1. Introduction to pharmacology. Basic terminology. Prof. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague Cycle II, Subject: General Pharmacology Charles University in Prague, Third Faculty of Medicine 1st Teaching Unit ID9234

2. PHARMACOLOGY Searches for new drugs Investigates effects of known drugs WHAT IS PHARMACOLOGY ? pharmacologists are drug hunters mechanism of action, evidence of effect, adverse reactions,, fate in the body (absorption, distribution, elimination), dosage, course of effect …

3. Pharmacy deals with the preparation (compounding, manufacture), distribution and supply of medicines PHARMACOLOGY x PHARMACY Pharmacology is the study of effects of drugs (chemicals) on the functioning of the body

4. THE AIM OF TEACHING PHARMACOLOGY 1/ To UNDERSTAND how drugs act (mechanism of action) and general pharmacological principles 2/ To know how to prescribe a drug

5. Recommended textbook: PHARMACOLOGY - Rang H. P., et al. 7th ed. Churchill Livingstone, 2011, 2012 or 6th ed 2007. https://is.cuni.cz/studium/eng/predmety

6. Alternative Textbooks Basic & clinical pharmacology -. Katzung BG - 11th ed. - Lange Medi. Books - McGraw-Hill 2009 or 12th ed. 2012 Lippincott‘s Illustrated Reviews Pharmacology. 4th ed. Howland RD, et al. : 2008 or 5th ed. Harvey R.D. et al. 2012 https://is.cuni.cz/studium/eng/predmety

7. Additional texts for suplementary reading: Medical Pharmacology at a Glance - M. J. Neal. 6th ed. Wiley-Blackwell, 2009 Pharmacology Condensed Dale NN, Haylett DG, 2nd ed., Churchill Livingstone, 2009 British National Formulary No. 62 [or higher] - BMJ Books, September 2011[or more recent editions]. https://is.cuni.cz/studium/eng/predmety

8. BASIC TERMS: generic namesx trade names paracetamol xPANADOL, PARALEN, etc SPC = Summary of Product Characteristics ATC = Anatomical Therapeutic Chemical (ATC) Classification of drugs BNF, AISLP, Micromedex = electronic drug databases generic drug =copies when patent expires compliance= adherence to a treatment plan [non-proprietary] (brand, proprietary)

