Mansoura Clinical Pharmacology For Medical Students Volume 1 PDF

Copyrighhts © 2016 by b the Deparrtment of Clin nical Pharma acology at Fa aculty of Meedicine, Mnas...

Copyrighhts © 2016 by b the Deparrtment of Clin nical Pharma acology at Fa aculty of Meedicine, Mnas soura Universitty, Egypt. Previouss editions copyright © 20 015, 2014, 20 013, 2012, 2011, 2010, 2009, 2 2008, 22000 by the Departm ment of Cliniccal Pharmacoology at Facu cine, Mnasou ulty of Medic ura Universitty, Egypt. No part of this book may be reprroduced or d distributed in n any form orr by any meaans, or stored d in a databasee or retrievall system, witthout the prio or written pe ermission of the t copyrighhts owner, Departm ment of Cliniccal Pharmaco ology at Facuulty of Mediccine, Mansouura Universitty. This is a copyrightedd work and is s protected b by the Egypttian Intellectu ual Property Law 82 of 2002. Use of this w work is subjec ct to this law w. The Departrtment of Clin nical Pharmaacology at MMansoura Fac culty of Medicine e reserves alll rights in an nd to the worrk. 2000 ‫سنة‬ ‫ لس‬1456 :‫رقم اإليداع بدار الككتب‬ ‫م‬ 2000/9/6 ‫بتاريخ‬ Preface C linical training for undergraduate students often focuses on diagnostic rather than therapeutic skills. Sometimes students are only expected to copy the prescribing behavior of their clinical teachers, or existing standard treatment guidelines, without explanation as to why certain treatment is chosen. Books may not be much help either. Pharmacology reference works and formularies are drug-centered, and although clinical textbooks and treatment guidelines are disease-centered and provide treatment recommendations, they rarely discuss why these therapies are chosen. Different sources may give contradictory advice. This book in primarily intended for under graduate medical students who are about to enter the clinical phase of their studies. It will provide step by step guidance to the process of rational prescribing together with many illustrative examples. It teaches also skills that are necessary throughout a clinical career. Postgraduate students and practicing doctors may also find it a source of straightforward information. I wish to acknowledge the ongoing efforts of my contributing authors, and we are deeply grateful to all those who have with such good grace given us their time and energy to supply valuable facts and opinions, they principally include:  Prof. Hussein El-Beltagi who took over the preparation of all books since the 1st edition in 1995 including the revision process, printing control, distribution and selling control.  Assist. Prof. Mohamed-Hesham Daba who took over the revision process and amendments of the last two editions.  Assist. Prof. Abdel-Motaal Fouda who prepared the last two editions in a readable up- to-date text to provide essential information necessary throughout the clinical career.  Dr. Sameh Abdel-Ghany who assisted in the revision process. Much of any merit this book may have is due to the generosity of those named above. Gamal M. Dahab (MD, PhD) Professor Emeritus in Clinical Pharmacology Mansoura Faculty of Medicine iii  Miss sion and a Vis sion Our mission The Clinnical Pharm macology Department D is seeking excellence e and leadeership in fou ur major core acctivities: edu ucation, ressearch, com mmunity serrvice, and faculty f and staff development. We are e connectin ng basic medical m sc iences with clinical care c througgh innovattive and disciplin ned teachin ng of clinica al pharmaco ology in an integrative i manner m Our v vision The dep partment off Clinical Ph harmacolog gy is aiming g to be a premier acad demic model in the field of pharmacoloogy and the erapeutics in Egypt annd Middle East E throug h promoting use of the bestt therapeutics and dev veloping new wer experimmental and clinical reseearch proje ects. Value es The gu uiding prin nciples and beliefs ffor the dep partment  Excellence, creativity, innovation, fairness, honesty, transparenncy, collab boration, teammwork and lifelong learning  Reccognition tha at our stude ent comes ffirst  All m members ofo our department musst see them mselves as integral to the successs of our misssion and ouur departmeent as integ ral to their personal p su uccess.  As we subscrribe to the ese values,, we shall be profes ssionals in the profes ssion of education. iv Contributers Effat A. Haroun MD, PhD Somaya A. Mokbel MD, PhD Prof. of Clin Pharmacology Prof. of Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Elhamy M. El-Kholy MD, PhD Amany A. Shalaby MD, PhD Prof. of Clin Pharmacology Prof. of Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Gamal M. Dahab MD, PhD, MSc (Int.Med) Amal Abdel-Hamid MD, PhD Prof. of Clin Pharmacology Prof. of Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Farida M. El-Banna MD, PhD Essam A. Ghyati MD, PhD Prof. of Clin Pharmacology Assist. Prof. of Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Aly M. Gaballah MD, PhD, MSc (int.Med) Mohamed-Hesham Y. Daba MD, PhD Prof. of Clin Pharmacology Assist. Prof. of Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Layla T. Hanna MD, PhD Abdel-Motaal M. Fouda MD, PhD Prof. of Clin Pharmacology Assist. Prof. of Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Mohamed Kheriza MD, PhD, MSc (Int.Med) Vivian Boshra MD, PhD Prof. of Clin Pharmacology Assist. Prof. of Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Abdel-Rahman A. Yassin MD, PhD Hala A. Al-Ashri MD, PhD Prof. of Clin Pharmacology Assist. Prof. of Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Mohmmad A. Attia MD, PhD Nageh Rizk MD, PhD Prof. of Clin Pharmacology Lecturer in pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Mohamed Abdel-Ghani MD, PhD Elsayed A. Hassan MD, PhD Prof. of Clin Pharmacology Lecturer in Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Hussien M. El-Beltagi MD, PhD Mohamed Abdel-Monem MD, PhD Prof. of Clin Pharmacology Lecturer in Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Karawan M. Abdel-Rahman MD, PhD Mahmoud A. Naga MD, PhD Prof. of Clin Pharmacology Lecturer in Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine v  Ahmad Hassan MD, PhD Mohamed Abou El-khair MD, PhD Lecturer in Clin Pharmacology Lecturer in Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Ahlam El-masry MD, PhD Sameh A. Abdel-Ghani MSc. Lecturer in Clin Pharmacology Assist. Lecturer in Clin Pharmacology Mansoura Faculty of Medicine Mansoura Faculty of Medicine Rehab Hamdy MD, PhD Lecturer in Clin Pharmacology Mansoura Faculty of Medicine vi Table of Contents CHAPTER 1: GENERAL PRINCIPLES Part 1: Pharmacodynamics 1 Receptors 2 Ion channels 7 Enzymes 8 Carrier molecules 8 Part 2: Factors affecting