5

C U P R I N S

Prefa la ediia I................................................................................................................17 Prefa la ediia a II-a ........................................................................................................19

1. FARMACOLOGIE GENERAL. NOIUNI INTRODUCTIVE.............................21 1.1. Ramurile farmacologiei.........................................................................................21

1.1.1. Ramurile principale........................................................................................21 1.1.2. Alte ramuri n dezvoltare ...............................................................................22

1.2. tiine de grani cu farmacologia .......................................................................23 1.3. Utilitatea practic a farmacologiei .......................................................................23 1.4. Fazele evoluiei medicamentului n organism, de la administrare

pn la apariia efectului terapeutic.....................................................................24 1.4.1. Faza biofarmaceutic .....................................................................................24 1.4.2. Faza farmacocinetic .....................................................................................24 1.4.3. Faza farmacodinamic ...................................................................................26

2. NOIUNI DE BIOFARMACIE GENERAL ............................................................27 2.1. Biodisponibilitatea medicamentelor.....................................................................27

2.1.1. Aspecte generale............................................................................................27 2.1.2. Tipurile de biodisponibilitate i modalitile de determinare ........................29

2.2. Factorii care influeneaz biodisponibilitatea .....................................................38 2.2.1. Aspecte generale............................................................................................38 2.2.2. Factorii fizico-chimici ce influeneaz dizolvarea i biodisponibilitatea.......40 2.2.3. Factorii dependeni de organism, ce influeneaz absorbia

i biodisponibilitatea......................................................................................44 2.2.4. Modificri ale absorbiei i ale biodisponibilitii, per os..............................49

3. FARMACOCINETIC GENERAL .........................................................................58 3.1. Transferul prin membranele biologice ................................................................58

3.1.1. Aspecte generale............................................................................................58 3.1.2. Tipuri de transfer prin membranele biologice ...............................................61

3.2. Absorbia medicamentelor n organism...............................................................67 3.2.1. Aspecte generale............................................................................................67 3.2.2. Absorbia pe ci naturale ...............................................................................72 3.2.3. Absorbia pe ci artificiale (injectabile).........................................................89

3.3. Distribuirea medicamentelor n organism...........................................................95 3.3.1. Transportul medicamentelor n snge............................................................96 3.3.2. Difuzarea medicamentelor n esuturi..........................................................103 3.3.3. Distribuirea propriu-zis a medicamentelor n esuturi................................109 3.3.4. Fixarea medicamentelor n esuturi..............................................................114

3.4. Epurarea medicamentelor din organism ...........................................................117 3.4.1. Clearance .....................................................................................................117 3.4.2. Biotransformarea (metabolizarea) medicamentelor.....................................119 3.4.3. Eliminarea medicamentelor .........................................................................156

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3.5. Variabilitatea profilului farmacocinetic ............................................................168 3.5.1. Farmacocinetica compuilor chirali. Stereoizomeria n farmacocinetic ..........168 3.5.2. Influena interaciunilor medicamentoase....................................................170 3.5.3. Influena unor variabile fiziologice..............................................................170 3.5.4. Influena strii patologice ............................................................................186 3.5.5. Alimentaia ..................................................................................................189 3.5.6. Variabilitatea interindividual n farmacocinetic .......................................190 3.5.7. Profilul farmacocinetic i clasificarea farmacocinetic a medicamentelor........192

3.6. Analiza matematic farmacocinetic. Exprimarea cantitativ a proceselor farmacocinetice ...............................................................................195

3.6.1. Tipuri de procese cinetice, n cadrul fazelor biofarmaceutic i farmacocinetic ........................................................................................195

3.6.2. Analiza matematic farmacocinetic. Calculul parametrilor farmacocinetici ..........................................................................................200

4. FARMACODINAMIE GENERAL .........................................................................214 4.1. Aciunea farmacodinamic .................................................................................214

4.1.1. Etapele fazei farmacodinamice....................................................................214 4.1.2. Parametrii definitorii ai aciunii farmacodinamice ......................................214 4.1.3. Tipurile de aciune farmacodinamic ..........................................................224

4.2. Factorii care influeneaz aciunea farmacodinamic .....................................226 4.2.1. Factorii ce influeneaz aciunea farmacodinamic, dependeni

de medicament .............................................................................................226 4.2.2. Factorii dependeni de organism..................................................................236 4.2.3. Factorii dependeni de mediu i de alte condiii ..........................................251 4.2.4. Bioritmurile (Elemente de cronofarmacologie) ...........................................253 4.2.5. Asocierea medicamentelor. Interaciuni medicamentoase...........................259

4.3. Variabilitatea farmacologic inter- i intraindividual....................................273 4.3.1. Mecanismele variabilitii farmacologice....................................................274 4.3.2. Tipurile de variabilitate farmacologic ........................................................275 4.3.3. Manifestrile clinice ale variabilitii farmacologice...................................276

4.4. Exprimarea cantitativ a aciunii farmacodinamice. Relaii doz-efect i concentraie-efect .............................................................................................276

4.4.1. Parametrii cantitativi ai aciunii farmacodinamice ......................................276 4.4.2. Tipurile de relaii doz - efect......................................................................277 4.4.3. Efectul mediat de receptori (R)....................................................................279 4.4.4. Variabilitatea relaiilor doz-efect, ntr-o populaie.

Curbele frecven-distribuie .......................................................................286

5. FARMACOTOXICOLOGIE GENERAL ..............................................................291 5.1. Efecte secundare...................................................................................................293 5.2. Efecte toxice ..........................................................................................................294

5.2.1. La nivelul SNC ...........................................................................................294 5.2.2. La nivelul aparatului cardiovascular...........................................................295 5.2.3. La nivel sanguin..........................................................................................296 5.2.4. La nivelul aparatului digestiv ....................................................................296 5.2.5. La nivelul ficatului......................................................................................296 5.2.6. La nivelul rinichiului ..................................................................................297 5.2.7. La nivelul aparatului respirator ..................................................................298

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5.2.8. La nivelul urechii........................................................................................298 5.2.9. La nivelul ochiului......................................................................................298 5.2.10. La nivelul muchilor i al esutului conjunctiv ...........................................299 5.2.11. La nivelul pielii............................................................................................301

5.3. Efecte adverse cancerigene ..................................................................................302 5.4. Efecte adverse mutagene .....................................................................................303 5.5. Intolerana ............................................................................................................303

5.5.1. Intolerana congenital. Idiosincrazia ..........................................................303 5.5.2. Intolerana dobndit ..................................................................................310

5.6. Efecte adverse imunosupresive...........................................................................315 5.6.1. Agranulocitoza.............................................................................................316 5.6.2. Deficiena imunitar latent.........................................................................317 5.6.3. Gravitatea efectelor adverse imunosupresive ..............................................319 5.6.4. Msurile de profilaxie a efectelor adverse imunosupresive.........................319

5.7. Tolerana ..............................................................................................................320 5.7.1. Tolerana nnscut .....................................................................................320 5.7.2. Tolerana dobndit ....................................................................................320

5.8. Farmacodependena ............................................................................................322 5.8.1. Farmacodependena psihic ........................................................................322 5.8.2. Farmacodependena fizic ..........................................................................322

