Basic Pharmacology - pharmacodynamics – the study of the efects of the drugs on receptors, reactions; principles of action - pharmacokinetics - the study of the movement of drugs through the body in time. (absorption, distribution, metabolism, excretion) Action of a drug requires presence of a certain concentration in the fluid bathing the target tissue. ¨ The magnitude of response (good or bad) depends on concentration of the drug at the site of action Pharmacokinetics Pharmacokinetics deals with the processes of absorption, distribution, metabolism excretion of the drug And their relationship with their biological (pharmacological) effect „WHAT DOES ORGANISM DO WITH THE DRUG“ “ADME“ elimination A D M E invasion permeation across the membranes lipophilic – difusion (passive) hydrophilic – through the pores active transport bonds of the drugs to: plasma proteins blood cells in the circulation tissue receptors perfusion of the tissues a) brain, heart, liver, kidney b) fat tissue What does influence the movements of the drug in the body? physico-chemical properties lipophilic/hydrophilic properties, molecule structure, pKa, charge… AH A- + H+ B + H+ BH+ Ionized compounds tend to be less lipid soluble. Non-Ionized compounds tend to be more lipid soluble. Stomach pH 1-2 Parietal cells + endothelium of vessels 7.2-7.4 HA H++AB+ + OH- BOH>>> >>> HA H++A-<<< B++OH- BOH<<< OATP, MDR, MRP diffusion active transport via transport proteins through the pores ABSORPTION Absorption – permeation of the soluted drug into the body fluids from the site of administration – necessary for the general (systhemic) effect Local effect – on the skin, mucous membranes… mouth, rectum, vagina - absorption is fault, can cause difficulties, adverse effects) (local aenesthetics, corticosteroids) Rate and extent of absorption are described by the parameters : C max - max. concentration of the drug in the plasma after single administration T max - time after administration, when is Cmax F - bioavailability (extent of absorption) time Plasmatic concentration of the drug Bioavailability • The fraction of the dose of a drug (F) that enters the general circulatory system, F= amt. of drug that enters systemic circul. Dose administered F = AUCp.o./AUCi.v. Relative bioavailability Influence of the various bioavailability on the plasmatic levels of the drug • P-glycoprotein – Resistance on chemotherapeutics – i. saquinavir First pass effect, presysthemic elimination www.icp.org.nz Other factors influencing the absorption gender, body weight, plasma volume, gastric amptying rate, age - pH, bile, enzyme levels and activity Patophysiological state – liver disseases, inflammation simultaneously eaten meal – acceleration/decelaration chemical incompatibilities function of the GIT = permeation from the body blood to the tissues and site of the action Is dynamic process rate - depends on: bond (with the plasmatic proteins) permeation across the membrabes blood perfusion through the organ state - distribution equilibrium; the the proportion of the free (unbounded) fractions of the drug in the blood and in the tissues are the same Barriers – the distribution is limited blood-brain barrier („leaky areas“ – area postrema), placental barrier… Distribution A bound drug has no effect! • Amount bound depends on: • 1) free drug concentration • 2) the protein concentration • 3) affinity for binding sites % bound: __[bound drug]__________ x 100 [bound drug] + [free drug] Volume of Distribution • C = D/Vd – Vd is the apparent volume of distribution – C= Conc of drug in plasma at some time – D = Total quantity (dose) of drug in system Vd gives one as estimate of how well the drug is distributed. Value < 0.071 L/kg indicate the drug is mainly in the circulatory system. Values > 0.071 L/kg indicate the drug has gotten into specific tissues. Volume of distribution – apparent, hypotethical the proportion of the quantity of the drug and reached plasmatic concentration Volumes of the water in human body water in general in whole the body extracellularintracellular intersticial plasma www.icp.org.nz www.icp.org.nz Perfusion through the organs organ perfusion rate % heart output (ml/min/g tkáně) brain 