Pharmacokinetics Deals with mechanisms and quantitative characteristics ( time - and concentration – dependence ) of : absorption distribution metabolism excretion These have a direct bearing on the magnitude and duration of responses to drugs. Pharmacokinetic properties of a drug depend on physicochemical characteristics: molecular weight solubility in lipid & aqueous medium ionization state

Relationship of Pharmacokinetic Factors Drug Drug Absorption Absorption Binding to unbound drug in Plasma proteins plasma Drug at Site of action Accumulation in Tissues Metabolized Excreted

Questions & Doubts  By what mechanism & what rate does the drug get into the body and what is the optimal route of administration since rate and route of administration affect its activity.  How is the drug distributed in the body and what factors influence the level of free (unbound) drug at its site of action/site of metabolism  How does the plasma concentration of a drug relate to its therapeutic and toxic actions  How is a drug metabolized & how does the metabolism affect its biological activity  How is the drug eliminated. How do disease states affect the elimination of the drug or its metabolites  Does the elimination of a drug have any further consequences

Routes of administration  Enteral- oral, buccal, sublingual, rectal  Parenteral (other than enteral) Injection -  Intra-dermal  Subcutaneous (s.c.)  Intramuscular (i.m.)  Intravenous (i.v.)  Intra-articular  Intraperitoneal (i.p.) etc  Pulmonary - inhalation  Topical application– Skin ointment  Eye drops etc.

The Routes

Routes of Administration Comparisons 1 Route Advantages Limitations Route Advantages Limitations Oral Convenient,relatively safe, economical slower onset of action Oral Convenient,relatively safe, economical slower onset of action self medication possible variety of factors can self medication possible variety of factors can influence rate/extent influence rate/extent of absorption of absorption Intravenous rapid onset, exact control over magnitude increased risk ofADRs & duration of response, no preabsorptive self medication imprac & duration of response, no preabsorptive self medication imprac inactivation, large volume, irritating drugs -tical, reqd asepsis, sol inactivation, large volume, irritating drugs -tical, reqd asepsis, sol risk of thrombophlebitis risk of thrombophlebitis Intramuscular poorly oral absorbed drugs given absorption may be ↓ if & or as repositories for sustained action circulation impaired, & or as repositories for sustained action circulation impaired, Subcutaneous bioavailability lowered if ppt’d or inactivated at if ppt’d or inactivated at site administered, pain. site administered, pain.

Comparisons 2 Drug Advantages Limitations Drug Advantages Limitations Sublingual rapid onset, minimal 1 st pass inactivation mucosal ulceration on repeated use, highly repeated use, highly irritant drugs precluded irritant drugs precluded Inhalation rapid onset, control on magnitude and limited to gases and duration of response liquid inhalants duration of response liquid inhalants Rectal Can use in uncoop or unconscious pts, absorption variable can minimize gastric irritant effect, (sup & Inf rectal vessels) can minimize gastric irritant effect, (sup & Inf rectal vessels) reduced !st pass hepatic inactivation reduced !st pass hepatic inactivation Transdermal convenient, less fluctuation in blood drug must be lipid sol ++ levels expensive levels expensiveMisc Intra arterial used to localize effects of highly toxic agents by reducing their systemic distribution distribution Intrathecal/epidural used to produce surgical anesthesia in the conscious patient and occasional drug delivery occasional drug delivery Intra peritoneal convenient & versatile, ( there is risk of infection and adhesions) Intra capsular, Intra ventricular, intra articular, Rubifacient and counter irritants

Drug Absorption The process by which a drug, in any form, is transferred either to the blood circulation or to the target cell after the drug has made contact with the body The process by which a drug, in any form, is transferred either to the blood circulation or to the target cell after the drug has made contact with the body Form is the physical state of the drug: powder, gas, liquid ( tablet, capsule, injectables, implants etc ) Form is the physical state of the drug: powder, gas, liquid ( tablet, capsule, injectables, implants etc ) Half-life(t 1/2 ) of a drug in the body is the time taken for the plasma concentration of the drug to reduce by half. Provides a quantitative measure of drug elimination and helps decide the dosage intervals. Half-life(t 1/2 ) of a drug in the body is the time taken for the plasma concentration of the drug to reduce by half. Provides a quantitative measure of drug elimination and helps decide the dosage intervals.

Absorption Drugs are absorbed through cell membranes either by active process or by passive diffusion. Drugs are absorbed through cell membranes either by active process or by passive diffusion. Liquids are absorbed faster than solids. Liquids are absorbed faster than solids. Buccal & sublingual routes – absorption is faster & the drug bypasses liver. Buccal & sublingual routes – absorption is faster & the drug bypasses liver. Oral absorption of drugs is slower & incomplete than when given by intravenous route. Oral absorption of drugs is slower & incomplete than when given by intravenous route. Intravenous route is preferred in emergencies due to fast action & 100% drug availability for action. Intravenous route is preferred in emergencies due to fast action & 100% drug availability for action. Topically administered drugs may act locally or get absorbed & produce systemic action. Topically administered drugs may act locally or get absorbed & produce systemic action.