5.9. Toxicomania (Drug addiction)........................................................................323 5.10. Reacii adverse la ntreruperea farmacoterapiei ............................................325

5.10.1. Tipurile de reacii adverse la ntreruperea brusc a farmacoterapiei ..........325 5.10.2. Medicamente incriminate n RA, la ntreruperea farmacoterapiei ..............328

5.11. Efecte adverse asupra procesului reproducerii...............................................329 5.11.1. Efecte adverse asupra gametogenezei.........................................................329 5.11.2. Efecte adverse asupra blastogenezei...........................................................329 5.11.3. Efecte adverse asupra embriogenezei .........................................................330 5.11.4. Efecte adverse asupra fetogenezei ..............................................................332 5.11.5. Efecte adverse, n perioadele prenatal i obstetrical................................333

5.12. Efecte adverse asupra sugarului.......................................................................334

6. FARMACODINAMIE FUNDAMENTAL (CELULAR I MOLECULAR) .....337 6.1. Locul aciunii farmacodinamice .........................................................................337

6.1.1. Locul de aciune asupra microorganismelor ................................................337 6.1.2. Locul de aciune asupra macroorganismului ...............................................337

6.2. Mecanismele aciunii farmacodinamice.............................................................338 6.2.1. Mecanismele aciunii farmacodinamice asupra microorganismelor ............339 6.2.2. Mecanismele aciunii farmacodinamice asupra macroorganismului ...........340

6.3. Aciunea farmacodinamic la nivel molecular, biochimic ...............................342 6.3.1. Aciunea asupra farmacoreceptorilor (R).....................................................342 6.3.2. Aciunea asupra enzimelor (E) ....................................................................345 6.3.3. Aciunea asupra mediatorilor i a mesagerilor celulari................................347 6.3.4. Aciunea asupra altor substraturi biochimice i metabolii ..........................349 6.3.5. Mecanismul de tip antimetabolit..................................................................350

6.4. Aciunea n metabolismul radicalilor liberi ai oxigenului ................................351 6.4.1. Funcia microbicid a radicalilor liberi ai oxigenului ..................................351 6.4.2. Patologia radicalilor liberi ai oxigenului......................................................352

8

6.4.3. Mecanismele fiziologice de protecie contra agresiunii radicalilor liberi ai oxigenului ................................................................................................352

6.4.4. Farmacologia metabolismului radicalilor liberi ai oxigenului .....................353 6.5. Aciunea farmacodinamic la nivel celular .......................................................353

6.5.1. Aciunea la nivelul membranei celulare.......................................................353 6.5.2. Aciunea la nivelul veziculelor i al granulelor intracitoplasmatice ............356 6.5.3. Aciunea la nivelul organitelor celulare.......................................................357 6.5.4. Aciunea la nivel de nucleu..........................................................................357

6.6. Aciunea farmacodinamic asupra canalelor ionice dependente de voltaj ..........357 6.6.1. Canalele de sodiu, dependente de voltaj ......................................................359 6.6.2. Canalele de calciu, dependente de voltaj .....................................................360 6.6.3. Canale de potasiu.........................................................................................360

6.7. Farmacoreceptorii (R).........................................................................................361 6.7.1. Definiia farmacoreceptorilor ......................................................................361 6.7.2. Structura biochimic a R .............................................................................361 6.7.3. Formarea complexului medicament - receptor (M-R). Tipuri de legturi.........362 6.7.4. Rezerva de receptori ....................................................................................363 6.7.5. Factorii care influeneaz numrul i funcionalitatea R .............................363 6.7.6. Situarea R ...................................................................................................365 6.7.7. Tipuri de sisteme R. Structura general a sistemelor R ...............................366 6.7.8. Mecanismul intim al funcionrii R .............................................................367 6.7.9. Clasificarea receptorilor (R) ........................................................................371

6.8. Aciunea farmacodinamic la nivel sinaptic......................................................371 6.8.1. Sinapsa electric ..........................................................................................372 6.8.2. Sinapsa chimic ...........................................................................................372 6.8.3. Mecanisme de aciune farmacodinamic asupra transmisiei

sinaptice chimice .........................................................................................379 6.9. Aciunea farmacodinamic la nivelul sistemelor de transmisie

(farmacologia transmisiilor)................................................................................380 6.9.1. Clasificarea transmisiilor .............................................................................380 6.9.2. Transmisia colinergic.................................................................................384 6.9.3. Transmisia adrenergic ................................................................................394 6.9.4. Transmisia dopaminergic ...........................................................................406 6.9.5. Transmisia serotoninergic ..........................................................................410 6.9.6. Transmisia histaminergic ...........................................................................415 6.9.7. Transmisia GABA-ergic ............................................................................419 6.9.8. Transmisia glutamatergic ...........................................................................424 6.9.9. Transmisia opioidergic...............................................................................428 6.9.10. Transmisia icosanoidergic .........................................................................437 6.9.11. Transmisia canabinoidergic .......................................................................453 6.9.12. Transmisia purinergic ................................................................................462

7. FARMACOGRAFIE GENERAL............................................................................472 7.1. Noiuni generale de farmacografie .....................................................................472

7.1.1. Medicamentul ..............................................................................................472 7.1.2. Denumirea medicamentului.........................................................................472 7.1.3. Formele farmaceutice ..................................................................................473 7.1.4. Reeta (prescripia) medical .......................................................................473

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7.1.5. Reglementri privind prescrierea i eliberarea medicamentelor ..................473 7.1.6. Stabilirea schemelor farmacografice ..........................................................474

7.2. Noiuni generale de posologie .............................................................................476 7.2.1. Doza.............................................................................................................477 7.2.2. Concentraia plasmatic i zona terapeutic ................................................477 7.2.3. Metaboliii activi de importan clinic .......................................................481 7.2.4. Posologia standard.......................................................................................482 7.2.5. Scheme posologice ......................................................................................482

7.3. Individualizarea posologiei .................................................................................483 7.3.1. Adaptarea dozelor n funcie de factorii fiziologici biometrici ....................484 7.3.2. Individualizarea dozelor n insuficiena renal ............................................488 7.3.3. Individualizarea dozelor n enzimopatii.......................................................490

7.4. Supravegherea terapeutic i optimizarea posologiei.......................................491 7.4.1. Supravegherea pe criteriul clinic..................................................................492 7.4.2. Supravegherea pe criteriul biochimic...........................................................492 7.4.3. Supravegherea pe criteriul farmacocinetic (Monitorizarea farmacografiei) ......492

7.5. Monitorizarea farmacografiei ............................................................................492 7.5.1. Metodele analitice ........................................................................................494 7.5.2. Eantionul recoltat........................................................................................494 7.5.3. Momentul prelevrii eantionului ................................................................495 7.5.4. Metodologia de monitorizare i de optimizare a farmacografiei..................495 7.5.5. Metode de monitorizare a farmacografiei, pe baza dozei-test ..................496

8. FARMACOTERAPIE GENERAL..........................................................................503 8.1. Noiuni generale de farmacoterapie ...................................................................503

