of clinical trial Histopathological examination performed on all organs. Other answers are true. Special toxicities are: 2 T Mutagenicity 2 T Carcinogenicity 2 T Fertility testing 2 T Teratology testing 2 T Peri-and postnatal development testing All answers are true. Testing of fertility, teratogenicity and that of peri-and postnatal development form REPRODUCTIVE testing. Clinical trials should be: 2 T prospective 2 T randomized 2 T double-blind 2 T organized in two parallel groups A and B or in cross-over design with wash-out period 2 T controlled All answers are true. Two parallel groups A and B are organized if comparizon of two drugs in required Parallel group studies 2 T are those in which patients are randomized to receive different treatments 2 F can be organized in a crossover design without wash-out period 2 T can be organized in a crossover design, wash-out period is necessary 2 T are controlled by a placebo when possible 2 T can be controlled by the standard, established treatment of choice

Patients are randomized to receive different treatments. In a crossover design (where each subject acts as his or her own control) there must be an adequate "wash-out" period to prevent a carryover effect from the previous treatment. Studies are controlled either by a placebo (absolute efficacy), or by the standard reference drugs of established efficacy (relative efficacy) . The placebo 1 T is a preparation without the defined effective compound 1 T can induce an effect in any subject 1 F a placebo effect is elicited only in naive subjects 1 F needs not to be prepared very carefully 1 T frequency of a placebo effect can reach approx. 30% Is a preparation without the defined effective compound. Can induce an effect in any subject even in informed physicians. Should be prepared very carefully to avoid "nocebo effect" i.e. negative reaction in the case of unpleasant properties (color, smell). Frequiency of a plycebo effect can reach approx. 30%. Randomization gives the patients (healthy volunteers) an equal chance of 1 T receiving treatment A or B that are to be compared in a cross over system. 1 F receiving the same dose of a new drug 1 F obtaining the informed consent 1 F selection for participation in a study 1 F higher financial award Receiving treatment A or B ina cross over system. The dose of a new drug is extrapolated from data of preclinical studies. Each subject must be given the informed consent. Selection for participation is regulated by exclusion/inclusion criteria. Financial award is offered in the informed consent. The documentation of the clinical trial mainly involves: 1 T the informed consent 1 T the case report 1 T the protocol of the study 1 T the final report 1 T the approval of Ethics Committee and that of Ministry of Health All answers are true. The informed consent A. is to inform the subject..... B. must be..... 1 T A. about the goal of the trial 1 T A. about the risks of the trial 1 T B. written in the language of the subject 1 T B. completely understood by the subject 1 T B. signed by the subject About the goal of the trial. About the risks of the trial. Written in the language of the subjects. Completely understood by the subject. Must be signed by the subject before the start of the study. The case report 1 T comprises all medical examination of one subject 1 F consists of medical examinations of all subjects 1 F is conclusion of the whole study 1 F represents the guidelines for the trial 1 F contains the names and prenames of the subjects Comprises medical examinations (clinical chemistry, hematological values, physical examinations etc.) of one patient. Conclusions are announced in the final report. The guidelines belong to the protocol. Neither names nor prenames are mentioned in any part of the study documentation. Only initials can be used (JB instead of John Brown). The trial placebo controlled can be organized in subjects on 1 T hypnotics/sedatives 1 F antidiabetics 1 F antiasthmatics 1 F antibiotics in severe infections 1 T antihypertensive drugs in mild hypertension

Hypnotics/sedatives. Antihypertensive drugs in mild hypertension. In others the trial controlled by the reference drug of established efficacy is more convenable. Phase I of the clinical study is characterized: 2 T first administration in humans 2 T safety evaluation 2 T usually healthy male volunteers are used 2 T 12-100 subjects /protocol 2 F only a single dose regimen is used Multiple dosing studies are performed under the same, strictly controlled conditions. Phase II of the clinical: 2 T provides initial SAFETY evidence 2 T provides initial EFFICACY evidence 2 T is usually double blind, randomized and sometimes placebo controlled 2 T single or multicenter (100-500 patients in total) 2 F involves only healthy volunteers The first patient studies are implemented which are designed to determine the initial safety profile of the drug (1), to establish clinical efficacy (2) and to define the dose range to be used in the next stage of clinical trials - phase III (3). The use of placebo depends on risks due to the disease (cannot be used in patients with cancer, diabetes mellitus and so on)

Phase III of the clinical study 2 T provides information on overall benefit/risk 2 T gives collection of data on a large patient population with indication 2 T is large multicenter (1000-5000 patients in total) 2 F represents a postmarketing study 2 T is usually blind and controlled The medical advisers are gathering together the large amount of data necessary to make formal application to the Licencing Authority for a product licence. A factual data sheet giving information for medical practice on each new medicine is prepared both for physicians and for patients (as a simplified form). This phase cannot involve the postmarketing studies. Phase IV : 2 T is postmarketing study (i.e. after marketing approval - the granting of a Product Licence) 2 T is exposure of drug to a wider population 2 T provides detection and definition of previously unknown or inadequately quantified adverse effects 2 F is not to investigate new formulations, dosage requirements, drug interactions 2 T new age, races and other types of patients are studied Is to investigate new formulations, dosage requirements and drug interactions. The generic drug producers 3 F have to repeat all preclinical and clinical studies 3 T are asked to demonstrate that their version of the drug is bioequivalent to the standard formulatio 3 F are not asked to supply the marketing approval 3 F are not allowed to reduce the cost of the drug formulation 3 F pay some charge to the original drug producers Are asked to demonstrate that their version of the drug is bioequivalent to the standard formulation. This usually means that the plasma concentration-time curves for the generic product must be demonstrated to be sufficiently similar to the standard preparation to be clinically equivalent. They asked for the marketing approval. Ethics Committee 2 F is dependent on the Management of the Hospital 2 T protects the subjects of research 2 T preserves the rights of research subjects 2 T provides public reassurance 2 T reviewes and approves all protocols for clinical trials Is a properly constituted quite independent committe.