9. paracetamol Proprietary Names Martindale 222 AF (Johnson & Johnson, Canad.),4-Way Cold Tablets (Bristol-Myers Products, USA),Abajos (Nufarindo, Indon.),Abatem (Wermar, Mex.),Abdine Cold Relief (Bell, UK),Abenol (Pendopharm, Canad.),Abflex (Xeragen, S.Afr.),Abrol (Rekah, Israel),Abrolet (Rekah, Israel),Acamol (Teva, Israel),Acamol (Volta, Chile),Acamol Compuesto (Volta, Chile),Acamoli (Teva, Israel),Acamoli Cold (Teva, Israel),Acamol Tsinun Day (Teva, Israel),Acamol Tsinun Night (Teva, Israel),Acecat (Tiedra, Spain),Acenol (Galena, Pol.),Acephen (G & W, USA),Acertol (Lacer, Spain),Acet (Euro-Med, Philipp.),Acet (Pharmascience, Canad.),Acet (Pharmascience, Malaysia),Acet (Pharmascience, Singapore),Acet-2, Acet-3 (Pharmascience, Canad.),Aceta (Century, USA),Acetab (Romilo, Canad.),Acetaco (Legere, USA),Acetacol (PP Lab, Thai.),Acetadol (Medi-Rx, Philipp.),Acetafen (Infinity, Venez.),Acetafen (Rayere, Mex.),Aceta-Gesic (Rugby, USA),Acetalgine (Streuli, Switz.),Acetalis (Proula, Venez.),Acetamil (Ducto, Braz.),Acetaminophen, Aspirin, and Caffeine Tablets USP 32,Acetaminophen, Chlorpheniramine Maleate, and Dextromethorphan Hydrobromide Tablets USP 32,Acetaminophen, Dextromethorphan Hydrobromide, Doxylamine Succinate, and Pseudoephedrine Hydrochloride Oral Solution USP 32,Acetaminophen, Diphenhydramine Hydrochloride, and Pseudoephedrine Hydrochloride Tablets USP 32,Acetaminophen and Aspirin Tablets USP 32,Acetaminophen and Caffeine Tablets USP 32,Acetaminophen and Codeine Phosphate Capsules USP 32,Acetaminophen and Codeine Phosphate Oral Solution USP 32,Acetaminophen and Codeine Phosphate Oral Suspension USP 32,Acetaminophen and Codeine Phosphate Tablets USP 32,Acetaminophen and Diphenhydramine Citrate Tablets USP 32,Acetaminophen and Pseudoephedrine Hydrochloride Tablets USP 32,Acetaminophen Capsules USP 32,Acetaminophen Extended-Release Tablets USP 32,Acetaminophen for Effervescent Oral Solution USP 32,Acetaminophen Oral Solution USP 32,Acetaminophen Oral Suspension USP 32,Acetaminophen Suppositories USP 32,Acetaminophen Tablets USP 32,Acetaminophen with Codeine (Pharmascience, Canad.),Acetamol (Abiogen, Ital.),Acetamol (Bergamo, Braz.),Aceta-P (PP Lab, Thai.),Acetapon (Pharmagen, S.Afr.),Acetapyrin-C (PP Lab, Thai.),Acetasil (Silom, Thai.),Aceta with Codeine (Century, USA),Acetazone Forte (Rougier, Canad.),Acetazone Forte C8 (Rougier, Canad.),Acet Codeine (Pharmascience, Canad.),Acetif (Novag, Mex.),Acetofen (Medley, Braz.),Acetolit (Mertens, Arg.),Aceval (Valmor, Venez.),Ac-Fast (Hormona, Mex.),Acide acetylsalicylique comp. "Radix" (Streuli, Switz.),Acid-X (BDI, USA),Acifein (Herbacos, Cz.),Aclophen (Nutripharm, USA),Actidue (Pfizer Consumer, Ital.),Actifed (Pfizer Sante, Fr.),Actifed-A (Wellcome, Canad.),Actifed Cold & Fever (GSK, S.Afr.),Actifed Cold & Sinus (Warner- Lambert, USA),Actifed jour et nuit (Pfizer Sante, Fr.),Actifed Plus (GSK, India),Actifed Plus (Pfizer Consumer, Canad.),Actifed Plus (Wellcome, USA),Actifed Sinus Daytime (Wellcome, USA),Actifed Sinus Nighttime (Wellcome, USA),Actiflu Plus (Cipla, India),Actigesic (GSK, Indon.),Actigrip (Pfizer Consumer, Ital.),Actimol (Pharmed, India),Actron (Bayer, Fr.),Actron (Bayer, Spain),Actron (Bayer, UK),Actron Compuesto (Bayer, Spain),Acuflu P (Apotex, S.Afr.),Acugesil (Apotex, S.Afr.),Acurate (Apotex, S.Afr.),Acustop (Apotex, S.Afr.),Acuten (Farma, Venez.),Acxen (Loren, Mex.),Adafen (Akdeniz, Turk.),Adalgen (Andromaco, Chile),Adalgur (Teofarma, Spain),Adalgur N (Angelini, Port.),Adco-Dol (Adcock Ingram, S.Afr.),Adco-Flupain (Adcock Ingram, S.Afr.),Adco-Kiddipayne (Adcock Ingram, S.Afr.),Adco- Payne (Adcock Ingram, S.Afr.),Adco-Sinal Co (Adcock Ingram, S.Afr.),Ado C (Kwizda, Austria),Adol (Julphar, UAE),Adol Allergy Sinus (Julphar, UAE),Adol Cold (Julphar, UAE),Adol Compound (Julphar, UAE),Adolef (Biomed, Ital.),Adolen (Konsuma, Venez.),Adol Extra (Julphar, UAE),Adolorin (Kwizda, Austria),Adol PM (Julphar, UAE),Adol Sinus (Julphar, UAE),Adoluron CC (Kwizda, Austria),Adona (Silesia, Chile),Aeknil (Therapeutic, Philipp.),AF Anacin (Whitehall-Robins, Canad.),Afebrin (Konimex, Indon.),Afebrin (Westmont, Hong Kong),Afebryl (Azevedos, Port.),Afebryl (Galephar, Fr.),Afebryl (Galepharma, Turk.),Afebryl (SMB, Belg.),Aferadol (Oberlin, Fr.),A-ferin (Bilim, Turk.),A-ferin (Bilim, Turk.),A-ferin (Bilim, Turk.),A-ferin (Bilim, Turk.),Afluvit (IPS, Neth.),Agrip (Plata, Arg.),Agrippin (Bernofarm, Indon.),Agurin (Nolver, Venez.),Akindol (Fournier, Fr.),Akindol (Fournier, Spain),Aknil (Sunthi Sepuri, Indon.),Alacetan (Asconex, Ger.),Alaxan (United Laboratories, Philipp.),Alaxan PI (Great Eastern, Thai.; Therapharma, Thai.),AlbaTemp (Alba, USA),Alcinal Plus (Rekah, Israel),Aldolor (CTI, Israel),Alergical Expect (Juventus, Spain),Alerid Cold (Cipla, India),Alex (Glenmark, India),Alex-P (Glenmark, India),Algafan (Darrow, Braz.),Algi-Butazolon (Dovalle, Braz.),Algi-Butazolon (Dovalle, Braz.),Algicler (Monserrat, Arg.),Algi-Danilon (Allergan-Frumtost, Braz.),Algidol (Almirall, Spain),Algidol (Sintesa, Belg.),Algifen (Sintofarma, Braz.),Algifene (Ferraz, Lynce, Port.),Algiflamanil (Neo Quimica, Braz.),Algi-Itamanil (Neo Quimica, Braz.),Algik (Azevedos, Port.),Algine (Adelco, Gr.),Alginflan (Teuto, Braz.),Alginina (Upsamedica, Spain),Algion (Saval, Chile),Algio-Truxa (Raffo, Arg.),Algi Peralgin (Infabra, Braz.),Algi-Reumac (Windson, Braz.),Algi-Reumatril (Hertz, Braz.),Algiseda (Sanitas, Arg.),Algisedal (Viatris, Fr.),Algisin (Ram, USA),Algist (Hoechst Marion Roussel, S.Afr.),Algi-Tanderil (Klinger, Braz.),Algitrin (Schering-Plough, Mex.),Algizolin (Luper, Braz.),Algoced (Pharmascience, Fr.),Algocod (SMB, Belg.),Algofina (Sanamed, Austria),Algogen (Nakornpatana, Thai.),Algolysin (Teva, Israel),Algomen (Menarini, Spain),Algon (Lavipharm, Gr.),Algophene (SMB, Belg.),Algopirina (Medisint, Ital.),Algostadol N (Stada, Ger.),Algostase (SMB, Belg.),Algostase Mono (SMB, Belg.),Algotropyl (Alpharma, Fr.),Alikal Dolor (GSK, Arg.),Alipal Forte (Arex, Venez.),Alivax (Vivax, Venez.),Alivet (Leti, Venez.),Alivet Dia (Leti, Venez.),Alivetforte (Leti, Venez.),Alivetnoc (Leti, Venez.),Aljil (Yeni, Turk.),Alka-Seltzer Advanced Formula (Miles Consumer Healthcare, USA),Alka-Seltzer Plus Cold (Miles Consumer Healthcare, USA),Alka-Seltzer Plus Cold & Cough (Bayer Consumer, USA),Alka-Seltzer Plus Cold & Cough (Miles Consumer Healthcare, USA),Alka-Seltzer Plus Day & Night Cold (Bayer Consumer, USA),Alka-Seltzer Plus Day & Night Cold (Bayer Consumer, USA),Alka-Seltzer Plus Day Cold (Bayer, USA),Alka-Seltzer Plus Day Non-Drowsy Cold (Bayer Consumer, USA),Alka-Seltzer Plus Night Cold (Bayer Consumer, USA),Alka-Seltzer Plus Night-Time Cold (Miles Consumer Healthcare, USA),Alka-Seltzer Plus Nose & Throat (Bayer, USA),Alka-Seltzer Plus Original Cold Formula (Bayer Consumer, USA),Alka-Seltzer Plus Regular Seltzer Multi-Symptom Cold Relief (Bayer, USA),Alka-Seltzer Plus Sinus (Bayer Consumer, USA),Alka-Seltzer XS (Bayer Consumer, UK),Alkasol-P (Stadmed, India),Alka XS Go (Bayer Consumer, UK),Allerest Allergy & Sinus Relief (Heritage Consumer, USA),Allerest Headache Strength (Ciba, USA),Allerest Sinus Pain Formula (Ciba, USA),Allergy Sinus (Vita Health, Canad.),All-Nite Cold Formula (Major, USA),Almigripe (Jaba, Port.),Alpara (Molex Ayus, Indon.),Alphamol (Molex Ayus, Indon.),Alpirex (Berman, Mex.),Alres (Elmor, Venez.),Alsiphene (Alsi, Canad.),Alsogil (Also, Ital.),Alsogil (Also, Ital.),Alumadrine (Fleming, USA),Alvedon (Astra, Norw.),Alvedon (AstraZeneca,