8.1.1. Locul farmacoterapiei n terapeutic ...........................................................503 8.1.2. Metode farmacoterapeutice alternative .......................................................504 8.1.3. Tipuri de farmacoterapie..............................................................................505 8.1.4. Medicamente eseniale.................................................................................506 8.1.5. Clasificarea ATC a medicamentelor............................................................507 8.1.6. Produse farmaceutice cu asocieri fixe de medicamente...............................507 8.1.7. Selectivitatea clinic ....................................................................................509 8.1.8. Tendine privind administrarea medicamentelor. Farmacomania

i farmacofobia ............................................................................................511 8.1.9. Medicamente OTC ......................................................................................512

8.2. Principii pentru o farmacoterapie tiinific i raional.................................513 8.3. Aspecte privind ncetarea farmacoterapiei .......................................................516 8.4. Supravegherea terapeutic i optimizarea farmacoterapiei ............................518

8.4.1 Etapele optimizrii farmacoterapiei, prin mecanismul de feed-back al supravegherii terapeutice...........................................................................518

8.4.2. Particularitile supravegherii terapeutice .....................................................519 8.4.3 Tipurile de supraveghere terapeutic ............................................................521

9. FARMACOEPIDEMIOLOGIE GENERAL..........................................................524 9.1. Noiuni introductive ............................................................................................524 9.2. Statistica reaciilor adverse i a morbiditii medicamentoase .......................525 9.3. Procesul farmacoepidemiologic..........................................................................525

9.3.1. Etapele .........................................................................................................526 9.3.2. Formele de manifestare................................................................................529 9.3.3. Factorii farmacoepidemiologici...................................................................529

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9.4. Activitatea de farmacoepidemiologie .................................................................530 9.4.1. Activitatea de profilaxie .............................................................................530 9.4.2. Activitatea de combatere ............................................................................533

9.5. Farmacovigilena (FV) ........................................................................................534 9.5.1. Definiie i obiective....................................................................................534 9.5.2. Sistemul de FV ............................................................................................534 9.5.3. Sursele de informaie asupra RA .................................................................535

10. FARMACOLOGIE INFORMAIONAL SAU FARMACOINFORMATOLOGIE (FI) ..........................................................536 10.1. Sinteze de farmacologie informaional .........................................................536

10.1.1. Necesitatea apariiei farmacologiei informaionale (FI)..............................536 10.1.2. Bazele cibernetice - informaionale ale farmacologiei informaionale........537 10.1.3. Farmacodinamia informaional .................................................................541 10.1.4. Farmacotoxicologia informaional ............................................................550 10.1.5. Implicaii practice ale farmacologiei informaionale ..................................552

10.2. Analize de farmacologie informaional ..........................................................553 10.2.1. Medicamentul ca semnal ............................................................................553 10.2.2. Cauzalitatea informaional a efectului medicamentului ............................556 10.2.3. Farmacologia informaional a dozelor ......................................................560 10.2.4. Izo-, homeo-, alo- i enantio-reglarea farmacologic a sistemului

biocibernetic uman. Noiuni de farmacocibernetic ...................................566 10.2.5. Natura informaional a reaciilor adverse..................................................569

Bibliografie specific pentru capitolul 10.......................................................................573

Index ..................................................................................................................................577

Bibliografie selectiv ........................................................................................................587

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C O N T E N T

Foreword to 1st Edition ......................................................................................................17 Foreword to 2nd Edition .....................................................................................................19

1. GENERAL PHARMACOLOGY. INTRODUCTION................................................21 1.1. Subdivisions of Pharmacology..............................................................................21

1.1.1. Main Subdivisions ..........................................................................................21 1.1.2. Other Developing Subdivisions ......................................................................22

1.2. Border Sciences......................................................................................................23 1.3. The Practical Usefulness of Pharmacology..........................................................23 1.4. Phases of Drug Evolution in the Body, from Administration until Time

of Therapeutic Effect ............................................................................................24 1.4.1. Biopharmaceutic Phase ...................................................................................24 1.4.2. Pharmacokinetic Phase ...................................................................................24 1.4.3. Pharmacodynamic Phase.................................................................................26

2. INTRODUCTION IN GENERAL BIOPHARMACY ................................................27 1.1. Drug Bioavailability ..............................................................................................27

2.1.1. General Aspects ..............................................................................................27 2.1.2. Types of Bioavailability and Ways of Determining........................................29

2.2. Factors Influencing Bioavailability ......................................................................38 2.2.1. General Aspects ..............................................................................................38 2.2.2. Physicochemical Factors Influencing Dissolution and Bioavailability...........40 2.2.3. Organism-Related Factors Influencing Absorption and Bioavailability .........44 2.2.4. Changes in per os Absorption and Bioavailability..........................................49

3. GENERAL PHARMACOKINETICS..........................................................................58 3.1. Drug Transport Across Biological Membranes (Biotransport) .........................58

3.1.1. General Aspects ..............................................................................................58 3.1.2. Types of Biotransport......................................................................................61

3.2. Drug Absorption ....................................................................................................67 3.2.1. General Aspects ..............................................................................................67 3.2.2. Absorption in Enteral and Other Natural Routes ............................................72 3.3.3. Absorption in Parenteral Routes .....................................................................89

3.3. Drug Distribution ..................................................................................................95 3.3.1. Drug Transport into the Blood Stream............................................................96 3.3.2. Drug Diffusion into the Tissues ....................................................................103 3.3.3. Drug Distribution into the Tissues ................................................................109 3.3.4. Drug Tissue Binding .....................................................................................114

3.4. Drug Elimination .................................................................................................117 3.4.1. Clearance.......................................................................................................117 3.4.2. Drug Biotransformation (Drug Metabolism) ................................................119 3.4.3. Drug Excretion..............................................................................................156

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3.5. The Variability of the Pharmacokinetic Profile ................................................168 3.5.1. Pharmacokinetics of Chiral Compounds.......................................................168 3.5.2. Influence of Drug Interactions ......................................................................170 3.5.3. Influence of Some Physiological Variables ..................................................170 3.5.4. Influence of Pathological State .....................................................................186 3.5.5. Influence of Food ..........................................................................................189 3.5.6. Interindividual Variability in Pharmacokinetics ...........................................190 3.5.7. Pharmacokinetic Profile and Pharmacokinetic Drug Classification..............192

3.6. Mathematical Analysis of Pharmacokinetic Data. Quantitative expression of pharmacokinetic processes .............................................................................195

3.6.1. Types of Kinetic Processes in Biopharmaceutic and Pharmacokinetic Phases .........................................................................195

3.6.2. Pharmacokinetics Mathematical Analysis. Calculation of Pharmacokinetic Parameters.....................................................................200

4. GENERAL PHARMACODYNAMICS .....................................................................214 4.1. Pharmacodynamic action....................................................................................214

4.1.1. Stages of Pharmacodynamic Action .............................................................214 4.1.2. Fundamental Parameters of Pharmacodynamic Action ................................214 4.1.3. Types of Pharmacodynamic Action ..............................................................224

4.2. Factors Influencing Pharmacodynamic Action.................................................226 4.2.1. Drug-Related Factors ....................................................................................226 4.2.2. Organism-Related Factors.............................................................................236 4.2.3. Environmental Factors and Others................................................................251 4.2.4. Biorhythms (Elements of chronopharmacology) ..........................................253 4.2.5. Associated Drug Administration. Drug Interactions .....................................259