the dose-response relationship 8 Factors related to the drug 8 Factors related to the patient 10 Part 3: Clinical pharmacokinetics 13 Absorption of drugs 13 Distribution of drugs 15 Elimination of drugs 16 Metabolism of drugs 20 Part 4: Adverse drug reactions 23 Drug induced liver injury 24 ADR on pregnancy 25 Part 5: Principles of drug interactions 26 Pharmacokinetic interactions 26 Pharmacodynamic interactions 28 Review questions 30 CHAPTER 2: AUTONOMIC PHARMACOLOGY Part 1: Basic information 39 Part 2: Adrenergic agonists 46 Direct acting sympathomimetic drugs 46 Indirect acting sympathomimetic drugs 51 Mixed acting sympathomimetic drugs 52 Part 3: Adrenergic receptor antagonists 53 Alpha adrenergic blockers 53 Beta adrenergic blockers 58 Part 4: Sympathoplegic drugs 62 Centrally acting sympathoplegic drugs 62 Adrenergic neuron blockers 63 Part 5: Parasympathomimetic drugs 64 Direct acting parasympathomimetics 64 Indirect acting parasympathomimetics 67 vii  Part 6: Muscarinic antagonists 71 Part 7: Ganglion blocking drugs 74 Part 8: Neuromuscular blockers 74 Review questions 78 CHAPTER 3: DIURETIC AGENTS AND VOLUME BALANCE Part 1: Basic information 85 Part 2: Diuretic classes and agents 87 Loop diuretics 88 Thiazide diuretics 89 Potassium sparing diuretics 90 Osmotic diuretics 92 Part 3: Advantages and disadvantages of diuretics in some edematous 94 conditions Congestive heart failure 94 Chronic kidney disease 94 Liver cirrhosis 95 Lower limb edema due to pregnancy 95 Part 4: Volume depletion and fluid replacement 96 Part 5: Disorders of serum sodium and potassium 97 Part 6: Manipulation of the urine pH 100 Review questions 102 viii █ Intro oductory definitions Medica al pharma acology is a basic c science.. It the science s deealing with h small molecu ules used tot prevent, diagnose , or treat diseases. d Clinicaal pharma acology is s the scieence concerned with the raational, sa afe and effectivve use of drugs d in hu umans. It ccombines elements of o basic phharmacoloogy with clinical medicine e; in other words, it involves the t complex interacction betweeen the drug and the pattient. A drug g is any chemical molecule that can interact with w bodyy systems at the molecu ular level and produc ce effect. The drrug-body interaction ns Part 1 1: Ph harmaco odynamiics (Mec chanism of drug a action) Pharmaacodynam mics is summmarized a as what a drug does to the b body; a drug may produc ce its effectts through: Interraction witth body co ontrol systtems (regulatory prote eins): (a a) Receptorrs (b) Ion n channelss (c c) Enzymess (d) Caarrier molec cules Direc ct chemica al or physic cal mecha anisms. Interraction with certain metabolic m p pathways. 1  A. REC CEPTORS S Receptors: they are protein macrom molecules. When W they y combine with a dru ug, they may be e activated d or blocke ed. Ligand d: is any molecule tha at can com mbine with the recepptors. A ligaand that ac ctivates the rec ceptor is called agonist. a A ligand that t block ks the reeceptor is called antago onist. y: it is the empathy of Affinity o the rece eptor to the ligand. It determinnes the nummber of receptoors occupied by the drug. █ Typ pes of rec ceptors Ion channel--linked re eceptors (direct ligand-gated d ion channnels): - The receptor is an ion n channell consists s of 5 transsmembran ne subunits s (α1, α2, β,, γ, δ). - Bindding of thee agonist to t the extrracellular part p of the rreceptor causes c opeening of th he channe el for a speccific ion. - The response of these re eceptors iss very fast and their duration d is very shortt. - Exam mples:  N Nicotinic Ach e ion channnel opens for Na+ d-plate: the A recepttors in the motor end ions in ressponse to stimulation s n by Ach.  The Gama a aminobuteric acid (GABA) re n the brainn: the ion channel eceptors in c - opens for Cl ions in response to stimulation by GAABA. G-protein-lin nked rece eptors: - The receptor co onsists of 7 membranne subunits. - Bind ding of the e agonist too the extra acellular part of the receptor ca auses ac ctivation of acellular G--protein. intra - Wheen the G-p protein is activated, a unit its α subu bindds to GTP to be pho osphorylateed and bring stimulatory or inhibitory response. - Their responsse is slow wer than ion chann nel receeptors but their t duration is long ger. - Stim mulatory G-protein G (Gs) leadss to increa ase enyl cyclase enzyme → ↑ cAMP ade P → activation of specific proteins s (proteinn kinase es). Exa amples of Gs-couple G ed receptorrs are the β1 and d β2-adrenergic receptors. 2 - Inhibitory G-protein (G Gi) leads to o decrease yclase enzzyme → ↓ cAMP e adenyl cy c → inhibition of protein kinases. Exxamples of o Gi-coup pled recep ptors are the t α2- adreenergic rec ceptors an nd M2 musscarinic rec ceptors. - Gq--coupled receptorrs: they increase inositol triphosp phate (IP3 3) and 2+ diac cylglyceroll (DAG). IP3 3 increasess free intrac cellular Ca. Exampl es of Gq-ccoupled rece eptors are the α1-ad drenergic reeceptors, M1M and M3 3 muscarinnic recepto ors. Tyro osine kinase (TK)--linked re eceptors:: - The receptor consists of 2 largee domainss: an extraacellular hormone-b h binding doomain and d an intra acellular TKK-binding domain c onnected by a transsmembran ne segment. - Bindding of the e agonist to the hoormone-binnding dommain cause es activattion of th he intrace ellular dommain to ac ctivate TK enzyme → activatio on of seveeral protein ns known as a “signalin ng proteinss”. - Exam mples: insu ulin recepttors. Intra acellular recepto ors: - Theyy are located inside the t cell eith her in the cytoplasm c or directlyy on the DNA. D - Theyy regulate transcripti t on of genees in the nuucleus or the mitoch ondria. - Their agonist must m enter inside the e cell to reaach them. - Theyy have twoo importantt features:  Their response is slo ow (time iss required for f synthes sis of new proteins).  