12. week Teach. Unit No. LECTURES Teach.Unit No. PRACTICALS 1. ID92 34 Introduction to pharmacology. Principles of pharmacokinetics M. Kršiak 2. ID9238 Basic terminology in pharmacology. Organization of teaching and testing. Basics of drug prescription M. Šustková 2. 3. ID92 31 Autonomic pharmacology – sympathetic system. M. Šustková 4. ID9252 QUIZ - Basics of pharmacokinetics Pharmacokinetics, single and repeated dose administration, changes in disease states - computer simulations P. Potměšil 3. 5. ID92 45 Autonomic pharmacology – parasympathetic system. P.Potměšil 6. ID9246 QUIZ - Autonomic pharmacology – sympathetic systém Alfa/beta agonists, antagonists, catecholamines. Case study, drug prescription. T. Celtová GENERAL PHARMACOLOGY Syllabus 2013/2014 https://is.cuni.cz/studium/eng/predmety

13. Conditions for credits & examination in General Pharmacology (in 2013-2014) credit > at least 80% attendance of practicals and success in 4 interim tests during semester : 1st TEST for credit - PHARMACODYNAMICS I (Pharmacology of autonomic nervous systém) - Teaching Unit (TU) 3, 5,6,8)- 5th week of the semester 2nd TEST for credit - PHARMACOKINETICS (basic principles, biotransformation and elimination of DRUGS, TU drugs TU 1,4,7,10) - 7th week of the semester 3rd TEST for credit PHARMACODYNAMICS II ( pharmacology of selected receptors, ion channels, enzymes and regulatory systems - TU 9, 11-16, 18)- 10th week of the semester 4th TEST fro credit - DRUG PRESCRIPTION - 13th week of the semester https://is.cuni.cz/studium/eng/predmety

14. Examination: final test (general pharmacology) Examination will be in a form of final multiple-choice test Terms of exam (Final tests): Jan 23, 2014 - 15:30 Jan 30, 2014 - 10:00 Feb 6, 2014 - 10:00 Feb 13, 2014 - 10:00 In case of failure, a student will have a possibility of another test (2nd test). In case of failure in the 2nd test, a 3rd test will be possible as the last chance. https://is.cuni.cz/studium/eng/predmety

15. Basic terminology in pharmacology Principles of pharmacokinetics Autonomic pharmacology - sympathetic system. Autonomic pharmacology - parasympathetic system. Biotransformation and elimination of drugs, drug interactions. Drugs acting by inhibition of enzymes Drugs acting via ion channels and transporters Principles of pharmacologic blood pressure control Drug and remedy addiction Biological therapy, gene therapy, pharmacogenetics Drug discovery and development. Preclinical and clinical trials. EBM. Placebo. Adverse drug reactions. Regulatory agencies (EMA etc). Pharmacovigilance. Pharmacoeconomics. Complementary and Alternative Medicine (CAM), homeopathy Principles of toxikology - intoxications, termination of drug effect. The questions (in a multiple choice form) of the final test will be stemming from the following topics: https://is.cuni.cz/studium/eng/predmety