4.3. Inter- and Intraindividual Pharmacological Variability..................................273 4.3.1. Mechanisms of Pharmacological Variability ................................................274 4.3.2. Types of Pharmacological Variability...........................................................275 4.3.3. Clinical Manifestations of Pharmacological Variability ...............................276

4.4. Quantitative Expression of Pharmacodynamic Action. Dose-Effect and Concentration-Effect relationships .............................................................276

4.4.1. Quantitative Parameters of the Pharmacodynamic Action............................276 4.4.2. Types of Dose-Effect Relationships..............................................................277 4.4.3. Receptor-Mediated Drug Effect ....................................................................279 4.4.4. Variability of Dose-Effect Relationships in Populations. Frequency-

distribution curves ........................................................................................286

5. GENERAL PHARMACOTOXICOLOGY ...............................................................291 5.1. Secondary Side Effects ........................................................................................293 5.2. Toxic Side Effects.................................................................................................294

5.2.1. Nervous system Toxic Side Effects ..............................................................294 5.2.2. Cardio-vascular Toxic Side Effects ..............................................................295 5.2.3. Blood Toxic Side Effects ..............................................................................296 5.2.4. Gastrointestinal Toxic Side Effects...............................................................296 5.2.5. Hepatic Toxic Side Effects ..........................................................................296 5.2.6. Renal Toxic Side Effects..............................................................................297 5.2.7. Respiratory Toxic Side Effects .....................................................................298 5.2.8. Ear Toxic Side Effects ..................................................................................298

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5.2.9. Eye Toxic Side Effects..................................................................................298 5.2.10. Musculoskeletal and Connective Tissue Toxic Side Effects......................299 5.2.11. Skin Toxic Side Effects...............................................................................301

5.3. Carcinogenic Side Effects....................................................................................302 5.4. Mutagenic Side Effects ........................................................................................303 5.5. Drug Intolerance..................................................................................................303

5.5.1. Inborn (congenital) Intolerance. Idiosyncrasy...............................................303 5.5.2. Acquired Intolerance.....................................................................................310

5.6. Immunosuppressive Side Effects ........................................................................315 5.6.1. Agranulocytosis ............................................................................................316 5.6.2. Delayed Immune Deficiency. Acquired Immune Deficiency Syndrome

(AIDS)...........................................................................................................317 5.6.3. Severity of Immunosuppressive Side Effects................................................319 5.6.4. Prophylaxis of Immunosuppressive Side Effects..........................................319

5.7. Drug Tolerance ....................................................................................................320 5.7.1. Inborn (congenital) Tolerance.......................................................................320 5.7.2. Acquired Tolerance.......................................................................................320

5.8. Pharmacodependence..........................................................................................322 5.8.1. Psychic Pharmacodependence ......................................................................322 5.8.2. Physiological Pharmacodependence .............................................................322

5.9. Drug Addiction ....................................................................................................323 5.10. Side Effects after Discontinuation of Therapy ................................................325

5.10.1. Side Effects after Sudden Withdrawal of Pharmacotherapy .......................325 5.10.2. Drugs Inducing Side Effects after Discontinuation of Therapy ..................328

5.11. Side Effects on the Reproductive Process ........................................................329 5.11.1. Side Effects in Gametogenesis....................................................................329 5.11.2. Side Effects in Blastogenesis .....................................................................329 5.11.3. Side Effects in Embryogenesis....................................................................330 5.11.4. Side Effects during Fetal Development ......................................................332 5.11.5. Side Effects during the Prenatal and Obstetrical Period .............................333

5.12. Side Effects in Nursing Period..........................................................................334

6. FUNDAMENTAL PHARMACODYNAMICS (CELLULAR AND MOLECULAR) ..........................................................................337 6.1. Sites of Pharmacodynamic Action......................................................................337

6.1.1. Sites of Drug Action In Microorganisms ......................................................337 6.1.2. Sites of Drug Action In Macroorganisms .....................................................337

6.2 Mechanisms of Pharmacodynamic Action .........................................................338 6.2.1. Mechanisms of Drug Action on Microorganisms .........................................339 6.2.2. Mechanisms of Drug Action on Macroorganisms ........................................340

6.3. Pharmacodynamic Action in Molecular and Biochemical Level.....................342 6.3.1. Drug Effect on Receptors..............................................................................342 6.3.2. Drug Effect on Enzymes ...............................................................................345 6.3.3. Drug Effect on Mediators and Cellular Messengers .....................................347 6.3.4. Drug Effects on Other Biochemical Substrates and Metabolites ..................349 6.3.5. Mechanism of Action Antimetabolite like ...................................................350

6.4. Effects on the Metabolism of Oxygen Free Radicals ........................................351 6.4.1. Microbicidal Function of Oxygen Free Radicals ..........................................351 6.4.2. Oxygen Free Radicals Pathology ..................................................................352

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6.4.3. Physiological Mechanisms of Protection against Oxygen Free Radicals ................................................................................................352

6.4.4. Pharmacology of Oxygen Free Radicals Metabolism...................................353 6.5. Pharmacodynamic Action in Cellular Level .....................................................353

6.5.1. Effect on Cell Membranes ............................................................................353 6.5.2. Effect on Intracitoplasmatic Granules and Vesicles......................................356 6.5.3. Effect on Intracellular Organelles .................................................................357 6.5.4. Effects on Cell Nucleus.................................................................................357

6.6. Pharmacodynamic Effect on Voltage-Gated Ion Channels .............................357 6.6.1. Voltage-Dependent Sodium Channels ..........................................................359 6.6.2. Voltage-Dependent Calcium Channels .........................................................360 6.6.3. Potassium Channels ......................................................................................360

6.7. Pharmacoreceptors (R) .......................................................................................361 6.7.1. Definition ......................................................................................................361 6.7.2. Biochemical Structure...................................................................................361 6.7.3. The Drug-Receptor Complex. Types of Drug-Receptor Binding .................362 6.7.4. Receptor Reserve ..........................................................................................363 6.7.5. Factors Influencing the Receptors Number and Function.............................363 6.7.6. Pharmacoreceptor Localization.....................................................................365 6.7.7. Types of Receptor-Effector Systems. General Structure ..............................366 6.7.8. Intimate Mechanism of Action of the Receptor-Effector System .................367 6.7.9. Receptor Classification .................................................................................371

6.8. Pharmacodynamic Action at Synaptic Level ....................................................371 6.8.1. Electrical synapse..........................................................................................372 6.8.2. Chemical synapse..........................................................................................372 6.8.3. Mechanisms of pharmacodynamic action on chemical synapses..................379

6.9. Pharmacodynamic Action on Transmission Systems (Pharmacology of Transmissions).................................................................................................380

6.9.1. Classification of Transmissions ....................................................................380 6.9.2. Cholinergic Transmission .............................................................................384 6.9.3. Adrenergic Transmission ..............................................................................394 6.9.4. Dopaminergic Transmission .........................................................................406 6.9.5. Serotoninergic Transmission.........................................................................410 6.9.6. Histaminergic Transmission..........................................................................415 6.9.7. GABA-ergic Transmission............................................................................419 6.9.8. Glutamatergic Transmission .........................................................................424 6.9.9. Opioidergic Transmission .............................................................................428 6.9.10. Eicosanoid System ......................................................................................437 6.9.11. Cannabinoid Transmission..........................................................................453 6.9.12. Purinergic Transmission .............................................................................462