Their effeccts persist for long tiime after the agonistt is removeed. - Exam mples: receptors for corticoste eroids, sexx hormone es, thyroxinn, etc. Types s of drug g-recepto or bonds s The ionic bon nd: It is an electric cal attraction betwee en two opp posing cha arges. It is strong but reeversible. The hydrogen n bond: It is an attraction betwe een two h hydrogen bonds. b It is weak and reversible. The covalent bond: Veryy strong an nd irreversible. If oc ccurred bettween drugg and rece eptor, the receptor r be ecomes permmanently blocked. b 3  █ BIOL LOGICAL RESPONS SE TO DRU UG-RECE EPTOR BIN NDING (Dose e-response relatiionship s studies) When a drug com mbines with a recepto or, this ma ay lead to one o of the following: Agoonist effect: meanss that the drug com mbines with the recceptor andd gives resp ponse. Anttagonist effect: e mea ans that thhe drug combines with w the reeceptor bu ut gives NO response e, and prev vents the re eceptor fro om binding g to anotheer drug. ▌Agon nist effe ect Accord ding to the “dose-rresponse relations es”, theree are 2 ty ship curve ypes of responses to drugs: Graded respon nse Qu uantal res ponse - The response is increase ed - The T respon nse does nnot increas se prop portionally y to the do ose of the proportiona p ally to the agonist bu ut it is agon nist e.g. the response e of the he eart all-or-none a e responsee e.g. prevvention to addrenaline. of o convulsions by anttiepileptic drugs - It is tthe respon nse to mos st drugs. - Itt is responnse to few drugs. - The response could be tested in on ne - The T respon nse could nnot be testted in or mmore anima als. one o animal and mustt be tested d in a group g of animals. Effecttiveness s and saffety Effic cacy - It is tthe ability of a drug to t produce e response e (effect) affter binding g to the receptor. - It is measured d by the Emax (the m maximal re esponse that a drug g can eliciit at full conc centration)): 4  Full agonist is the d drug that gives maximal m rresponse at full conceentration (aat full occu upancy). al agonistt is that ag Partia gonist givees submax ximal resp ponse even n at full conceentration i..e. never g ives Emax Pote ency - ED5 ve Dose) is the dose 50 (Effectiv e of the dru ug that giv ves 50% o of the Emaxx, or it is the d dose that gives g the desired d effe ect in 50% % of a test populationn of subjec cts. - A drug that givves ED50 byb smaller doses is described d as a “potentt” drug. - Poteency of dru ugs is gene erally less clinically importantt than efficcacy becauuse you can increase the dose of o a less po otent drug to obtain the effect of a moree potent one (provided that it is not toxic). Safe ety - TD5 50 (Toxic Dose) D is th he dose o f the drug needed to cause a harmful effect e in 50% % of a test population n of subjec cts. - LD5 50 (Lethal Dose) is th he dose ne eeded to cause c deatth in 50% of a test group g of anim mals. It is experiment e al term tha at can be determined d d in animalls. 5  - Therrapeutic in ndex (TI) LD50/ED5 L 50: - It is the ratio between b th he LD50 an nd the ED5 50. It is a measure m off safety; if there is a larrge differe ence betweeen the do ose of a drug d that produces p tthe desired d effect and the dose that t producces a toxic c effect, it is said tha at the drug has a large TI. - Druggs with higgh TI are more m safe ffor clinical use, and vice v versa (e.g. warfa arin has arrow TI and requires careful th erapeutic monitoring a na g). ▌Anta agonist effect e  Anta agonist is the ligand d that com mbines with h the recep ptor and d does not activate a it. Itt has no intrinsic activity, bu ut may cause a pha armacolog gical respoonse by inhibbiting the actions a of endogenou e us substan nces or othher drugs.  If thee antagoniist binds to o the same e site of thhe agonist on the recceptor, it is s called com mpetitive antagonist a t. If the an ntagonist binds b to an nother sitee on the re eceptor, and prevented d the action n of the aggonist, it is called nonn-competiitive antag gonist.  Com m may be reversible mpetitive antagonism a e or irreve ersible:  R e antagonist makess weak bo Reversible ond with th he recepto or so as you y can o overcome the t block byb giving h high doses s of the ago onist, and even you can get th he maximaal response in preseence of the e antagonis mountable effect). st (i.e. surm T The duratio on of block k is short b because the antagonist can be easily wasshed off th he recepto ors.  Irrreversible nist make s covalen e antagon nt bond with the recceptor so as you ccannot oveercome the block o r get the maximal responser b by increas sing the ddose of the e agonist (ii.e. non-su urmountable effect). TheT occup pied recepttors are ppermanently blocked d, so the d duration off block is long, and the bodyy has to ssynthesize new recepptors to reg gain the orriginal state e. 6 Other types of drug anttagonism Che emical anttagonism: e.g. one acidic dru ug when added a to a basic drrug can causse precipita ation of ea ach other’ss Exammple: the addition of o gentamyycin (basic drug) to carpenicilli c in (acidic drug) d in the ssame syrin nge causes s chemical complex. Physsical antaagonism: antagonissm betwee en two drug gs carrying opposite charges. c Exammple: pro otamine is s used ffor treatm ment of hepa dose because protam arin overd mine carries +ve charrge while heparin h ca arries –ve charge. One O mg of prrotamine can c neutrallize 100 un nits of hepa arin. Phys siological antagonism: antaggonism be etween two drugs producing opposite effe ects by acttivation of diifferent rec ceptors. Exammple: adre enaline is the physio ological an ntagonist of o histaminne becausse while hista amine cauuses hypo otension a and bronchoconstric ction throuugh activa ation of hista amine H1 receptors,, adrenalin ne causes hypertens sion and bronchodiilatation throu ation of adrrenergic α & β recepttors respec ugh activa ctively. Pharmacokinetic antag gonism: (seee drug intteractions)). - One drug mayy prevent absorptio a on of anoth her drug e.g. antacidds ↓ absorption of iron & aspirin. - One drug maay increas se metabo olism of another a drrug e.g. ri fampicin induces i hepaatic enzymmes and ↑ metabolism m m of oral co ontraceptivve pills. - One drug mayy ↑ excretion of anoother drug e.g. NaHC CO3 causee alkalinizaation of e and ↑ exc urine cretion of acidic a drug gs like asppirin. B. ION N CHANNE ELS How drugs could modulatte ion cha annels?  Phyysical block: e.g. blocking of Na+ channels by lo ocal anesth hetics.  Thee ion chaannel mayy be parrt of the receeptor e.g. ion i channe el-linked re eceptors.  Thee ion chann nel may be modulatted by G- prottein linked receptors.  Ion channels may be modulated m by intracellular ATPP e.g. ATPPase senssitive K+ channels in the pancre eatic β cellls, rise off intracellu ular ATP ccauses clo osure of + pancreatic K channels. 7  C. ENZ ZYMES How drugs could affect enzymes?  Thee drug mayy act as a competitivve inhibito or of the enzyme e.g g. neostigmmine on cholinesterasee enzyme.  Thee drug mayy act as irrreversible inhibitor of o the enzy yme e.g. o organophos sphates on ccholinesterrase enzym me.  Thee drug mayy act as a fa alse subst rate for the e enzyme e.g. e α-metthyldopa is s a false substrate for dopa d arboxylase.. deca  Thee drug mayy induce orr inhibit hep patic microosomal enzymes acttivity (see later). D. CARRIER MO OLECULES  Theese are sm mall protein n molecule c moleculees across the cell es that carrry organic memmbrane whhen they arre too large e or too po olar.  