Farmacologie generala. Editia a II-a

 de Cristea, Aurelia Nicoleta

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Farmacologie generala. Editia a II-a

Farmacologie generala. Editia a II-a

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Farmacologie generala. Editia a II-a

Lucrarea de fata trateaza in exclusivitate notiunile specifice si legile generale ale proceselor si fenomenelor farmacologice. Editia a II-a apare in 2009, la 10 ani de la prima editie (1998). Continuarea vietii acestei carti de Farmacologie generala, prin reeditarea intr-o editie noua, revizuita si up-datata, se justifica prin faptul ca editia I a cartii a fost foarte bine apreciata, de catre cititorii carora le-a fost adresata (studenti, absolventi, licentiati, profesionisti in domeniu), pentru pregatirea lor in diferite etape (anul III de facultate, examen de licenta, concurs de rezidentiat, examen de atestare in specialitate). De la aparitia ei, in editia I, cartea se afla pe lista bibliografiei recomandate la nivel national, pentru examenul de licenta in farmacie, concursul de rezidentiat in farmacie si examenul de atestare in specialitatile de Laborator farmaceutic si Farmacie clinica.
Aceasta editie a II-a este revizuita si completata cu noutatile in domeniu. Sunt introduse cunostintele noi, referitoare la: sistemele enzimatice oxidazice dependente de citocromul P450 (enzimele familiei CYP), precum si inductorii si inhibitorii medicamentosi si alimentari; polimorfismul enzimatic determinat genetic; interventia determinismului genetic in manifestarea farmacologica a factorilor sex, varsta, etnie si rasa; variabilitatea inter- si intraindividuala a raspunsului terapeutic, determinata de polimorfismul genetic enzimatic si al receptorilor, factorii sex, varsta, etnie, rasa, stare de graviditate si patologie asociata (insuficientele hepatica si renala, precum si obezitate); chiralitatea (stereoizomeria) ca factor de variabilitate farmacoterapeutica; bioritmurile (cronofarmacologia); fenomenele placebo-nocebo in farmacoterapie; tipologia psihoneuroendocrina (adrenergica, opioida, serotoninergica, etc.), ca factor de variabilitate in reactivitatea la medicamente; alimentatia ca factor major de interactiuni biofarmaceutice si farmacologice cu medicamentele; biomarkeri farmacogenomici de predictie clinica a incidentei reactiilor adverse (RA) in populatie; transmisiile semnalizatoare ca loc de actiune farmaco­dinamica, revizuite si up-datate (colinergica, adrenergica, dopaminergica, serotoninergica, histaminergica, GABA-ergica, opioidergica, icosanoidergica), precum si nou introduse (glutamatergica, cannabinoidergica, purinergica).
Numeroasele exemple de medicamente date in carte sunt revizuite si completate cu medicamentele moderne, frecvent indicate in terapeutica.
Aceasta carte este un manual de invatamant dar si un ghid practic pentru profesionisti. De aceea cartea are o constructie didactica, schematica, usor de abordat atat de catre incepatori, cat si de catre profesionisti. Pentru avansati sunt utile exemplele practice prezentate in numeroasele tabele ale cartii. Prezentarea fiecarei notiuni si fiecarui fenomen este insotita de exemplele cele mai concludente din farmacologia practica. Tabelele nu sunt exhaustive, ci contin acele exemple care trebuie strict cunoscute si retinute, fiind alese dupa criteriile semnificatiei si frecventei de implicare in fenomenul discutat. De aceea, de cele mai multe ori, aceste exemple nu sunt listate in ordine alfabetica, ci in ordinea importantei.
In aceasta carte de Farmacologie generala, sunt dezvoltate in capitole separate cele 6 ramuri mari ale farmacologiei; trei fundamentale (farmacocinetica, farmacodinamia, farmacotoxicologia) si trei aplicative corespunzatoare (farmacografia, farmacoterapia, farmacoepidemiologia). Ramurile aplicative (farmacoterapie si farmacografie) sunt dezvoltate de maniera sa poata constitui o baza de studiu de Farmacie Clinica, utila atat pentru studenti, cat si pentru rezidentii in specialitate. Actualizarea datelor privind transmisiile semnalizatoare (in cadrul cap. 6) a fost realizata de tinere cadre didactice, din centrele universitare Bucuresti si Iasi.