7. GENERAL PHARMACOGRAPHY ..........................................................................472 7.1. General Aspects of Pharmacography ................................................................472

7.1.1. Pharmaceutical Drug.....................................................................................472 7.1.2. Name of Pharmaceutical Drug ......................................................................472 7.1.3. Pharmaceutical Forms...................................................................................473 7.1.4. Medical Prescription .....................................................................................473 7.1.5. Legal Considerations regarding Drug Prescription and Delivery .................473 7.1.6. Determination of Pharmacographic Schemes ...............................................474

15

7.2. General Notions of Posology ...............................................................................476 7.2.1. Dose ..............................................................................................................477 7.2.2. Plasma Concentration and Therapeutic Range..............................................477 7.2.3. Active Metabolites of Clinical Significance .................................................481 7.2.4. Standard Posology ........................................................................................482 7.2.5. Posologic Scheme .........................................................................................482

7.3. Dosage Individualization.....................................................................................483 7.3.1. Dosage Individualization based on Physiological

Biometrical Factors.......................................................................................484 7.3.2. Dosage Individualization in Renal Failure....................................................488 7.3.3. Dosage Individualization in Enzymopathies.................................................490

7.4. Therapeutic Surveillance and Dosage Optimization ........................................491 7.4.1. Clinical Criterion ..........................................................................................492 7.4.2. Biochemical Criterion ...................................................................................492 7.4.3. Pharmacokinetics Criterion (Pharmacography Monitoring) .........................492

7.5. Pharmacography Monitoring .............................................................................492 7.5.1. Analytical Methods .......................................................................................494 7.5.2. Samplings......................................................................................................494 7.5.3. Samplings Intervals.......................................................................................495 7.5.4. Pharmacography Monitoring and Dosage Optimization Methods ................495 7.5.5. Pharmacography Monitoring Based on TestDose Method......................496

8. GENERAL PHARMACOTHERAPY ........................................................................503 8.1. General Aspects of Pharmacotherapy ...............................................................503

8.1.1. The Role of Pharmacotherapy in Therapeutics .............................................503 8.1.2. Alternative Pharmacotherapeutic Methods ...................................................504 8.1.3. Types of Pharmacotherapy............................................................................505 8.1.4. Essential Drugs .............................................................................................506 8.1.5. Anatomical Therapeutical Chemical (ATC)

Classification System of Drugs ....................................................................507 8.1.6. Fixed Drug Combinations .............................................................................507 8.1.7. Clinical Selectivity........................................................................................509 8.1.8. Trends in Drug Administration. Pharmacomania and Pharmacophobia .......511 8.1.9. OTC Drugs....................................................................................................512

8.2. Principles of a Rational and Scientific Pharmacotherapy................................513 8.3. Abrupt Drug Withdrawal Aspects .....................................................................516 8.4. Therapeutic Surveillance and Pharmacotherapy Optimization......................518

8.4.1. Stages of Pharmacotherapy Optimization Based on the Feed-Back Mechanism of Therapeutic Surveillance.......................................................518

8.4.2. Specific Features of Therapeutic Surveillance..............................................519 8.4.3. Types of Therapeutic Surveillance................................................................521

9. GENERAL PHARMACOEPIDEMIOLOGY (DRUGS EPIDEMIOLOGY) ........524 9.1. Introductive Aspects............................................................................................524 9.2. Side Effects and Drug Morbidity Statistics .......................................................525 9.3. Pharmacoepidemiological Process .....................................................................525

9.3.1. Stages ............................................................................................................526 9.3.2. Types.............................................................................................................529 9.3.3. Pharmacoepidemiological factors .................................................................529

16

9.4. Pharmacoepidemiology Activities ......................................................................530 9.4.1. Prophylactic Activity ....................................................................................530 9.4.2. Combating Activity.......................................................................................533

9.5. Pharmacovigilance (FV)......................................................................................534 9.5.1. Definition and Objectives .............................................................................534 9.5.2. Pharmacovigilance system............................................................................534 9.5.3. Sources of Information on Side Effects (Undesired Effects) ........................535

10. INFORMATIONAL PHARMACOLOGY ..............................................................536 10.1. Informational Pharmacology Synthesis ...........................................................536

10.1.1. The Necessity of the Development of Informational Pharmacology ..........536 10.1.2. CyberneticInformational Basis of Informational Pharmacology...............537 10.1.3. Informational Pharmacodynamics ..............................................................541 10.1.4. Informational Pharmacotoxicology.............................................................550 10.1.5. Practical Involvements of Informational Pharmacology.............................552

10.2. Informational Pharmacology Analysis ............................................................553 10.2.1. Drug as a Signal ..........................................................................................553 10.2.2. Informational Causality of the Drug Effect.................................................556 10.2.3. Informational Pharmacology of Dosages ....................................................566 10.2.4. Pharmacological Iso-, Homeo-, Allo- and Enantio-regulation of the

Human Biocybernetic System. Notions of Pharmacocybernetics ...............566 10.2.5. Informational Nature of Side Effects (Undesired Effects) ..........................569

140

Metabolizatorii rapizi (cu gen CYP2D6*2 duplicat sau multiduplicat) sunt reprezentai diferit n diferite populaii. De exemplu: procentul nregistrat este de 1% printre suedezii de tip caucazian, 3,6% n Germania, 7 10% n Spania, 20% n Arabia Saudit. Frecvena maxim de metabolizatori rapizi a fost nregistrat la negrii etiopieni, fiind 29%.

Polimorfismul CYP2C19 Deficiena de CYP2C19 (cunoscut ca deficiena de mefenitoin hidroxilaz)

este semnificativ la populaia asiatic, fiind identificat la un procent de aproxi-mativ 20% dintre indivizi i existnd ntr-un procent sub semnificaia statistic (3 5%) la populaia caucazian.

Deficiena de CYP2C19 este motenit ca o trstur autosomal recesiv i au fost identificate, pn n prezent, patru allele deficiente (defective).

3.4.2.3.7.2. Polimorfismul sintetazelor Activitatea unor enzime ale fazei a II-a de metabolizare a medicamentelor la

indivizii umani este exprimat polimorfic. Polimorfismul la N-Acetiltransferaza-2 (NAT-2) Mutaiile enzimei N-acetiltransferaza-2 (NAT-2) sunt frecvente. Ele induc

variabilitate farmacocinetic, dar pn n prezent nu au fost evideniate consecine importante asupra efectului farmacodinamic.

Fenotipul acetilator lent este asociat cu motenirea a dou allele nefuncionale NAT-2.

Proporia de indivizi acetilatori NAT-2 leni i respectiv rapizi ntr-o populaie variaz, n funcie de originea etnic i geografic, pe o scar foarte extins. Astfel, procentul de acetilatori NAT-2 leni variaz de la numai 1 5% la eschimoii canadieni, la cca 7% la polinezieni i 15 22% la chinezi, la 42 55% la americanii de origine caucazian i african i la 49 57% la africani, crescnd pn la 33 70% la europeni i la americanii de origine european i la 55 75% la populaiile mediteraneene (evrei israelieni etc.), atingnd 82% la egipteni [9].