Drug gs could affect a carrie er molecul es by bloc cking their recognitio on site. Part 2 2: Fac ctors afffecting dose-re esponse relation nship A. FAC CTORS RE ELATED TO O THE DR RUG 1. Drug g shape (s stereoisom merism): - Mosst drugss have multtiple stere eoisomers (enaantiomers) (e.g. L- thyrooxin an nd D- thyrooxin). The receptor site is usually sensitive for one sterreoisomer and not suittable for anotther, like the hand and the glo ove. This mea ans that on ne isomer mayy be hundrred times more e potent than the otheer. In other instances one isome er is benefficial while the other is toxic. - This phenomeenon may explain hhow a sin ngle drug could actt as agon nist and antaagonist (i.ee. partial agonist) a b ecause many m drugss are pressent in “ra acemic mixttures” rath her than asa pure isoomers; or how one isomer is effective and a the otheer isomer iss toxic. 8 2. Molecular weight (MW): - Most drugs have MW between 100-1000 Da. Drug particles larger than MW 1000 Da cannot be absorbed or distributed. They should be given parenterally. - Drug particles larger than MW 1000 Da cannot cross placental barrier. 3. Time of drug administration (Chronopharmacology): - Many body functions (e.g. liver metabolism, RBF, blood pressure, HR, gastric emptying time, etc.) have daily circadian rhythm. Some enzymes responsible for metabolism of drugs are active in the morning or evening. - Also many diseases (e.g. asthma attacks, myocardial infarction, etc.) are circadian phase dependent. - Chronopharmacology is the science dealing with tailoring drug medication according to the circadian rhythm of the body to get better response and/or to avoid possible side effects. - Examples: - Episodes of acute bronchial asthma are common at night due to circadian variation of cortisol and other inflammatory mediators, so it is better to give the anti-asthmatic medications in the evening. - Blood pressure is at its peak during afternoon, so it is better to give the antihypertensive medications at morning. 4. Drug cumulation: Cumulation occurs when the rate of drug administration exceeds the rate of its elimination (especially in patients with liver or renal disease). Some drugs are cumulative due to their slow rate of elimination e.g. digoxin. 5. Drug combination: Drug combination is very common in clinical practice. When two or more drugs are combined together, one of the following may occur: a) Summation or addition: - Summation means that the combined effect of two drugs is equal to the sum of their individual effects (i.e. 1+1=2). It usually occurs between drugs having the same mechanism, for example, the use of two simple analgesics together. b) Synergism and potentiation: - Synergism means that the combined effect of two drugs is greater than the sum of their individual effects (i.e. 1+1=3). The two drugs usually have different mechanisms of action, for example, the use of penicillin with aminoglycosides to exert bactericidal effect. 9  - Potentiation is similar to synergism but, in potentiation, the effect of one drug itself is greatly increased by intake of another drug without notable effect (i.e. 1+0=2), for example, Phenobarbitone has no analgesic action but it can potentiate the analgesic action of aspirin. c) Antagonism: One drug abolishes the effect of the other i.e. 1+1=0 (see before). B. FACTORS RELATED TO THE PATIENT 1. Age, sex, and weight. 2. Pathological status: Liver or kidney diseases significantly alter the response to drugs due to altered metabolism. Also the failing heart is more sensitive to digitalis than the normal heart. 3. Pharmacogenetic factors (idiosyncrasy): It is abnormal response to drugs due to genetic abnormality in drug metabolism. These are some examples: ▌Examples of heritable conditions causing EXAGGERATED drug response: a) Pseudocholinestrase deficiency: Succinylcholine is a neuromuscular blocker metabolized by pseudo- cholinestrase enzyme. Some individuals with deficient PsChE, when they take succinylcholine, severe muscle paralysis occurs due to lack of succinylcholine metabolism, and may lead to death from respiratory paralysis (succinylcholine apnea). b) Glucose-6-phosphate dehydrogenase (G6PD) deficiency: - G6PD is the most common human enzyme defect. G6PD enzyme catalyzes the reduction of NADP+ into NADPH which maintains glutathione in the RBCs in its reduced form. Reduced glutathione keeps Hb in the reduced (ferrous) form and prevent formation of methemoglobin and cell membrane injury (hemolysis) by oxidizing drugs. - Individuals with deficiency of G6PD may suffer acute hemolysis if they are exposed to oxidizing drugs e.g. nitrates, antimalarial drugs, and others. c) Thiopurine methyltransferase (TPMT) deficiency: - Thiopurine methyltransferase (TPMT) is an enzyme that methylates thiopurine anticancer drugs (e.g. 6-mercaptopurine and 6-thioguanine) into less toxic compounds. 10  - G eficiency in TPMT lea Genetic de ads to incre eased conversion of parent thiopurine d drugs into more toxic compou unds, leadiing to seveere myelottoxicity an nd bone m marrow supppression which mayy be fatal. - T TPMT defiiciency prrevalence is 1:300. Screening for TPM MT deficieency is n necessary in patients s treated byy thiopurin ne anticanc cer drugs. d) Acetylator phenotyp p es: M Many drugs are me etabolized in the liver by ac cetylation (e.g. isoniazid). Ac cetylation reaction is under g genetic co ontrol and d people ccan be classified ac ccording to o their rate e of acetyla ation into rapid r and slow acetyylators: - In n rapid ac cetylators: excessive e isoniazid toxic mettabolites aaccumulate e in the liver causin ng hepatoc cellular nec crosis. - In n slow acetylators s: isoniazzid accum mulates in p peripheral tissues causing c peeripheral neuropathy d due to inteerference with w pyrido oxine metaabolism, (so p pyridoxine “vit B6” iss added to o isoniazid therapy to p prevent neu urotoxicity y). - S Some drug gs that are metabolize ed by acettylation can c cause systtemic lupus erythem matosis-like e syndrome (S SLE) in slo ow acetylattors (see bbox). ▌Exa amples off heritable e condition ns causing g DECREA ASED drug g respons se: a) Resistance e to couma arin (warfa arin) antic coagulants s: - In n normal individuals, warfarin anticoagu ulant acts by b inhibitinng the enzzyme vit K epoxide reductase r ble for redu responsib uction of th he oxidized d vit K (inac ctive) to itts reduced d form (active). - S Some indivviduals havve another variant of this enzymme making g them nee eding 20 times the usual u dose of coumarrin to get the response. b) R Resistance e to vit D (v vit D-resisstant ricke ets): C Children witth vit D-res sistant rickkets need huge h doses s of vit D to o be treate ed. c) Re esistance e to mydria atics: Dark eyes are a genetically less re esponsive to the effect of mydrriatics. 