Ultimul capitol este consacrat Farmacologiei cibernetice – informationale, care reprezinta o prioritate absoluta intr-o carte de farmacologie. In acest capitol se abordeaza aspectul informational al farmacoterapiei si se prezinta medicamentul ca semnal ce interfereaza cu semnalele biologice si actioneaza asupra unor me­canisme de reglare cibernetica. Sunt prezentate, intr-o forma didactica sintetica, concluziile la care autoarea a ajuns in studiile teoretice si experimentale pe care le-a realizat in anii 1985 – 1997, in scopul introducerii conceptiei informationale in farmacologie. Colectia de lucrari teoretice si experimentale, comunicate si publicate in tara si in strainatate de autoare, privind conceptia informationala aplicata la farmacologie, a fost apreciata de Academia Romana, cu premiul " C. I. Parhon”, pentru anul 1994. Consideram ca aceasta reeditare este oportuna, avand in vedere valoarea intrinseca a cartii (din punct de vedere atat al extinderii pe toate ramurile principale ale farmacologiei generale si al consistentei datelor, cat si al sistematizarii didactice).


C U P R I N S


Prefata la editia I................................................................................................................17
Prefata la editia a II-a........................................................................................................19
1. FARMACOLOGIE GENERALA. NOTIUNI INTRODUCTIVE.............................21
1.1. Ramurile farmacologiei.........................................................................................21
1.1.1. Ramurile principale........................................................................................21
1.1.2. Alte ramuri in dezvoltare ...............................................................................22
1.2. Stiinte de granita cu farmacologia .......................................................................23
1.3. Utilitatea practica a farmacologiei .......................................................................23
1.4. Fazele evolutiei medicamentului in organism, de la administrare pana la
aparitia efectului terapeutic ...................................................................................24
1.4.1. Faza biofarmaceutica .....................................................................................24
1.4.2. Faza farmacocinetica .....................................................................................24
1.4.3. Faza farmacodinamica ...................................................................................26
2. NOTIUNI DE BIOFARMACIE GENERALA............................................................27
2.1. Biodisponibilitatea medicamentelor.....................................................................27
2.1.1. Aspecte generale............................................................................................27
2.1.2. Tipurile de biodisponibilitate si modalitatile de determinare ........................29
2.2. Factorii care influenteaza biodisponibilitatea .....................................................38
2.2.1. Aspecte generale............................................................................................38
2.2.2. Factorii fizico-chimici ce influenteaza dizolvarea si biodisponibilitatea.......40
2.2.3. Factorii dependenti de organism, ce influenteaza absorbtia si
biodisponibilitatea..........................................................................................44
2.2.4. Modificari ale absorbtiei si biodisponibilitatii, per os ...................................49
3. FARMACOCINETICA GENERALA .........................................................................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. Absorbtia medicamentelor in organism...............................................................67
3.2.1. Aspecte generale............................................................................................67
3.2.2. Absorbtia pe cai naturale ...............................................................................72
3.2.3. Absorbtia pe cai artificiale (injectabile).........................................................89
3.3. Distribuirea medicamentelor in organism...........................................................95
3.3.1. Transportul medicamentelor in sange............................................................96
3.3.2. Difuzarea medicamentelor in tesuturi..........................................................103
3.3.3. Distribuirea propriu-zisa a medicamentelor in tesuturi................................109
3.3.4. Fixarea medicamentelor in tesuturi..............................................................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 compusilor chirali. Stereoizomeria in farmacocinetica..........168
3.5.2. Influenta interactiunilor medicamentoase....................................................170
3.5.3. Influenta unor variabile fiziologice..............................................................170
3.5.4. Influenta starii patologice ............................................................................186
3.5.5. Alimentatia ..................................................................................................189
3.5.6. Variabilitatea interindividuala in farmacocinetica.......................................190
3.5.7. Profilul farmacocinetic si clasificarea farmacocinetica a medicamentelor........192
3.6. Analiza matematica farmacocinetica. Exprimarea cantitativa a proceselor
farmacocinetice ....................................................................................................195
3.6.1. Tipuri de procese cinetice, in cadrul fazelor biofarmaceutica si
farmacocinetica............................................................................................195
3.6.2. Analiza matematica farmacocinetica. Calculul parametrilor
farmacocinetici ..........................................................................................200