Variabilitatea frecvenei de distribuie a fenotipului acetilator rapid, n grupurile populaionale cu diferite origini etnice, este sintetizat n continuare (sintez dup Averys, 1997):

Grupurile etnice de origine asiatic au frecvena distribuiei = 40 100%; Grupurile etnice de origine african au frecvena distribuiei = 20 59%; Grupurile etnice de origine european au frecvena distribuiei = 30 67%; Grupurile etnice de origine mediteraneean au frecvena distribuiei =

18 45%. Polimorfismul la Tiopurin S-metil transferaz (TPMT) Polimorfismul a fost evideniat la mai multe metil transferaze, ntre care:

Topurin S-metiltransferaz (TPMT) i catecol O-metil transferaz (COMT).

204

Fig. 3.17. Cinetica n modelul bicompartimentat, dup administrare intravascular: faza = distribuia n compartimentul periferic; faza = eliminarea din compartimentul central.

3.6.2.1.2.3. Reprezentarea grafic: vezi figurile 3.16 b i 3.17. n cazul medicamentelor ce se fixeaz i se depoziteaz n organul de

eliminare, n etapa de eliminare apare i o a treia faz, faza de eliminare tardiv din compartimentul profund.

Acestei faze i corespunde un timp de njumtire lung. Exemplu: aminoglicozidele (tip streptomicin) care se fixeaz n cortexul renal. n consecin, aminozidele au doi timpi de njumtire n etapa de eliminare: T 1/2 scurt (al fazei ) = 1,5 2,5 ore; T 1/2 lung (al fazei ) = 50 120 ore. Faza este responsabil pentru nefrotoxicitatea aminoglicozidelor. n cazul n care medicamentele se administreaz oral, modelul compartimental

farmacocinetic se complic prin procesul de absorbie. Apare un compartiment suplimentar, cuprinznd volumul din care se face absorbia (fig. 3.18 i 3.19).

Fig. 3.18. Curba, n modelul monocompar-timentat, dup administrare extravascular.

Fig. 3.19. Curba, n modelul bicomparti-mentat, dup administrare extravascular.

299

Cataract, nistagmus, diplopie provoac fenitoina; Glaucom cu unghi deschis prin creterea presiunii intraoculare pot provoca

glucocorticosteroizii administrai sistemic sau aplicai topic la nivelul ochiului, pe fondul unei boli genetice. Frecvena n populaia SUA este sub 5%.

5.2.10. LA NIVELUL MUCHILOR I AL ESUTULUI CONJUNCTIV

Un numr considerabil de medicamente este incriminat n tulburrile musculare i ale esutului conjunctiv (tabelul 5.6) [37, 55], de tip:

tremor; sindrom miastenic; miopatii i neuropatii nsoite sau nu de mialgii; rabdomiolize (distrucii musculare); hipertermia malign; colagenoze (cu manifestare de lupus sau de poliartrit reumatoid).

Tabelul 5.6 Miopatii i rabdomiolize medicamentoase

Tulburri musculare Medicamente (exemple) 1 2

MIOPATII Miopatii fr mialgie Miopatii cu mialgie Polimiozite cu mialgie

Miastenii (anomalii de transmisie neuromuscular)

Corticoizi, -blocante Fluoroquinolone, ciclosporine, acid nalidixic Antihistaminice-H2 (cimetidina, ranitidina), piritinol D-penicilamina Aminoglicozide, polimixine, -blocante, piritinol

NEUROPATII Neuropatii fr mialgie Neuropatii cu mialgie

Antimalarice (clorochina, hidroxiclorochina) Hipokaliemiante, hipofosfatemiante

RABDOMIOLIZE Anestezice generale (halotan) Analgezice (paracetamol, salicilai) Antibiotice (peniciline) Antidepresive (IMAO, litiu) Antiinflamatoare nesteroidiene (AINS) (ibuprofen) Antiinflamatoare steroidiene (AIS) (fluoroprednisolon) -blocante Curarizante Diuretice (furosemid) Hormoni (vasopresina, insulina) Simpatomimetice Neuroleptice anti-D2 Opiacee Statine hipocolesterolemiante inhibitori de HMG-CoA reductaz, la doze mari i n asociere cu fibrai (gemfibro-zil); cerivastatin Baycol, Lypobay retras n 2001 Precauii: monitorizarea funciei musculare; sistarea tratamentului la primele semne

312

5.5.2.5. Tipurile de RA alergice

RA alergice sunt de patru tipuri, dup mecanismul imunologic implicat (tabelul 5.10).

Tabelul 5.10 Tipurile de RA alergice

Tipul de RA alergic Agentul Mecanism

Reacii imediate TipI

anafilactic

Tip II citotoxic Tip III

mediat prin complexe imune

IgE reactiv

IgG, IgM

IgG, IgM

reacia antigen-IgE, la nivelul mastocitelor sau al bazofilelor, cu eliberare de histamin i de alte substane tisular-active

reacia ntre IgG i celulele sanguine purttoare de antigen, cu efect citotoxic

complexele circulante antigen-IgG, depuse n vasele mici, mediaz inflamaia

Reacii ntrziate Tip IV

mediat celular (tip tuberculin)

Limfocite T sensibilizate

limfocitele T sensibilizate elibereaz limfokine, ce mediaz infiltrate monocelulare perivenulare

Medicamentele alergizante produc diferite tipuri de RA, cu diferite mani-festri clinice alergice. Medicamentele cu potenial mare alergizant pot declana mai multe tipuri de RA alergice (tabelele 5.11 5.14) [37].

Tabelul 5.11 Medicamente ce declaneaz RA alergice de tip I anafilactic

Manifestri clinice Medicamente alergizante oc anafilacticx, astm bronic alergic, edem glotic, edem Quincke, conjunctivit i rinit alergice, erupii cutanate (prurit, urticarie)

Peniciline (penicilina G inj.x, ampicilina etc.), cefalosporine, dextrani, substane iodate radiografice de contrast, anestezice locale i.v., acid acetilsalicilic, metamizol, procain, antihipertensive IEC

Tabelul 5.12 Medicamente ce declaneaz RA alergice de tip II citotoxic

Manifestri clinice Medicamente alergizante Anemie hemolitic imun Peniciline, sulfonamide, rifampicina, PAS,

izoniazida, fenacetina, chinidina Granulocitopenie imun Peniciline, sulfonamide, fenilbutazona, metamizol,

izoniazida, sulfoniluree hipoglicemiante, tiouracili Trombocitopenie imun Sulfonamide, rifampicina, tiouracili, chinina,

chinidina, tiazide diuretice, izoniazida

323

Evidenierea se face prin apariia sindromului de abstinen, sau de retragere (withdrawal syndrom), manifestat prin simptome caracteristice psihice, vege-tative i somatice, opuse aciunilor farmacodinamice ale substanei. De ex., n sindromul de abstinen la morfinomimetice apar simptome de tip adrenergic.

Farmacodependena fizic reclam necesitatea continurii administrrii sub-stanei, pentru a evita tulburrile i simptomele neplcute, i uneori grave, ale sindromului de abstinen.

Mecanismul instalrii sindromului de abstinen const n sensibilizarea unui sistem, a crui activitate este modulat de sistemul asupra cruia acioneaz drogul.