4. Hypo oreactivity y to drugs s: (Tolera ance; tach hyphylaxiss; drug res sistance) Tolerance mean ns progressive decre ease in drug respon nse with suuccessive admin- istration. The sam me respons se could b be obtained d by highe er doses. Itt occurs ovver long period.. Tachyphy ylaxis is an acute typ pe of tolerance that occurs o verry rapidly. 11  Mechanism of tolerance:  Pharmacodynamic tolerance: may occur due to:  Receptor desensitization: prolonged exposure to the drug leads to slow conformational changes in the receptors by which the receptor shape becomes no longer fitted well with the drug.  Receptor down-regulation: prolonged exposure to the drug leads to decrease number of the functional receptors.  Exhaustion of mediators: e.g. depletion of catecholamines by amphetamine.  Pharmacokinetic tolerance:  Due to ↑ metabolic degradation of a drug by induction of hepatic enzymes e.g. with chronic administration of ethanol.  Behavioral tolerance:  It occurs by a drug independent learning of the brain how to actively overcome a certain drug-induced effect through practice e.g. with psychoactive drugs. 5. Hyperreactivity to drugs: (Rebound and withdrawal effect) Rebound effect: is recurring of symptoms in exaggerated form when a drug is suddenly stopped after a long period of administration. Mechanism: prolonged administration of the antagonist leads to up-regulation (increase number) of receptors. When the antagonist is suddenly stopped, severe reaction occurs e.g. severe tachycardia and arrhythmia occurs after sudden stopping of beta-blockers. Withdrawal effect (syndrome) is recurring of symptoms in exaggerated form plus addition of new symptoms when a drug is suddenly stopped e.g. withdrawal effects that occur after sudden stopping of opioids in opioid addicts. N.B. Some examples of drugs should not be stopped suddenly: Drug Sudden withdrawal can lead to: Beta-blockers : Severe tachycardia, arrhythmia, and even myocardial infarction. Clonidine : Severe hypertension (hypertensive crisis). Cimetidine : Severe hyperacidity and even peptic ulceration. Corticosteroids : Acute Addisonian crisis. Morphine : Withdrawal symptoms (see CNS). Warfarin : Thrombotic catastrophes 12 Part 3: Cllinical pharmac cokinetic cs Definittion: it is th he journey of the dru g inside th he body. It includes 4 processe es: Abssorption ution Distribu m Metabolism M Excreetion █ ABS SORPTION N OF DRUG GS Definittion: it is th he passage e of drug f rom the sitte of administration tto the plassma. The ma ain routes s of administration: o oral, sublin ngual, recta al, inhalatio on, injection, etc. Factorrs affectiing drug absorptio a on: A. Facttors relate ed to the drug d - Mollecular sizee: small mo olecules arre absorbe ed than large molecuules. - Dosse: absorpttion increa ases with in ncreasing the dose (up to limit)). - Drug formulattions: e.g. sustained--release ta ablets are slow s in abssorption. - Loccal effects of the drugg: e.g. druggs producing VC ↓ thheir own ab bsorption. - Drug combina v C ↑ abssorption off iron. ation: e.g. vit - Lipid solubilityy, drug ion nization, an nd the pKaa of the dru ug. B. Facttors relate ed to the absorbing a g surface: - Rouute of administration: i.v. route is the fastest while rectal r is thee slowest. - Inte egrity of the e absorbinng surface: may ↑ or ↓ absorptio on. - Loccal blood flow: ischemmia ↓ abso orption. - Speecific facto ors: e.g. ap poferritin syystem for iron, etc. The pK Ka and drug ioniz zation Princip ples - Ionized (polarr; charged d) drugs a are poorly absorbed d, while unionized (non-p polar, non--charged) drugs are e more absorbe ed. - Mosst drugs are a weak acids or b bases. Theey become e ionizzed or non--ionized ac ccording to the pH aroound them. - Acid dic drugs (e.g. ( aspirin) are morre ionized in alkaline pH and vicce versa. - Bassic drugs (ee.g. amphe etamine) a re more ionized in ac cidic pH annd vice verrsa. - pKa a of a drug g: is the pH at whic h 50% of the drug is ionized and 50% is non- ioniized. (W Where p = inverse log g; Ka = association/d dissociatio on constant). 13  Examp ple of pH variation v and a drug k kinetics with w aspirin n: Aspirin is an acid dic drug; its s pKa = 3.5 5 The pHH of the sto omach is 1.5 Th e pH of the intestine e is 8.5 ►Wheen aspirin is put in th he stomac ch:  Asppirin is acid dic drug annd become es more abbsorbable in acidic p pH.  Logg (Unionize ed /Ionized)* = pKa – pH = 3.5 – 1.5 = 2 (log ( 2 =1022 ).  Thiss means th hat the rattio of union nized: ionized = 100/1 (or accuurately 0.9 99 parts are absorbed and 0.01 parts are n non-absorbbed). ►Wheen aspirin is put in thhe intestin ne:  Asp pirin is acid dic drug annd become es less abssorbable in n alkaline p pH.  Log g (Unionize ed/Ionized)* = pKa – ppH = 3.5 – 8.5 = – 5 (log -5 =1 0–5 ).  Thiss means thhat the ratio of union nized/ionize ed = 1/1000000 (or acccurately 0.00001 0 partts are absoorbed and 0.99999 p parts are non-absorb bed). The above rule applies only to a *N.B. T acidic drugs s like aspirrin. For bassic drugs, the t ratio would b be reversed d. ►Ion ttrapping of o aspirin: In the stomach, aspirin is more abssorbable in nto stomacch cells buut once entered the cells, the pH changees from 1.5 outside to 7.4 insside the cell. So asppirin becom mes ionize ed inside tthe cells and a can’t diffuse outsside them again a → ga astric ulcer. al significa Clinica ance of pK Ka  Know wing the site of drug g absorptio on from the e GIT (see principles)).  Treaatment of drug d toxicitty: - Tooxicity witth acidic drugs d (e.g. aspirin) could be treated byy alkaliniza ation of urrine, which h renders this drug m more ionize ed in urine and less reeabsorbab ble. - Tooxicity with basic drrugs (e.g. aamphetam mine) couldd be treateed by acidiification off urine, which renderrs this drugg more ionized in urinne and lesss reabsorb bable.  Ion ttrapping in n breast milk: - Thhe pH of the t breast milk is 7 i.e. it is coonsidered acidic in rrelation to plasma (p pH 7.4). - Basic drugss (with pKa a > 7.2) ten nd to be ionized, and thus trappped, insidee breast m milk more thhan acidic c drugs; heence, the milk/plasm m a ratio (M//P ratio) would be hiigh. 