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Pharmacokinetics Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
What is Pharmacokinetics ,[object Object],[object Object],[object Object]
Relationship – Dynamics and Kinetics Dosage Regimen Concentration in Plasma Concentration at the site of action Absorption Distribution Metabolism Excretion Pharmacokinetics Pharmacodynamics Effect
The Pharmacokinetic Process Blood
The Pharmacokinetic Process
Biological Membrane - image
Drug Transportation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Passive transport  (down hill movement) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Passive transport ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Remember ! ,[object Object],[object Object]
pH Effect ,[object Object],[object Object],[object Object]
Henderson–Hasselbalch Equation ,[object Object],pKa = negative logarithm of acid dissociation constant [A-] = ionized Drug [HA] = unionized drug [A-] [HA] [HA-] [A-]
pH Vs ionization
Implications ,[object Object],[object Object],[object Object],[object Object],[object Object]
Examples – common concept ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Filtration ,[object Object],[object Object],[object Object],[object Object]
Filtration
Carrier Mediated Transport ,[object Object],[object Object],[object Object],[object Object]
Facilitative transporters ,[object Object],[object Object],[object Object]
Active Transport –  energy dependent ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Major Drug Transporters ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Pinocytosis ,[object Object]
Images from Text  book
1.  Absorption of Drugs ,[object Object],[object Object],[object Object],[object Object]
Factors affecting absorption ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Factors affecting absorption – contd. ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Factors affecting absorption – contd. ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Factors affecting absorption – contd. ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Oral Administration – 1 st  pass metabolism ,[object Object]
1 st  pass Elimination – Metabolism in liver Buccal cavity Stomach Intestine Rectum Portal vein Vena cava
Buccal and Rectal – bypasses liver Vena  cava
Absorption – contd. ,[object Object],[object Object],Inhalation->Sublingual->Rectal->intramuscular->subcutaneous->oral->transdermal  Example – Nitroglycerine: IV effect – immediate, SL – 1 to 3 min and per rectal – 40 to 60 minute
  Route for administration  -Time until effect- ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Bioavailability – Practical Parameter ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Biovailability  - AUC Plasma concentration (mcg/ml) Time (h) 0 5 10 15 AUC p.o. F = ------------ x 100% AUC i.v. AUC   – area under the curve F –   bioavailability
Biovailability – contd. MTC MEC
2. Distribution of Drugs ,[object Object],[object Object],[object Object]
Volume of Distribution (V) ,[object Object],[object Object],[object Object],Dose administered IV Plasma concentration
Volume of Distribution (V) Total Body Fluid = 42 L (approx.)
Volume of Distribution (V) ,[object Object],[object Object],(WHY ?) `Vd`  is an imaginary Volume of Fluid which will accommodate the entire quantity of the drug in the body, if the concentration throughout this imaginary volume were same as that in plasma
Volume of Distribution (V)  Vd = IV dose/C
Factors influencing Vd  ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Clinical Significance - Summary ,[object Object],[object Object],[object Object],[object Object],[object Object]
Redistribution ,[object Object]
Brain and CSF Penetration ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Brain and CSF Penetration – contd. ,[object Object],[object Object],[object Object],[object Object],[object Object]
Placental Transfer ,[object Object],[object Object],[object Object],[object Object]
Plasma Protein Binding ,[object Object],[object Object],[object Object],[object Object],[object Object]
Plasma Protein Binding – contd. ,[object Object],[object Object],[object Object],[object Object]
Tissue storage ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
3. Biotransformation Metabolism of Drugs
What is Biotransformation?  ,[object Object],[object Object],[object Object],[object Object]
Results of Biotransformation ,[object Object],[object Object],[object Object],[object Object],[object Object]
Biotransformation - Classification ,[object Object],[object Object],[object Object]
Phase I - Oxidation ,[object Object],[object Object],[object Object]
Oxidation – contd. ,[object Object],[object Object]
Phase I - Oxidation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Oxidation - CYP CYP3A4/5
Nonmicrosomal Enzyme Oxidation ,[object Object],[object Object],[object Object],[object Object],[object Object]
Phase I - Reduction ,[object Object],[object Object],Levodopa (DOPA)  Dopamine DOPA-decarboxylase
Phase I - Hydrolysis ,[object Object],[object Object],Ester + H 2 0  Acid + Alcohol Esterase
Phase I – contd.  ,[object Object],[object Object]
Phase II metabolism ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Phase II metabolism – contd. ,[object Object],[object Object],[object Object],[object Object],[object Object]
Phase II metabolism – contd. ,[object Object],[object Object],[object Object],[object Object],[object Object]
Phase I and Phase II Reaction Drug Metabolite Metabolite EXCRETION Metabolite Phase I Phase II Phase II Metabolism
Factors affecting Biotransformation ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Enzyme Inhibition ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Microsomal Enzyme Induction ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Microsomal Enzyme Induction – contd. ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
4. Excretion
Organs of Excretion ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Hepatic Excretion ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Portal vein Bile  duct Intestines
Renal Excretion ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Glomerular Filtration ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Tubular Re-absorption ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Tubular Secretion ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Renal Excretion – must remember! ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Kinetics of  Elimination ,[object Object],AUC p.o. F = ------------ x 100% AUC i.v. 10 mcg/ml Drug in >10 mcg/ml Plasma 500mcg/min 10 mcg/ml = 50 ml/min CL =  500 mcg/min Organ of Drug Elimination (Kidney, liver etc.)
Clearance ,[object Object],[object Object],[object Object],[object Object]
Kinetics of Elimination ,[object Object],[object Object],[object Object],[object Object],[object Object]
Plasma half-life ,[object Object],[object Object],[object Object],[object Object],[object Object],CL = RoE/C V = dose IV/C
Kinetics of Elimination Zero Order  1st Order conc. Time
Plasma half-life ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],50 + 25 + 12.5 + 6.25 = 93.75 93.75 + 3.125 + 1.56 =  98% after 5 HL
Repeated Dosing ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],target Cpss x CL F V  max  x (C) K m  + C Dose Rate Ave Cpss 1 st  order O  order
Excretion - The Platue Principle ,[object Object],[object Object],[object Object]
Target Level Strategy ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],target Cpss x CL F
Monitoring of Plasma concentration ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Prolongation of Drug action ,[object Object],[object Object],[object Object],[object Object]
Summary – Must Know ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
 