Processes of Drug Absorption  Passive diffusion based on lipid solubility  Size limited diffusion through pores of different sizes  Carrier-mediated (facilitated ) diffusion Lipid solubility Concentration gradient Degree of ionization Facilitated diffusion requires concentration gradient Active transport against a concentration gradient requires source of energy (usually ATP)

Equation  Fick’s Equation for passive diffusion Rate = D A ΔC K Δx Δx Where D = diffusion coefficient of the molecule in lipid phase A = surface area of absorption A = surface area of absorption ΔC = concentration gradient of drug across barrier ΔC = concentration gradient of drug across barrier K = drug partition coefficient K = drug partition coefficient Δx = thickness of the barrier Δx = thickness of the barrier

Protein binding & Distribution of drugs  Drugs exist in plasma as free fraction & protein bound fraction.  Protein bound fraction of a drug remains in blood as it does not cross cell membranes while free fraction enters tissues and produces action.  Drugs which cross placenta can affect the fetus.

Factors affecting absorption Size of drug particle (smaller the better) Surface area of absorption (villi and micro villi in the intestine and brush borders in the glomeruli) Increased circulation Porosity of absorbing areas Pinocytosis (engulfing & carry across) Lipid solubility (more lipid soluble more absorbed – water soluble get excreted ) Unionized ( acid in acidic and bases in alkaline medium ) Burns and abrasions can absorb more Food - delays Short circuiting surgery of GIT reduces surface area Gastric emptying time – fast – less absorbed and vice versa Vomiting & diarrhea Malabsorption syndrome

Bioavailability Characteristics Bioavailability is the fraction of unchanged drug reaching the systemic circulation following administration of a drug by any route Bioavailability is the fraction of unchanged drug reaching the systemic circulation following administration of a drug by any route IV route – bioavailability assumed as IV route – bioavailability assumed as 100 % 100 % Oral route – bioavailability less due to Oral route – bioavailability less due to (a) incomplete extent of absorption (a) incomplete extent of absorption (b) First pass elimination (b) First pass elimination

Routes of Administration Bioavailability General Characteristics Route Bioavailability Characteristics % IV 100 Most rapid onset IV 100 Most rapid onset IM 75 – 100 Large volumes often IM 75 – 100 Large volumes often feasible, may painful feasible, may painful SC 75 – 100 Smaller volumes, -do- SC 75 – 100 Smaller volumes, -do- Iontophoresis Large volumes, infants Iontophoresis Large volumes, infants PO 5 to <100 Most convenient, First PO 5 to <100 Most convenient, First pass significant pass significant PR 30 to<100 Lesser First pass cf PO PR 30 to<100 Lesser First pass cf PO Inhalation 5 to <100 Often very rapid onset Inhalation 5 to <100 Often very rapid onset Transdermal 80 – 100 Slow onset, prolonged action, used since no First pass since no First pass

Definitions Zero Order ( absorption ) – when the rate is independent of the amount of drug remaining in the gut. Zero Order ( absorption ) – when the rate is independent of the amount of drug remaining in the gut. First Order – when full dose is dissolved in GIT fluids the rate of absorption is proportional to the GIT concentration. First Order – when full dose is dissolved in GIT fluids the rate of absorption is proportional to the GIT concentration. Clearance (C) - measure of the ability of the body to eliminate the drug. Can be affected by disease states ( Liver & Kidney). C b (blood), C p (plasma) C u (water – unbound drug ) Clearance (C) - measure of the ability of the body to eliminate the drug. Can be affected by disease states ( Liver & Kidney). C b (blood), C p (plasma) C u (water – unbound drug ) Volume of Distribution (V d ) : the measure of the apparent space in the body to contain the drug. Volume of Distribution (V d ) : the measure of the apparent space in the body to contain the drug. V d = amount of drug in the body V d = amount of drug in the body C

Look Into The routes / their advantages and limitations The routes / their advantages and limitations Definitions of absorption and bioavailability Definitions of absorption and bioavailability and pharmacokinetics and Half-life & First and pharmacokinetics and Half-life & First Pass Effect, Zero & First order kinetics, Clearance, Volume of distribution. Pass Effect, Zero & First order kinetics, Clearance, Volume of distribution. Steps and subdivisions of the process of absorption Steps and subdivisions of the process of absorption Factors affecting drug absorption and their significance (HOW?) Factors affecting drug absorption and their significance (HOW?) Characteristics of Bioavailability Characteristics of Bioavailability