14 █ DIST TRIBUTIO ON OF DRU UGS Sites o of drug disstribution  Plassma: 3 liters  Extrracellular water: w 9 liters  Intraacellular water: w 29 2 liters ▌Volum me of dis stribution n (Vd) Definittion: The apparent a volume v of water into o which the druug is distributed in the body after distrribution equilibrrium. Calcula ation: Total amount a off the drug in the body y Vd d = ————————————— —————————— ————— L Plassma conc of the drugg (after dis stribution equilibrium) e ) Clinica al significa ance:  Deteermination of the site e of drug d on e.g.: distributio - A total Vd < 5 L: means that the e drug is confined c to o the vascuular compartment an nd can be removed by b dialysiss. - A total Vd 5-15 L: mea ans that thhe drug is restricted r to t the ECF F. - A total Vd > 41 L: me eans that tthe drug is s highly bo ound to tisssue prote eins and ca annot be reemoved by y dialysis.  Calcculation of the total amount o of drug in the body y by singlee measuremment of plasma concen ntration (from the eq quation).  Calcculation off the loading dosse (LD) needed to attain a desired plasma conccentration (Cp): LD = Vdd x Cp.  Calcculation of drug cleaarance: ▌Binding of dru ugs to pla asma pro oteins  Mosst drugs wh hen introdu uced into tthe body are a bound tot plasma proteins.  Albu umin: the most m impo ortant plasmma protein n and it ca an bind –vve or +ve charged c drug gs. Clinica al significa ance:  The pharmaco ological efffect of the e drug is related only y to its fre ee part no ot to its bounnd part (th he bound part p acts o only as a re eservoir fro om which tthe drug is s slowly relea ased). 15   Bind ding of drugs to plasm ma protein ns prolong gs their effe ects.  Wheen the drugg has high h plasma p nding (e.g. 99% for warfarin), the protein bin t free part that exertts the phaarmacologiic effect is s 1%. Anyy small dissplacement of the boun nd part by another drug d (say fo or example e another1% is displlaced) can lead to drammatic toxic city (double es the amo ount of the free part in plasma)..  Man ny disease e states (e.g. chron nic liver disease, pregnancy, renal failuure) can affec ct the level of albumiin and the nature of plasma pro oteins, thuus causing serious probblems with some drugs. █▌EXC CRETION AND ELIM MINATION N OF DRUG GS ation of dru Elimina ugs may fo ollow one o of 2 proces sses (orderrs): First-ord der elimin nation Zero-order elim mination - Occcurs to mo ost drugs. - Occurs O to limited nuumber of drugs. - Connstant ratioo (%) of th he drug is - Constant C amount a off the drug is i elim minated per unit time i.e. the ratte of eliminated e per unit ti me i.e. the e rate of elim mination is proportional to plassma elimination e n is not pro oportional to conncentrationn. The higher the plasma p concentratio on. A familiar conncentrationn, the greatter the rate e of example e is s ethanol, cconcentrattions of elim mination. which w decline at a co onstant ratte of approxima a ately 15 mg g/100 mL/h h. - Elim mination do oes not deepend on - Elimination E n depends on satura able satuurable enz zyme system. enzyme e sy ystem. - Thee t1/2 of the drug is co onstant. - The T t1/2 of the drug iss not consttant. - Drug cumulation is not common c - Drug D cumu ulation is ccommon Examp ated by zerro-order: prednisolon ples of drugs elimina p ne, theophyylline. N.B. S Some drug gs are elim minated b by first-ord der elimina ation in low w doses and by zero-orrder elimination in hig gh doses e.g. aspirin and phenytoin. 16 Clinica al significa ance of ze ero-order elimina ation:  Mod dest chan nge in dru ug dose may prodduce unexxpected toxxicity.  Elim mination off drugs or attainmennt of Cpsss takes lo ong time.  Chaanges in drug form mulation may prodduce adveerse effects s.  Drug cumulattion and innteractionss are commmon. ▌Elimination half-life (t1/2) Definittion: It is the time taken forr the concen ntration of a drug in n blood to o fall half to its originall value. Calcula ation:  From m the plasm ntration ve rsus ma concen time e curve.  From m the equaation: Clinica al significa ance:  Deteermination of inter-d dosage intterval: dru ugs are giv ven every t1/2 to avo oid wide flucttuations off the peakk level (the highest plasma con ncentrationn of the drug) and trouugh level (the lowest plasma co oncentratio on).  Time e-course of drug accumulat a tion: if a drug d is started as a constant infusion, i the CCp will accuumulate to approach ssteady-statte after 4-5 5 t1/2.  Time e-course of drug elimination e n: If a drug g is stopped after aan infusion, the Cp will d decline to re each comp plete eliminaation after 4-5 t1/2.  Drug gs having long t1/2 could be give en once daily to imp prove patieent compliiance. ▌Stead dy-state plasma concentra c ation (Cps ss) Definittion: the steady le evel of d drug in plasma achieved whhen the rate of adminisstration eq quals the ra ate of elim ination. The rule of 5:  Thee Cpss is re eached aftter 4-5 t1/2. 17   If w we changedd the dose, the new CCpss is reaached afte er 4-5 t1/2.  If do osing stop ps, complete eliminattion of drug g from plasma occurrs after 4-5 5 t1/2. 18 ▌Therrapeutic drug d mon nitoring (T TDM) Definittion: monittoring of se erum drug concentra ations to optimize druug therapy y.  Serum drug samples s are a usuallyy taken wh hen the drrug has reeached the e CPSS (e.g g. at the tro ough level, just beforre the next dose).  TDM M can be done by monitoring g drug effect rather than con centration e.g. in warrfarin theraapy, TDM is a monitoring the INR (see blood s done via d). Clinica al significa ance:  To a avoid toxiicity in the e followingg situation ns: - Drugs withh a low ‘the erapeutic i ndex’ e.g. lithium, diigoxin, andd warfarin. - PPresence of disease e states (e..g. liver or renal dysffunction) thhat can afffect the d drug’s pha armacokine etics.  To improve efficacy e of drugs ha aving pharrmacokinettic problem ms e.g. ph henytoin and d other drugs with no on-linear kinetics.  Diffferentiatio en drug ressistance an on betwee nd patient non-comp pliance. ▌Clearance as a channe el of elim mination Definittion: plasm ma clearan nce of a su ubstance means m the e volume o of plasma cleared from th his substannce per min nute. Calcula ation: Clinica al significa ance of renal cleara ance: If the drug is clea ared by the kidney, cle earance caan help to determine whether th his drug is eliminated by reenal filtrattion or sec cretion: a drug d that is s eliminateed only by filtration f cannot exceed 12 27 ml/min. If clearanc ce > 127 ml/min m → th he drug is eeliminated also by tubularr secretion. Routess of eliminnation:  Kidn ney (the major m route)).  Bilee and liver.  Lunngs, intestine, milk, saliva and ssweat. Clinica al importance of kno owing the e route of eliminatio e on:  Help p to adjustt the dose to avoid c cumulation.  Avo oid drugs eliminated e by a disea ased organ n.  Targ geting theerapy: e.g g. drugs eliminatedd by the lung couuld be used as exp pectorants.. 19  █ MET TABOLISM M OF DRUGS (biotra ansformattion)  e liver is the major site of drug metabolism but The b other organs ca an also mettabolize drrugs e.g. kidney, lung gs, and adrenal gland ds.  