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Pharmacokinetics (updated 2011) - drdhriiti

Notes de l'éditeur

  1. The pH scale is logarithmic and as a result, each whole pH value below 7 is ten times more acidic than the next higher value. For example, pH 4 is ten times more acidic than pH 5 and 100 times (10 times 10) more acidic than pH 6. The same holds true for pH values above 7, each of which is ten times more alkaline (another way to say basic) than the next lower whole value. For example, pH 10 is ten times more alkaline than pH 9 and 100 times (10 times 10) more alkaline than pH
  2. A chemical substance that takes on oxygen or gives up electrons to another substance. Read more: Oxidation-Reduction Reaction - examples, body, used, water, process, life, plants, chemical, form, energy, gas, animals, carbon, oxygen, substance, plant, Redox and electron exchanges http://www.scienceclarified.com/Oi-Ph/Oxidation-Reduction-Reaction.html#ixzz0wPXCNZTp Reduction: A process in which a chemical substance gives off oxygen or takes on electrons. Read more: Oxidation-Reduction Reaction - examples, body, used, water, process, life, plants, chemical, form, energy, gas, animals, carbon, oxygen, substance, plant, Redox and electron exchanges http://www.scienceclarified.com/Oi-Ph/Oxidation-Reduction-Reaction.html#ixzz0wPXUgtyL
  3. Faeces: Liver actively transport drugs and its metabolites into bile (Glucoronides). OATP – orgnic acids and OCT – organic bases. Other lipophillic drugs – by P-gp. Most lucoronides are deconjugated by bacteria and reabsorbed in intestine – enterohepatic circulation. Drugs – erythromycin, rifmpicin and tetracycline etc. Ultimate excretion occurs in urine Milk – not importnt for mother but for fetus. Basic drugs can pass to milk as it has slightly lower pH Drugs – Saliva – Lithium, KI, heavy metals and rifampicin
  4. Although Cpss cn be calculated, its real value actually varies with individuls – deviation from averge ptients