4. FARMACODINAMIE GENERALA.........................................................................214
4.1. Actiunea farmacodinamica .................................................................................214
4.1.1. Etapele fazei farmacodinamice....................................................................214
4.1.2. Parametrii definitorii ai actiunii farmacodinamice ......................................214
4.1.3. Tipurile de actiune farmacodinamica ..........................................................224
4.2. Factorii care influenteaza actiunea farmacodinamica .....................................226
4.2.1. Factorii ce influenteaza actiunea farmacodinamica, dependenti
de medicament .............................................................................................226
4.2.2. Factorii dependenti de organism..................................................................236
4.2.3. Factorii dependenti de mediu si de alte conditii ..........................................251
4.2.4. Bioritmurile (Elemente de cronofarmacologie) ...........................................253
4.2.5. Asocierea medicamentelor. Interactiuni medicamentoase...........................259
4.3. Variabilitatea farmacologica inter- si intraindividuala....................................273
4.3.1. Mecanismele variabilitatii farmacologice....................................................274
4.3.2. Tipurile de variabilitate farmacologica........................................................275
4.3.3. Manifestarile clinice ale variabilitatii farmacologice...................................276
4.4. Exprimarea cantitativa a actiunii farmacodinamice. Relatii doza-efect si
concentratie-efect.................................................................................................276
4.4.1. Parametrii cantitativi ai actiunii farmacodinamice ......................................276
4.4.2. Tipurile de relatii doza - efect......................................................................277
4.4.3. Efectul mediat de receptori (R)....................................................................279
4.4.4. Variabilitatea relatiilor doza-efect, intr-o populatie.
Curbele frecventa-distributie .......................................................................286
5. FARMACOTOXICOLOGIE GENERALA..............................................................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 muschilor si tesutului conjunctiv...............................................299
5.2.11. La nivelul pielii............................................................................................301
5.3. Efecte adverse cancerigene..................................................................................302
5.4. Efecte adverse mutagene .....................................................................................303
5.5. Intoleranta ............................................................................................................303
5.5.1. Intoleranta congenitala. Idiosincrazia ..........................................................303
5.5.2. Intoleranta dobandita ..................................................................................310
5.6. Efecte adverse imunosupresive...........................................................................315
5.6.1. Agranulocitoza.............................................................................................316
5.6.2. Deficienta imunitara latenta.........................................................................317
5.6.3. Gravitatea efectelor adverse imunosupresive ..............................................319
5.6.4. Masurile de profilaxie a efectelor adverse imunosupresive.........................319
5.7. Toleranta ..............................................................................................................320
5.7.1. Toleranta innascuta.....................................................................................320
5.7.2. Toleranta dobandita ....................................................................................320
5.8. Farmacodependenta ............................................................................................322
5.8.1. Farmacodependenta psihica........................................................................322
5.8.2. Farmacodependenta fizica ..........................................................................322
5.9. Toxicomania ("Drug addiction”)........................................................................323
5.10. Reactii adverse la intreruperea farmacoterapiei ............................................325
5.10.1. Tipurile de reactii adverse la intreruperea brusca a farmacoterapiei ..........325
5.10.2. Medicamente incriminate in RA, la intreruperea 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, in perioadele prenatala si obstetricala................................333
5.12. Efecte adverse asupra sugarului.......................................................................334
6. FARMACODINAMIE FUNDAMENTALA (CELULARA SI MOLECULARA) .....337
6.1. Locul actiunii farmacodinamice .........................................................................337
6.1.1. Locul de actiune asupra microorganismelor ................................................337
6.1.2. Locul de actiune asupra macroorganismului ...............................................337
6.2. Mecanismele actiunii farmacodinamice.............................................................338
6.2.1. Mecanismele actiunii farmacodinamice asupra microorganismelor ............339
6.2.2. Mecanismele actiunii farmacodinamice asupra macroorganismului ...........340
6.3. Actiunea farmacodinamica la nivel molecular, biochimic ...............................342
6.3.1. Actiunea asupra farmacoreceptorilor (R).....................................................342
6.3.2. Actiunea asupra enzimelor (E) ....................................................................345