Manny lipid soluble drugs must bee converted d into a wa ble form (p ater-solub polar) to be e excreted.  Som me drugs area not me etabolized a at all and excreted e unchanged (hard dru ugs).  Mettabolism of o drugs may m lead tto: - Conversion of activ ve drug in nto inactiv olites → terrmination of drug ve metabo effect. - Conversion of activ ve drug in nto active metabolittes → prol ongation of drug effect e.g. codeine (a active drug g) is metab bolized to morphine m ((active pro oduct). - Conversion of inactive drug in nto active metabolites (prodru ugs) e.g. enalapril e (inactive drug) is mettabolized tto enalaprilat (active metabolitee). - Conversion of non--toxic dru ug into toxxic metab bolites (e.g g. paracetamol is converted into the to oxic produ ct N-acety ylbenzoquinone). Bioch hemical reactions r s involve ed in dru ug metab bolism The drug must enter e phasse I of che emical rea actions be excreted as water--soluble compoound. If thee drug is not n liable tto convers sion into water-solub w ble compo ound by phase I, it must enter e phase II to incrrease solub bility and enhance e el imination. ▌Phas se I reac ctions - Pha ase I reactions include oxidation, duction, an red nd hydroly ysis. - Enzzymes cataalyzing pha ase I react ions includ de cyto ochrome P450, ald dehyde a and alcoh hol deh hydrogenasse, deam minases, esterase es, amiidases, and d epoxide hydratase es. - Thee majority of phase I reactionss is done by b the cytochro ome P450 (CYP45 50) enzym me systtem locate ed primarily inside mmembranou us vesicles (micrrosomes) on o the surrface of th he smo ooth endoplasmiic retic culum of pareenchymal liver cells s. CYP450 0 activity is also o present in otherr tissue e e.g. kidneey, testtis, ovariess and GIT. 20 - Although this class has more than 50 enzymes, six of them metabolize 90% of drugs. The most important subfamily is CYP3A4 which is responsible for metabolism of over 50% of drugs. - Genetic polymorphism of several clinically important CYP450 enzymes is a source of variability of drug metabolism in humans. - Drugs may be metabolized by only one CYP450 enzyme (e.g. metoprolol by CYP2D6) or by multiple enzymes (e.g. warfarin). - Some drugs and environmental substances can induce (increase activity) or inhibit certain CYP450 enzymes leading to significant drug interactions. - Other examples of non-microsomal oxidation include xanthine oxidase (converts xanthine to uric acid) and monoamine oxidase (MAO) (oxidizes catecholamines and serotonin). Only the microsomal enzymes are subjected to induction or inhibition by drugs. Microsomal enzyme induction Microsomal enzyme inhibition  Microsomal inducers ↑ rate of  Microsomal inhibitors ↓ rate of metabolism of some drugs leading to metabolism of some drugs leading to ↓ their serum levels and therapeutic ↑ their serum levels and toxicity. failure.  Enzyme inhibition can occur after  Induction usually requires prolonged short period of exposure to the exposure to the inducing drug. inhibiting drug.  Examples of inducing agents:  Examples of inhibiting agents: phenytoin, phenobarbitone, macrolide antibiotics (e.g. carbamazepine, rifampicin, smoking, erythromycin), ciprofloxacin, chronic alcohol intake, St John's cimetidine, ketoconazole, ritonavir, Wort, grapefruit juice.  Clinical examples:  Clinical examples: - Rifampicin accelerates metabolism of - Ciprofloxacin inhibits metabolism of contraceptive pills leading to failure of warfarin (anticoagulant) leading to contraception. accumulation of warfarin and - Phenytoin accelerates metabolism of bleeding. cyclosporine-A leading to graft - Erythromycin inhibits metabolism of rejection. theophylline leading to toxicity of theophylline (cardiac arrhythmia). ▌Phase II reactions (conjugation) - It involve coupling of a drug or its metabolite to water-soluble substrate (usually glucuronic acid) to form water-soluble conjugate. - Glucuronyl transferase is a set of enzymes that is responsible for the majority of phase II reactions. This set of enzymes is also located inside liver 21  miccrosomes and is the e only phasse II reactio on that is inducible b by drugs and a is a posssible site of drug in nteractionss e.g. phen nobarbital induces gglucuronida ation of thyrroid hormoone and reduces theiir plasma levels. - Som me glucuroonide conjjugates seecreted in bile can be b hydrolyyzed by in ntestinal bac cteria and the free drug d can bbe reabsorbed again (enteroheepatic circu ulation), thiss can exten nd the actio on of somee drugs. - Oth her examples of non njugation reactions include sulphate n-glucuro unide con s con njugation (steroids), glycine conjugatio on (salicylic acid), and gluttathione con njugation (e ethacrynic acid). ▌Firstt-pass me etabolism stemic elimination m (pre-sys n) Definittion: metaabolism off drugs a at the sitee of administration before re eaching system he liver aft er oral administratio mic circulattion e.g. th on, the lung g after inh halation, the skin n after topical adminnistration, e etc. Hepatiic first-pas ss metabo olism:  Com mplete: lido ocaine.  Parttial: propraanolol, morphine, nitro oglycerine  Non ne: atenolo ol and mon nonitrates How to o avoid? - By iincreasing the dose of the drugg. - By ggiving the drug throu ugh other rroutes e.g. sublingua al, inhalatio on, or i.v. ▌Bioav vailability y Definittion: it is the t fraction of the d drug becom me availab ble for sysstemic effe ect after adminisstration. The bioavailability of d drugs given i.v. is 100%. 22 Factors affecting bioavailability:  Factors affecting absorption.  Factors affecting metabolism.  First-pass metabolism. Part 4: Adverse drug reactions (ADR) An ADR is any response to a drug which is noxious, unintended, and occurs at doses used in man for prophylaxis, diagnosis or therapy. Predisposing factors:  Multiple drug therapy.  Extremes of age: due to age related changes in pharmacokinetics and dynamics.  Associated disease: e.g. impaired renal or hepatic function.  Genetics: can affect the pharmacokinetics. Classification: ▌Type A (Augmented): These reactions are predictable from the known pharmacology of the drug. They may result from an exaggerated response (e.g. hypotension from an antihypertensive) or non-specificity (e.g. anticholinergic effects with tricyclic antidepressants). Prevention  Take a careful history for predisposing factors.  Use the smallest dose of the drug adequate for the desired effect.  Adjust dosage to therapeutic end-points, e.g. blood pressure or INR.  Adjust dosage to optimum plasma concentrations, e.g. digoxin.  