16. Principles of pharmacokinetics Prof. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague Cycle II, Subject: General pharmacology Charles University in Prague, Third Faculty of Medicine 1st Teaching Unit ID9234

17. 1. Fate of drugs in the body 1.1 absorption 1.2 distribution - volume of distribution 1.3 elimination - clearance 2. The half-life and its uses 3. The uses of the half-life 4. Plasma concentration-effect relationship M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague, 2008

18. ABSORPTION DISTRIBUTION ELIMINATION FATE OF DRUGS IN THE BODY ADMINISTERED ABSORBED „HIDDEN“ ELIMINATED ACTING WHAT HAPPENS TO DRUGS INSIDE THE BODY

19. 1.1 ABSORPTION Depends on: lipid solubility ionization (depends on pH) non-ionized (non-polar), local changes in the pH routes of administration - per os - presystemic elimination FIRST-PASS EFFECT - pharmaceutical technology BIOAVAILABILITY, bioequivalence - parenteral

20. FIRST-PASS EFFECT: loss of a drug by a metabolism mostly in the liver that occurs en route from the gut lumen to the systemic circulation e.g. in nitroglycerin, morphine

21. Clinical consequence of the first-pass effect: limited effect after oral administration great interindividual differences in dosage

22. BIOAVAILABILITY: the proportion of drug that reaches the systemic circulation It is usually calculated from the AUC (Area Under the Curve)

23. ABSORPTION DISTRIBUTION ELIMINATION FATE OF DRUGS IN THE BODY ADMINISTERED ABSORBED „HIDDEN“ ELIMINATED ACTING WHAT HAPPENS TO DRUGS INSIDE THE BODY

24. - membrane penetration - protein binding -plasma proteins -tissue proteins ONLY A FREE DRUG ACTS! The bound drug is inactive. Free and bound drug are in equilibrium. Displacement: drug-drug interactions 1.2 DISTRIBUTION Depends on:

25. ABSORPTION DISTRIBUTION ELIMINATION FATE OF DRUGS IN THE BODY ADMINISTERED ABSORBED „HIDDEN“ ELIMINATED ACTING WHAT HAPPENS TO DRUGS INSIDE THE BODY

26. 1.3 ELIMINATION: METABOLIC (biotransformation) mostly in the liver ENZYME INDUCTION/ INHIBITION oxidase enzymes - cytochrom P450 (CYP2D6 etc) GENETIC POLYMORPHISM EXCRETION kidneys metabolites or unchanged (almost completely unchanged e.g. digoxin, gentamycin) GIT... enterohepatic circulation e.g. tetracyclines

27. ABSORPTION depends on - membrane penetration which depends on -lipid solubility - ionization (depends on pH) - routes of administration DISTRIBUTION depends on: ELIMINATION ONLY A FREE DRUG ACTS! FIRST-PASS EFFECT BIOAVAILABILITY - membrane penetration - protein binding - metabolic - excretion FATE OF DRUGS IN THE BODY ADMINISTERED ABSORBED „HIDDEN“ ELIMINATED ACTING WHAT HAPPENS TO DRUGS INSIDE THE BODY

28. protein binding -plasma proteins -tissue proteins ONLY A FREE DRUG ACTS! The bound drug is inactive. Free and bound drug are in equilibrium. Displacement: drug-drug interactions VOLUME OF DISTRIBUTION Depends on:

29. Because the result of the calculation may be a volume greater than that of the body, it is an APPARENT (imaginary, not actual) volume For example, V d of digoxin is about 645 liters for a 70 kg man (i.e. about 9 times bigger than his actual volume) VOLUME OF DISTRIBUTION V d = Amount of drug in body / Concentration of drug in plasma

30. Clinical importance of volume of distribution: When V d of a drug is big it takes long time to achieve effective plasma concentration of the drug. In such cases a loading dose may be given to boost the amount of drug in the body to the required level. This is followed by administration of lower maintenance dose.