6.3.3. Actiunea asupra mediatorilor si mesagerilor celulari ..................................347
6.3.4. Actiunea asupra altor substraturi biochimice si metaboliti ..........................349
6.3.5. Mecanismul de tip antimetabolit..................................................................350
6.4. Actiunea in metabolismul radicalilor liberi ai oxigenului ................................351
6.4.1. Functia microbicida a radicalilor liberi ai oxigenului ..................................351
6.4.2. Patologia radicalilor liberi ai oxigenului......................................................352
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6.4.3. Mecanismele fiziologice de protectie contra agresiunii radicalilor liberi
ai oxigenului ................................................................................................352
6.4.4. Farmacologia metabolismului radicalilor liberi ai oxigenului .....................353
6.5. Actiunea farmacodinamica la nivel celular .......................................................353
6.5.1. Actiunea la nivelul membranei celulare.......................................................353
6.5.2. Actiunea la nivelul veziculelor si granulelor intracitoplasmatice ................356
6.5.3. Actiunea la nivelul organitelor celulare.......................................................357
6.5.4. Actiunea la nivel de nucleu..........................................................................357
6.6. Actiunea farmacodinamica 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. Definitia farmacoreceptorilor ......................................................................361
6.7.2. Structura biochimica a R .............................................................................361
6.7.3. Formarea complexului medicament - receptor (M-R).Tipuri de legaturi..........362
6.7.4. Rezerva de receptori ....................................................................................363
6.7.5. Factorii care influenteaza numarul si functionalitatea R .............................363
6.7.6. Situarea R ...................................................................................................365
6.7.7. Tipuri de sisteme R. Structura generala a sistemelor R...............................366
6.7.8. Mecanismul intim al functionarii R.............................................................367
6.7.9. Clasificarea receptorilor (R) ........................................................................371
6.8. Actiunea farmacodinamica la nivel sinaptic......................................................371
6.8.1. Sinapsa electrica ..........................................................................................372
6.8.2. Sinapsa chimica ...........................................................................................372
6.8.3. Mecanisme de actiune farmacodinamica asupra transmisiei
sinaptice chimice .........................................................................................379
6.9. Actiunea farmacodinamica la nivelul sistemelor de transmisie
(farmacologia transmisiilor)................................................................................380
6.9.1. Clasificarea transmisiilor .............................................................................380
6.9.2. Transmisia colinergica.................................................................................384
6.9.3. Transmisia adrenergica................................................................................394
6.9.4. Transmisia dopaminergica...........................................................................406
6.9.5. Transmisia serotoninergica..........................................................................410
6.9.6. Transmisia histaminergica ...........................................................................415
6.9.7. Transmisia GABA-ergica ............................................................................419
6.9.8. Transmisia glutamatergica...........................................................................424
6.9.9. Transmisia opioidergica...............................................................................428
6.9.10. Transmisia icosanoidergica .........................................................................437
6.9.11. Transmisia canabinoidergica .......................................................................453
6.9.12. Transmisia purinergica ................................................................................462
7. FARMACOGRAFIE GENERALA............................................................................472
7.1. Notiuni generale de farmacografie.....................................................................472
7.1.1. Medicamentul ..............................................................................................472
7.1.2. Denumirea medicamentului.........................................................................472
7.1.3. Formele farmaceutice ..................................................................................473
7.1.4. Reteta (prescriptia) medicala .......................................................................473
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7.1.5. Reglementari privind prescrierea si eliberarea medicamentelor ..................473
7.1.6. Stabilirea schemelor farmacografice ..........................................................474
7.2. Notiuni generale de posologie .............................................................................476
7.2.1. Doza.............................................................................................................477
7.2.2. Concentratia plasmatica si zona terapeutica ................................................477
7.2.3. Metabolitii activi de importanta clinica .......................................................481
7.2.4. Posologia standard.......................................................................................482