Adjust dosage in relation to renal function, hepatic function, or other drugs. ▌Type B (Bizarre): These are less common, less predictable, and may be severe. Examples are:  Immunologic: penicillin allergy  Genetic: haemolysis in G6PD deficiency  Disease: amoxycillin rash in glandular fever  Idiosyncratic: malignant hyperpyrexia in anesthesia. Prevention  Take a careful drug history, especially of allergies 23   Fam mily historyy: allergies or genetic c disease  Avo oid drugs susceptibl s e to ADRss in particular diseas se states, e.g. cloza apine in bon ne marrow depressio on. Type A (Augmen nted) Ty ype B (Biz zarre) - Pred dictable - Unpredictable - Dosee-dependeent - Dose-independent - High h incidence e - Low incid dence - Mayy respond to t dose ad djustment - Generally y need to sstop the drrug █ Drug g-induced d liver injjury (DILII) DILI ac ccounts forr up to 10% % of all advverse drug g reactionss and may be fatal. It may be classifie ed into:  Acccording to time courrse: acute or chronic.  Acccording to mechanis sm: dose-d dependentt, idiosynchhratic, or im mmune me ediated  Acccording to histologic g: hepatoce cal finding ellular, cho olestatic, o r mixed picture. Hepato ocellular (cytotoxic) ( ) DILI Cholestatic C c DILI Featurres: Features: F  The e drug or its metaboliites affectss  The drug or its meetabolites affect a pareenchymal liver cells leading l to the bilia ary canalicuuli leading to cell necrosis and a initiatioon of narrowin ng or dest ruction of biliary infla ammatory process. passage es.  It m may be spo otty, zonal, or diffuse..  Clinically it resemb bles obstruuctive  Clinnically it ressembles viral hepatittis jaundice e with prurritus and ↑ALP. A withh ↑ ALT and AST. Commmon drugs:: Common C drugs: d Parace etamol – methyldopa – Chloroprom C mazine – suulfonylureaas – amioda arone – iso oniazid – va alproic acid d oral o contrac ceptive pil ls – anabo olic steroids s – macrolides m s – co-amo oxiclav 24 █ ADR on pregnancy Key facts:  Fetal birth defects represent 2-3% of all births, the majority of which are related do drugs.  Some fetal defects may be impossible to identify, or can be delayed e.g. the use of diethylstilbesterol (estrogenic compound) during pregnancy is associated with development of adenocarcinoma of girls’ vagina at teen age.  Three factors determine the risk of teratogenicity: dose of the drug; duration of administration; and stage of pregnancy.  Most drugs with a MW Risk There is evidence of human fetal risk, but   D the potential benefit of the drug may outweigh its potential risk. Benefit > Risk Studies in animals and humans showed   evidence of fetal risk. The potential risk of X use in pregnant women clearly outweighs Risk > Benefit any potential benefit. Part 5: Principles of drug-drug interactions Classification: Pharmacokinetics interactions. Pharmacodynamic interactions. █ PHARMACOKINETIC INTERACTIONS Drug interactions in vitro: e.g. antipseudomonal penicillins and aminoglycosides form complexes in the infusion fluid (see chemotherapy). 26 Drug interactions in vivo: Absorption  Formation of complexes: - Tetracycline forms complexes with Ca2+, Mg2+ and Al3+ - Cholestyramine forms complexes with digitalis and thyroxin.  Absorption can be blocked: - Adrenaline ↓ absorption of local anesthetics due to VC. - Colchicine ↓ absorption of vitamin B12  Change in intestinal motility: - Anticholinergic drugs ↓intestinal motility → ↑ absorption of some drugs. - Prokinetic drugs ↑ intestinal motility → ↓ absorption of some drugs.  Changes in gastric pH: - Antacids ↓absorption of salicylates. - Ketoconazole is poorly absorbed in absence of gastric acidity. Distribution - Sulfonamides displace bilirubin from pl pr in premature infants → kernicterus. - Phenylbutazone displaces warfarin → excessive bleeding. Metabolism - Inhibition or induction of microsomal metabolism (see before). - Inhibition of non-microsomal enzymes: - MAO inhibitors ↓ metabolism of some drugs e.g. benzodiazepines, serotonin and norepinephrine. - Disulfiram inhibits acetaldehyde dehydrogenase enzyme → ↓ metabolism of acetaldehyde → accumulation of acetaldehyde causes flushing, nausea, vomiting, and tachycardia. Excretion  Reduction in urinary elimination: - Probenecid ↓ renal excretion of penicillin. - Quinidine ↓ renal excretion of digoxin.  Changes in urinary pH: - Alkalinization of urine (e.g. sodium bicarbonate) ↑ excretion of weak acids - Acidification of urine (e.g. ammonium chloride) ↑ excretion of weak bases. 27   Changes in urinary volume: Diuretics can increase toxicity of some drugs by reducing plasma volume e.g. thiazide can increase lithium toxicity.  Stimulation of biliary excretion: Phenobarbital ↑ biliary excretion of many drugs by increasing both bile flow and the synthesis of conjugating proteins. ██ PHARMACODYNAMIC INTERACTIONS  Antagonism: competitive, non-competitive, chemical, physical, etc.  Synergism: e.g. MAO inhibitors can cause toxic synergism with TCA.  Potentiation: e.g. ethanol can enhance CNS depression caused by opioids  Changes in the intracellular or extracellular environment: e.g. diuretic- induced hypokalemia can ↑ digitalis toxicity. 28 29 30 Review Questions Define the following pharmacokinetic parameters:  Volume of distribution  pKa of drugs  Elimination half life  First-pass metabolism  Bioavailability Mention the clinical significance of each of the following:  Volume of distribution  pKa of drugs  Plasma protein binding of drugs  Elimination half-life  Zero-order elimination  Microsomal enzyme induction  Hepatic conjugation of drugs Mention the main differences between:  Reversible and irreversible antagonism.  Graded response and quantal response.  First order elimination and zero order elimination.  Potency and efficacy.  Physical and physiological antagonism.  Habituation and addiction.  Oxidation and conjugation of drugs. Discuss 2 pharmacogenetic conditions associated with toxic drug response Discuss 2 pharmacogenetic conditions associated with reduced drug response Write short account on antagonism between drugs 31  Of each of the following questions, D. Sex hormones act on these types of select ONE BEST answer: receptors E. Corticosteroids act on these types of 1. A drug may act by all the following receptors mechanisms EXCEPT: A. Interaction with protein 5. The following statements are true macromolecules embedded in the cell for graded dose-response relationship membranes EXCEPT: B. Interaction with cell membrane ion A. It is the response to most drugs channels B. The response is directly proportional C. Interaction with intracellular enzymes to drug concentration (linear relation) D. Interaction with cell membrane C. It could be tested in one animal phospholipids D. It can be used for comparing the E. Interaction