31. METABOLIC (biotransformation) mostly in the liver the drug is made more hydrophilic – this increases its excretion in the urine EXCRETION mostly by the kidneys metabolites or unchanged GIT... enterohepatic circulation e.g. tetracyclines

32. CLEARANCE Clearance (CL) is the volume of plasma totally cleared of drug in unit of time (ml/min/kg) CL tot total CL R renal CL H hepatic CL NR nonrenal (= Cl tot - CL R )

33. Bathtube in a hotel with two holes, no plugs, and a plate indicating Vd= 1000 L, CL = 100 mL/min How would you regulate supply of water (water tap) to fill the bath in order to take a bath soon and for a longer time? Example – analogy for utilization of information on volume of distribution (Vd) and clearance (CL):

34. the half-life is the time taken for the plasma concentration to fall by half [plasmatic half-life]

35. Linear kinetics (First order) [t 1/2 is stable] In most drugs after therapeutic doses: plasma concentration falls exponentially The rate of elimination is proportional to the concentration

36. In most drugs after therapeutic doses: plasma concentration falls exponentially because elimination processes are not saturated [some robustness to dose increase ] Elimination is the bigger the higher is the level C max C min Linear kinetics (First order) The rate of elimination is proportional to the concentration

37. Elimination processes are saturated e.g. in alcohol, after higher doses of phenytoin, theophyllin [unstable t 1/2 ] Non-linear (Zero-order, saturation) kinetics For example, in alcohol the rate of metabolism remains the same at about 1 g of alcohol for 10 kg of body weight per hour The rate of elimination is constant

38. In a few drugs at therapeutic doses or in poisoning, elimination processes are saturated elimination is constant, limited C max C min Non-linear (Zero-order, saturation) kinetics [low robustness to dose increase]

40. T 1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half-lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

41. [t 1/2 = 1 - 2 h] Ampicillin - single dose

42. T 1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is accumulated if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half- lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes) THE USES OF THE HALF-LIFE

43. „PRINCIPLE OF 4-5 HALF-LIFES“: If a drug is administered in intervals shorter than 1.4 half-life, then a steady state is attained after approximately 4-5 half-lifes The time to attain the steady state is independent of dose. Steady state t 1/2 Plasma concentration

44. Attainment of steady state (SS) during multiple dosing of drug at intervals of 1 half-life Why SS is attained after 4-5 half-lifes?

45. T 1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half-lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes) THE USES OF THE HALF-LIFE

46. Elimination of a drug during 5 half-lifes of initial level % of total elimination

47. TIME TO STEADY STATE ( attained after 4-5 half-lifes) independen of dose FLUCTUATIONS proportional to dose intervals blunted by slow absorption STEADY-STATE LEVELS (CONCENTRATIONS) proportional to dose t 1/2 REPEATED ADMINISTRATION OF DRUGS

48. Steady-state concentrations are proportional to dose Linear kinetics - diazepam plasma concentrations daily Time (days) toxic therapeutic

49. Time (days) therapeutic toxic plasma concentrations Non-linear, saturation kinetics - phenytoin daily

50. TIME TO STEADY STATE ( attained after 4-5 half-lifes) independen of dose FLUCTUATIONS proportional to dose intervals blunted by slow absorption STEADY-STATE LEVELS (CONCENTRATIONS) proportional to dose t 1/2 REPEATED ADMINISTRATION OF DRUGS

51. How to reduce fluctuations in drug concentrations? by administering drugs slowly, continually, e.g.: slow i.v. injection, infusion, sustained–release (SR) tablets, slow release from depots (e.g. from patches transdermally, depot antipsychotics injected i.m.) by administering a total dose (e.g. a daily dose) in parts at shorter intervals (mostly inconvenient) or

52. Effects of drug correlate with plasma concentrations Therapeutic Drug Monitoring (TDM) (eg. gentamicin, lithium, some antiepileptics) do not correlate with plasma concentrations - „hit and run“ - tolerance or sensitisation - active metabolites

53. The *.ppt set of this lecture will appear at: http://vyuka.lf3.cuni.cz 1st Teaching Unit (ID9234)