7.2.5. Scheme posologice ......................................................................................482
7.3. Individualizarea posologiei .................................................................................483
7.3.1. Adaptarea dozelor functie de factorii fiziologici biometrici ........................484
7.3.2. Individualizarea dozelor in insuficienta renala ............................................488
7.3.3. Individualizarea dozelor in enzimopatii.......................................................490
7.4. Supravegherea terapeutica si 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. Esantionul recoltat........................................................................................494
7.5.3. Momentul prelevarii esantionului ................................................................495
7.5.4. Metodologia de monitorizare si optimizare a farmacografiei ......................495
7.5.5. Metode de monitorizare a farmacografiei, pe baza "dozei-test” ..................496
8. FARMACOTERAPIE GENERALA..........................................................................503
8.1. Notiuni generale de farmacoterapie...................................................................503
8.1.1. Locul farmacoterapiei in terapeutica ...........................................................503
8.1.2. Metode farmacoterapeutice alternative .......................................................504
8.1.3. Tipuri de farmacoterapie..............................................................................505
8.1.4. Medicamente esentiale.................................................................................506
8.1.5. Clasificarea ATC a medicamentelor............................................................507
8.1.6. Produse farmaceutice cu asocieri fixe de medicamente...............................507
8.1.7. Selectivitatea clinica ....................................................................................509
8.1.8. Tendinte privind administrarea medicamentelor. Farmacomania si
farmacofobia................................................................................................511
8.1.9. Medicamente OTC ......................................................................................512
8.2. Principii pentru o farmacoterapie stiintifica si rationala.................................513
8.3. Aspecte privind incetarea farmacoterapiei .......................................................516
8.4. Supravegherea terapeutica si optimizarea farmacoterapiei ............................518
8.4.1 Etapele optimizarii farmacoterapiei, prin mecanismul de feed-back al
supravegherii terapeutice ..............................................................................518
8.4.2. Particularitatile supravegherii terapeutice....................................................519
8.4.3 Tipurile de supraveghere terapeutica ............................................................521
9. FARMACOEPIDEMIOLOGIE GENERALA..........................................................524
9.1. Notiuni introductive ............................................................................................524
9.2. Statistica reactiilor adverse si morbiditatii 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. Farmacovigilenta (FV) ........................................................................................534
9.5.1. Definitie si obiective....................................................................................534
9.5.2. Sistemul de FV ............................................................................................534
9.5.3. Sursele de informatie asupra RA.................................................................535
10. FARMACOLOGIE INFORMATIONALA
SAU FARMACOINFORMATOLOGIE (FI) ..........................................................536
10.1. Sinteze de farmacologie informationala .........................................................536
10.1.1. Necesitatea aparitiei farmacologiei informationale (FI)..............................536
10.1.2. Bazele cibernetice - informationale ale farmacologiei informationale........537
10.1.3. Farmacodinamia informationala .................................................................541
10.1.4. Farmacotoxicologia informationala ............................................................550
10.1.5. Implicatii practice ale farmacologiei informationale ..................................552
10.2. Analize de farmacologie informationala..........................................................553
10.2.1. Medicamentul ca semnal ............................................................................553
10.2.2. Cauzalitatea informationala a efectului medicamentului ............................556
10.2.3. Farmacologia informationala a dozelor ......................................................560
10.2.4. Izo-, homeo-, alo- si enantio-reglarea farmacologica a sistemului
biocibernetic uman. Notiuni de farmacocibernetica ....................................566
10.2.5. Natura informationala a reactiilor adverse..................................................569
Bibliografie specifica pentru capitolul 10.......................................................................573
Index.................................................................................................................................577
Bibliografie selectiva ........................................................................................................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
12
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. Frequencydistribution
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
13
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
14
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 "Test – Dose” 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. Cybernetic – Informational 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
21
1
FARMACOLOGIE GENERALA.