Exemple n cazul morfinomimeticelor se instaleaz sensibilizarea receptorilor

adrenergici (up-regulation), sistemul adrenergic fiind modulat de ctre sistemul opioid endogen, la nivelul cruia acioneaz morfinomimeticele, n sensul diminurii eliberrii de neuromediator adrenergic;

n cazul barbituricelor (fenobarbital) se sensibilizeaz receptorii glutamat-ergici, deoarece eliberarea neuromediatorului specific acidul glutamic este inhibat de un tratament ndelungat cu barbiturice, prin stimularea activitii transmisiei inhibitoare GABA-ergice.

5.9. TOXICOMANIA (DRUG ADDICTION) Este o stare de intoxicaie cronic, ce totalizeaz trei efecte adverse: farmacodependena psihic; farmacodependena fizic; tolerana (obinuina). Tipuri de toxicomanii n funcie de numrul drogurilor, exist: monotoxicomanii politoxicomanii. n funcie de drog, sunt: toxicomanii minore (de ex.: la barbituricele hipnotice, tranchilizante, alcool); toxicomanii majore (de ex.: la morfin, heroin, canabis, LSD). Substane capabile s produc farmacodependena Sunt: deprimante SNC (alcool, hipnotice precum barbituricele, sedative,

tranchilizante, ca diazepamul i meprobamatul); morfinomimetice (tip morfin i heroin); stimulente SNC (tip amfetamin, tip cocain i tip khat); halucinogene (tip indol, precum dietilamida acidului lisergic LSD , i

tip mescalin); cannabis (marijuana, hai, tetrahidrocanabinol); solveni organici volatili (aceton, tetraclorur de carbon, toluen);

386

Tabelul 6.8 Subtipuri de R colinergici

R Agonist definitoriu Nicotinici (N) N1N2

nicotin (alcaloid din Nicotiana tabacum)

Muscarinici (M) M1M5

muscarina (alcaloid din Amanita muscaria)

Receptorii nicotinici: sunt mprii n dou tipuri: N1 (neuronali = NSNC; i ganglionari = NN) i

N2 = NM (jonciune neuromuscular); sunt receptori ionotropici, pentameri, alctuii din 17 subuniti (subu-

nitile 2-7 i 2-4 au fost identificate la om, restul au fost identificate la galinacee i obolani); subunitile au fost mprite n 4 subfamilii (I-IV); familia III a fost mprit n 3 triburi (vezi tabelul 6.9) [142].

Tabelul 6.9 Subunitile, subfamiliile i triburile receptorilor nicotinici

N1 (neuronal) N2 (muscular) Familia I Familia II Familia III Familia IV

Tribul 1 Tribul 2 Tribul 3 9, 10

7, 8 2, 3, 4, 6 2, 4 3, 5

1, 1, , /

Receptorul N2 (jonciunea neuromuscular) este alctuit din dou subuniti , o subunitate , o subunitate i o subunitate sau . n stadiul embrional receptorul N2 are subunitatea , care dup natere este nlocuit cu subunitatea [211].

Localizarea, efectul i liganzii farmacologici sunt prezentai n tabelul 6.10.

Tabelul 6.10 Subtipuri de R nicotinici, localizare, efecte i liganzii farmacologici selectivi

(dup Rang H.P., 2003, completat)

Tip de receptor Localizare Efect Agoniti Antagoniti

1 2 3 4 5 NM (muscular) (1)21 sau (1)21

jonciune neuromuscular

potenial excitator postsinaptic, crete permeabilitatea pentru K+ i Na+

Acetilcolina Carbacol Suxametoniu

-bungarotoxina -conotoxina Tubocurarina Pancuronium

NN (ganglionar) (3)2(4)3

ganglioni vegetativi

potenial excitator postsinaptic, crete permeabilitatea pentru K+ i Na+

Acetilcolina Carbacol Nicotina Epibatina Vareniclina

-bungarotoxina Hexametoniu Bupropion Dextrometorfan

453

Acizii grai polinesaturai se afl n competiie n special n privina desaturrii. n special acizii omega 3 sunt capabili s inhibe -6-desaturarea i -5-desaturarea. De exemplu, dac se dorete creterea concentraiei de acid dihomo -linolenic din care se sintetizeaz icosanoizi cu efecte benefice, atunci se recomand administrarea precursorului (acidul -linolenic) mpreun cu acidul eicosapentaenoic pentru a se bloca conversia (prin -5-desaturaz) ctre acidul arahidonic.

Suplimentarea dietei cu acizi grai omega 3 (ulei de pete, ulei de semine de in, ulei de nuc, ulei de rapi), concomitent cu administrarea de aspirin, crete producia de rezolvine cu efecte antiinflamatorii.

6.9.11. TRANSMISIA CANABINOIDERGIC

Sistemul semnalizator cannabinoid endogen (SCBE) este clasificat ca sistem lipidergic, n raport cu structura biochimic a mediatorilor chimici. Mediatorii chimici, denumii endocannabinoide, au fost sintetizai din lipidele membranelor celulare, ca i eicosanoidele, cu care au similitudine de structur chimic, derivnd de la acidul arahidonic. Receptorii cannabinoizi CB1 i CB2 au fost identificai prin clonare molecular, respectiv din creier, n 1990, i din splin, n 1993 [60].

Sistemul endocannabinoid a fost evideniat nu numai la vertebrate, ci i la nevertebrate, dar nu la toate, iar receptorii i funciile fiziologice ale acestora prezint diferene. Sistemul cannabinoid endogen (sau o parte dintre componentele sale) pare s fie conservat la aproape toate speciile animale, de la Hydra sp. la Homo sapiens [61]. Endocannabinoidele au fost identificate n cantiti mici i n cacao (semine fermentate de Theobroma cocoa) i n ciocolat.

SCBE ofer inte noi farmacologice pentru dezvoltarea medicaiei [104]. Exist ns o larg dezbatere n lumea tiinific, referitoare la urmtoarea dilem: prezint sau nu siguran, pentru pacient, introducerea n terapeutic a cannabinoidelor (de sintez sau semisintez) sau/i a unor compui ce pot crete nivelurile de cannabinoide endogene? Pericolul principal este reprezentat de potenialul de abuz i de riscul bolilor psihiatrice, cunoscute a fi induse la utilizarea pe termen lung a fitocannabinoidelor din cannabis (produsele rezultate din Cannabis indica cnepa indian , cunoscute sub numele generic de cannabis, sunt: marijuana = frunzele i inflorescena; i hai = rezina). Acest potenial de efecte adverse psihotrope este declanat prin activarea receptorilor canabinoizi CB1.

6.9.11.1. Neuromediatorii

Sunt cunoscute urmtoarele endocannabinoide: arahidonoyletanolamida (AEA), denumit anandamid; 2- arahidonoylglicerol (2- AG); 2-arachidonoylglicerol eter (noladin eter).

536

10

FARMACOLOGIE INFORMAIONAL SAU

FARMACOINFORMATOLOGIE (FI)

Farmacologia informaional sau farmacoinformatologia* este o ramur a farmacologiei, care studiaz natura informaional a medicamentului i a proceselor farmacologice. n forma actual, prezentat n carte, farmacologia informaional este fundamentat pe baza unui concept de farmacologie cibernetic - informaional, elaborat i dezvoltat teoretic i experimental (Cristea, A., 1985 1998).