0.5 14 fat 0.03 4 heart 0.6 4 kidney 4.0 22 liver 0.8 27 musculature 0.025 15 skin 0.024 6 ELIMINATION • Kinetics of the first order = rate of elimination is descending with the descending concentration in the blood (linear kinetics) • Kinetics of the zero order = rate of elimination is constant (nonlinear kinetics) Types of Kinetics Commonly Seen • Zero Order Kinetics • Rate = k • C = Co - kt • C vs. t graph is LINEAR First Order Kinetics • Rate = k C • C = Co e-kt • C vs. t graph is NOT linear, decaying exponential. • Log C vs. time graph is linear. Biotransformation – metabolism mostly in the liver, kidney, gut, but also in other organs and tissues Enzymatic • biodegradation • bioactivation (prodrug) enalapril-enalaprilate codein-morphine bromhexin - ambroxol ELIMINATION 1. Phase : oxidation, hydrolysis Cytochrom P450, dehydrogenases 2. Phase : conjugation – metabolites are more soluble in the water Metabolite - effective („more / less / in other way“) - ineffective - toxic men plants insect funghi yeast bacteria molluscs animals CYP 450 CYP 2D6 30% CYP 1A2 2% CYP 2C9 10% other 3% CYP 3A4 55% CYP 3A4 CYP 2D6 CYP 2C9 CYP 1A2 other INDUCERS of CYP 450 • dexamethason • phenobarbital • rifampicine • phenytoin • St. John`s Wort (Hypericum perforatum) • Ginkgo biloba INHIBITORS of CYP 450 • antidepresives (fluoxetin, fluvoxamin, paroxetin) • quinine, quinidine • chloramphenicol, erythromycin • ketoconazol, itraconazol • grapefruit juice tubulární sekrece glomerulární filtrace konjugace s aminokyselinami glukuronidace acetylace porod 10 20 30 2 3 4 5 6 dny měsícedays months tubular secretion glomerular filtration acetylation conjugation with glucuronic acid conjugation with aminoacids birth Excretion Kidney (urine) liver (bile) lungh (air) saliva, skin, hair, breast milk... • MW < 60.000 D (MW albumin = 68.000 D) • tubular secretion – organic acids • furosemid • thiazide diuretics • penicilins • glucuronides – organic bases • Morphine • Atropine • Histamine… • tubular reabsorption Kidney acidification acetazolamid (inhibitor of CA) ammonium chloride alcalization sodium bicarbonate Liver Billiar excretion, clearance. enterohepatic circulation Pharmacokinetic parameters in practice Mathematical description of the pharmacokinetic processes When evaluating pharmacokinetics, we have to know plasmatic concentration of the drugs administered T [min] C [mg/ml] s.c. p.o. i.m. i.v. - after administration the concentration increases depending on the absorption rate and extent . - Tmax - Cmax. -F Single- dose administration AUC Area under the concentration curve • For IV bolus, the AUC represents the total amount of drug that reaches the circulatory system in a given time. Dose = CLT AUC AUC = D/Cl = C0/Ke = D/Ke.Vd Bioavailability • The fraction of the dose of a drug (F) that enters the general circulatory system, F= amt. of drug that enters systemic circul. Dose administered Bioavailability • A concept for oral administration • Useful to compare two different drugs or different dosage forms of same drug • Rate of absorption depends (in part) on rate of dissolution • Also first-pass metabolism is a determining factor Extravascular route - 0-100% (resp. 0-1). Intravenous - 100% = 1 If F is 0-20% = 0-0,2 – not suitable route of administration (in spite of that fact, some drugs are administered, even if the F is 2-5 % SET, bisphosphonates). F = AUCpo/AUCiv (same drug, same dose, same patient) Example: Therapeutic dose of the morphine i.v. is 10 mg. It`s bioavailability after p.o. admin. is 1/6 that is 16 %. If the same effect needed, the dose for the p.o. route of admin has to be 6-times higher - 60 mg. Bioavailability Distribution • Vd = D/C – Vd is the apparent volume of distribution – C= Conc of drug in plasma at some time – D = Total quantity (dose) of drug in system Volume of distribution Vd = hypothetical volume, apparent Vd can has values about 50000 litres (antimalarics). 1) Get know, how the drug is distributed Drug VD Comments Warfarin 8L Reflects a high degree of plasma protein binding. Theophylline , Ethanol 30L Represents distribution in total body water. Chloroquine 15000L Shows highly lipophilic molecules which sequester into total body fat NXY-059 8L Highly-charged hydrophilic molecule. 