NOTIUNI INTRODUCTIVE
Farmacologia este stiinta care studiaza interactiunile dintre medicamente si
organism. Etimologic deriva de la pharmakon (grec.) = medicament, logos (grec).
= stiinta.
Farmacologia generala studiaza aspectele generale ale relatiilor dintre
medicament si organism si legile obiective pe baza carora se desfasoara aceste
relatii.
Definitii ale medicamentului
– Medicament (definitia O.M.S.) este o substanta sau produs destinat sau utilizat
pentru studierea sau modificarea unui sistem fiziologic sau unei stari
patologice, in interesul subiectului caruia i se administreaza.
– Medicament este o substanta sau preparat destinat sau utilizat pentru
diagnosticarea, prevenirea, ameliorarea sau vindecarea unei suferinte.
1.1. RAMURILE FARMACOLOGIEI
1.1.1. RAMURILE PRINCIPALE
Farmacologia moderna cuprinde sase ramuri principale, trei cu caracter predominant
fundamental si trei cu caracter predominant aplicativ. Fiecarei ramuri cu
caracter fundamental ii corespunde o ramura aplicativa [77].
FARMACOLOGIA
Ramuri cu caracter Ramuri cu caracter
fundamental aplicativ
Farmacocinetica Farmacografia
Farmacodinamia Farmacoterapia
Farmacotoxicologia Farmacoepidemiologia
(preluat dupa Dobrescu D., 1981).
Farmacodinamia si farmacotoxicologia studiaza actiunile medicamentului
asupra organismului, iar farmacocinetica studiaza actiunile organismului asupra
medicamentului.
22
– Farmacocinetica – studiaza evolutia medicamentelor in organism.
-Farmacodinamia – studiaza efectele biologice ale medicamentului in organism
(actiunile farmacodinamice).
– Farmacotoxicologia – studiaza efectele adverse si intoxicatiile acute si cronice.
– Farmacografia – studiaza regulile de prescriere a medicamentelor,
referitoare la formele farmaceutice, caile, modul de administrare si posologie
(prescrierea dozelor).
– Farmacoterapia – studiaza indicatiile terapeutice.
– Farmacoepidemiologia – studiaza contraindicatiile si precautiile, precum si
bolile de etiologie medicamentoasa cu mare raspandire.
1.1.2. ALTE RAMURI IN DEZVOLTARE
Din cele sase ramuri principale ale farmacologiei, s-au desprins si sunt in curs
de dezvoltare alte noi ramuri, asa cum sunt:
– Farmacodinamia fundamentala biochimica;
– Farmacogenetica – Farmacogenomica, Farmacoproteomica;
– Farmacocibernetica;
– Farmacoinformatologia (Farmacologia informationala);
– Cronofarmacologia;
– Stereofarmacologia (Farmacologia stereoizomerilor sau Farmacologia
compusilor chirali);
– Gerontofarmacologia.
Farmacodinamia fundamentala biochimica – studiaza locul si mecanismele
actiunii medicamentului, la nivel celular si molecular biochimic. Este o ramura ce
s-a dezvoltat rapid, pe baza exploziei de cunostinte de biologie celulara si
moleculara.
Farmacogenetica – studiaza influentele variabilitatii genetice
(polimorfismului genetic) asupra efectului medicamentului.
Farmacocibernetica – studiaza interactiunile medicamentelor cu mecanismele
de reglare cibernetica ale organismului.
Farmacoinformatologia – studiaza natura informationala a medicamentului si
a procesel


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