Avnd n vedere noutatea i dificultatea de abordare a farmacologiei ciber-netice-informaionale, din punct de vedere didactic, capitolul 10 este mprit n dou mari pri:

10.1. Sinteze de farmacologie informaional; 10.2. Analize de farmacologie informaional.

10.1. SINTEZE DE FARMACOLOGIE INFORMAIONAL

10.1.1. NECESITATEA APARIIEI FARMACOLOGIEI INFORMAIONALE (FI)

Farmacologia, similar cu alte tiine nrudite (biologie, medicin), a evoluat de la farmacologia clasic, la nivel fiziologic (organe, aparate, sisteme), la farmacologia modern, la nivel biochimic (celular i molecular), cu un imens ctig n detaliu i profunzime (a se vedea la cap. 6).

Farmacologia modern i-a nsuit noiunile de semnal (biologic sau farma-cologic), informaie, receptor, acceptnd faptul, evident la nivelul actual de cunoa-tere, c medicamentul acioneaz prin informaia transmis sistemului receptor specific.

Evoluia fireasc a farmacologiei moderne este spre o farmacologie ultra-modern informaional, cu un ctig n regsirea conexiunilor, a principiilor i a legilor, la nivel sistemic cibernetic - informaional (fig. 10.1).

Necesitatea introducerii n farmacologie a concepiei informaionale (a teoriei generale a sistemelor, a teoriei generale a informaiei, a legilor informaiei i ale cauzalitii informaionale) a fost semnalat [4].

* Informatologia = tiina general a informaiei (Restian, A., 1983).

538

Traductorii: baro- i chemoreceptorii, aparatul juxta-glomerular renal, receptorii presinaptici modulatori etc.

Componentele sistemului informaional uman sunt: Sursele de semnale: nucleul cu acizii nucleici (ADN i ARN), depozitele de

mediatori chimici (vezicule presinaptice, granule mastocitare, glande endocrine etc.); Canalele de comunicaie a informaiei: nervoase (fibre, sinapse) i umorale

(snge, limf); Sistemele receptoare: receptorii celulari (membranari, citoplasmatici, nucleici). Mecanismele de reglare cibernetic a organismului uman sunt: mecanismul de feed-back (mecanism de retrocontrol): ex.: feed-back

endocrin i feed-back sinaptic; mecanismul de feed-before (mecanism de anticipare): ex.: feed-before de

stres i reflexele condiionate alimentare [46].

10.1.2.2. Sistemul mesager informaional al organismului uman Se bazeaz pe triada substanenergieinformaie, triad metodologic

descris de Norbert Wiener (1948), care a artat c informaia se deosebete de substan i de energie, informaia nefiind nici substan i nici energie [56].

Informaia este foarte greu de definit. Se poate accepta urmtoarea definiie: informaia reprezint expresia ordinii i a organizrii sau a noutii pe care o poate aduce o reorganizare sau o alt ordine.

Informaia reprezint un alt aspect al realitii, care are alte legi de transformare i conservare [47].

Astfel, trebuie reinut c: Informaia poate trece foarte uor de pe un substrat pe altul; de aceea, ea nu

trebuie i nu poate s fie confundat cu substana sau cu energia care o poart; Informaia poate suferi modificri importante, prin simpla reorganizare,

chiar dac substana i energia rmn perfect conservate. Informaia are i alte uniti de msur, fa de substan i energie (tabelul 10.1).

Tabelul 10.1 Exprimarea substanei, a energiei i a informaiei

Substan Energie Informaie MAS FOR ORDINE VOLUM CMP ORGANIZARE GRAM (MOL) CALORIE BIT

Mrimea informaiei (I) pe care o aduce un eveniment, n cazul n care feno-menele sunt echiprobabile, este dat de urmtoarea ecuaie (dup Hartley R. V., 1928) [35]:

I = log2n, unde: n = numrul de evenimente posibile.

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10.2.5. NATURA INFORMAIONAL A REACIILOR ADVERSE [7, 14, 15, 25]

10.2.5.1. Conceptul de farmacotoxicologie informaional

Conceptul de farmacologie informaional, dezvoltat ca un concept de baz n farmacologie i farmacoterapie [18], conform legilor cauzalitii informaionale, evideniaz faptul c: att efectele biologice benefice terapeutic, ct i reaciile adverse (RA) sunt de natur informaional.

Dezvoltnd farmacotoxicologia informaional, conceptul relev faptul c M poate fi i nociv, nu prin cantitatea (doza) de substan n sine, ci tocmai prin infor-maia purtat de aceasta, informaie ce poate deveni agresiv pentru biologic, n anumite condiii, n corelaie cu cantitatea sa, dar mai ales cu semnificaia pe care i-o acord substratul receptor i organismul, ntr-un context spaio-temporal. Pe aceast baz, se susine importana tratrii aspectului farmaco-toxicologic, ca un fenomen informaional i nu substanial, pentru a nelege ntreg pericolul pe care M l poate constitui n anumite situaii pentru organism, nu numai la doze mari, dar posibil i la doze mici i chiar infinitezimale de substan.

Pentru c, dac se poate spune, cu o anumit certitudine, c o cretere n anumite limite a cantitii de substan medicamentoas produce o cretere att a intensitii efectului terapeutic ct i a incidenei i a gravitii RA, corolarul nu este ntotdeauna valabil. Adic, o cantitate foarte mic de substan nu este o garanie a absenei sau reducerii RA.

Exemple numeroase pot susine aceast afirmaie. Astfel, gravitatea RA de tip alergic nu este dependent gradat crescent de doza de substan medicamentoas. Un exemplu concludent l reprezint RA alergice foarte grave, ca ocul anafilactic, ce pot fi declanate i de o doz foarte mic de substan medicamentoas, cauza fiind evident de natur informaional, imunologic.

De asemenea, M cele mai toxice acioneaz asupra biologicului la dozele cele mai mici.

Or, dac ntre gravitatea RA sau toxicitatea M i mrimea dozei de substan (n grame sau moli) nu exist ntotdeauna un raport direct proporional, rezult c acestea depind direct de mrimea informaiei (n bii) adus de M.

Pe de alt parte, conform legilor cauzalitii informaionale, efectul informaiei farmacologice este dependent nu numai de calitatea i de cantitatea de semnal, ci mai ales de semnificaia pe care o acord, mesajului decodificat, un anumit tip sau subtip de sistem receptor, n funcie de programul i de particularitile sale. Aa se ntmpl, de exemplu, cu efectul proagregant plachetar al acidului acetilsalicilic (AAS), ce apare la doze mari, antiinflamatoare, i este responsabil de accidentele trombotice cum sunt accidentele ischemice cerebrale i oculare sau infarctul miocardic, semnalate mai ales la bolnavii cu factori de risc. Este evident c nu doza mare de substan este cauza acestei RA a AAS, ci specificitatea informaional a acestei doze mari de informaie pentru un anumit substrat receptor, reprezentat de ciclooxigenaza situat n endoteliul vascular. Tot astfel se explic i efectul, n sens opus, al AAS, asupra agregrii plachetare. Adic, efectul terapeutic antiagregant plachetar al AAS se datoreaz specificitii informaionale a dozelor mici de AAS pentru ciclooxigenaza din plachetele sanguine.