2) If the rapid reaching of the effective level of the drug in plasma after single dose is needed, it`s possible to calculate the initial dose 3) For considering the influence of the haemodialysis and hemoperfusion on the pharmacokinetics of the drug (overdosing, forensic toxicology) (the drugs with extremely high Vd can not be eliminated in this way) Elimination constant ke = lnc1 – ln c2 / t2-t1 Half-life of the elimination – the drug is completely eliminated after 4-5 t 0,5 (1 t 0.5 = 50 %, 2 t 0.5 = 75 %, 3 t 0.5 = 87.5 % 4t 0,5 = 93.75 %) t 0,5 = ln2/ ke = 0,7/ ke clearance ClTOT = D/AUC = ke Vd Volume of the blood in a defined region of the body that is cleared of a drug in a unit time Elimination (first order) Kinetics of elimination of the 1st order – ln (c) time1 2 3 4 5 time1 2 3 4 5 10 8 6 4 2 5 2.5 1.25 ln ct = lnc0 - ke.t y = -ke . x +b ct = c0 . e(-k.t) c semilog plot (i.v. admin) Normal plot (i.v. admin) ln ct = ln c0 – Ke.t lnc1 – ln c2 t2-t1 ln (c) time1 2 3 4 5 ln c1 ln c2 Ke = t2t1 lnc1 – ln c2 t2-t1 tg α = Κα = Κα = Κα = Κe Half-Life • C = Co e - kt • C/Co = 0.50 in the time of 1 half-life • Thus: 0.50 = e – k t • ln 0.50 = -k t ½ • -0.693 = -k t ½ • t 1/2 = 0.693 / k ct = c0 . e(-k.t) ln ct = lnc0 - ke.t Clearance • Volume of blood that is cleared of a drug in a unit time. • Clearance is a more useful concept in reality than t 1/2 or kel since it takes into account blood flow rate • Clearance varies with body weight • Also varies with degree of protein binding - Continual drug administration - Administration of the drug e.g. by the infusion pump - if lasts longer, the plasma concentration of the drug increases until the elimination rate become equal to the drug intake – plasmatic concentration is steady the plateau state (Css). i.v. infusion I.v. infusion Time In steady state holds generally: Drug is already bound to all of the bonding sites = distribution is finished. The amount of the eliminated drug is equal to the administered dose in the same time interval. Inflow rate [mg/min] = elimination rate [mg/min] (1) I.v. infuion i.v. infusion End of the infusion Time [in half-lifes of elimination] Concentration intra- (repeated i.v. injections) or extravascular (e.g.p.o.). Accumulation of the drug -If the interval between the doses is too short and the drug is not eliminated Steady state - Elimination rate is equal to the „inflow rate“ – dose per hour inflow rate [mg/min] = Cl x Css Instead of Css is denominated average concentration in steady state (Cssplateau), what is average concentration calculated from the concentrations oserved during 1 interval between doses. Repeated drug administration The equation is usually modified by the factors: 1) F – bioavailibility 2) ττττ –dosing interval - the concentration fluctuates from the Cminplato to the Cmaxplato during 1 dosing interval The fluctuation is proportional to the dosing interval cxCl FxD plateauss= τ Repeated drug administration Repeated drug administration Repeated drug administration The Compartment Model Body = a series of interconnected well-stirred compartments within which the [drug] remains fairly constant. Movement BETWEEN compartments is important in determining when and for how long a drug will be present in body. i.v. Vd ke Vd ke A (GIT) ka The Compartment Model 1- compartment model D D i.v. Vd1 k10 Vd2 k12 k21 central compartment peripheral compartment D 2- compartment model Vd1 k10 Vd2 k12 k21 A (např. GIT) ka D 2- compartment model central compartment peripheral compartment Vd1 k20 Vd2 k12 k21 A (GIT) ka k10 D 2- compartment model central compartment peripheral compartment Vd1 k20 Vd2 k12 k21 central compartment A (např. GIT) ka peripheral compartment 1- compartment model Intravascular administration Extravascular application 2- compartment model Intravascular administration Extravascular application Basic pharmacokinetic parameters • Cmax • Tmax - time to reach Cmax • ka = absorption constant • ke = elimination constant = • t1/2 = • Vd = = • Cl = Clren + Clhep + Clpl ...+ Cli • AUC = D/ Cl = C0 / Ke = D/ ke.Vd ln c1 – ln c2 t2 – t1 [h-1] ln2 ke [h] F. D c0 F. D [l] AUC.ke [l .h-1] [mg. l-1 .h]