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Pharmacokinetics Absorption:

Pharmacokinetics Absorption Dr.S.P.Dhanya Assistant Professor Dept of Pharmacology Govt TD Medical College

Why to learn?:

Why to learn? Dose Route Frequency Duration Study the effect with minimum ADR

The biological membrane:

The biological membrane

Drug transport:

Drug transport Passive diffusion Filtration Specialized transport

Passive diffusion:

Passive diffusion Most important In the direction of concentration gradient More lipid soluble—greater diffusion Greater difference in conc ---faster diffusion

Filtration:

Filtration Passage through aqueous pores Osmotic pressure gradient Molecular size Rate of blood flow Bulk transport Through

Specialized transport:

Specialized transport Carrier mediated Facilitated diffusion Active transport Primary active transport Secondary active transport Pinocytosis

Carrier mediated:

Carrier mediated Combine transiently Undergo conformational change Specific Saturable - Michaelis menton kinetics Competitively inhibited Slower Density of transporter Genetic polymorphism Tissue specific distribution

Facilitated diffusion:

Facilitated diffusion SLC transporters No energy required In the direction of electrochemical radient E.g. GLUT4-glucose

Active transport:

Active transport Requires energy Against electrochemical gradient Inhibited by metabolic poisons E.g.levodopa and methyldopa-aromatic amino acid transporters

Primary active transport:

Primary active transport Energy obtained by hydrolysis of ATP E.g -P glycoprotein ABC transporter

Secondary active transport:

Secondary active transport Active transport Energy to pump one solute Down hill movement Symport Antiport /exchange transport OAT/OCT

Via ion channels:

Via ion channels Na+, Ca+ Endocytosis Receptor mediated Pinocytosis immunoglobulin

Absorption :

Absorption Movement-site of administration to circulation

Factors affecting absorption:

Factors affecting absorption 1. Formulation solution>suspension>capsule>tablet Particle size Salt form Amorphous form Anhydrous form Excipents and adjuvants

2. Degree of ionisation:

2. Degree of ionisation Influence of pH Ionisation -pH dependent Weakly acidic drugs-unionize in acidic pH Weakly basic drugs-unionize in alkalinepH

PowerPoint Presentation:

Pka = pH+log ( unionised ) ( ionised ) e.g. Decrease in pH from 3 to 2 for a drug with Pka 3 will increase the conc of unionised drug 10 times

Pharmacological factors:

Pharmacological factors Gastric emptying and GI motility Gastrointestinal disease Presence of food Drug-drug interactions Pharmacogenetic factors Area of absorbing surface State of blood circulation

Example:

Example pH=3,Pka=3 then 3=3+log( unionised ) ( ionised ) Antilog 0=( unionised ) ( ionised ) 1=( unionised ) ( ionised ) unionised = ionised pH=2,Pka=3 then 3=2+log( unionised ) ( ionised ) Antilog 1=( unionised ) ( ionised ) 10=( unionised ) ( ionised ) unionised is 10 times more than ionised

8. First pass metabolism:

8. First pass metabolism Metabolism-absorption-systemic circulation Orally administered Intestinal wall , liver , skin , lungs Determinant of oral bioavailability High oral dose Individual variation Liver disease competition

High first pass metabolism:

High first pass metabolism Not given orally Lignocaine Isoprenaline Hydrocortisone testosterone Orally given Morphine Salbutamol Glyceryl trinitrate Propranolol

100% oral bioavailability:

100% oral bioavailability Digitoxin Isosrbide mononitrate Linezolid

9.Route of administration:

9.Route of administration Oral Passive diffusion-lipid solubility pH-acidic drugs absorbed Active transport-P gp Slow and erratic destruction by HCl-PnG,Insulin Presence of food Altered flora and motility

PowerPoint Presentation:

pH Membrane Surface Area Transit Time By-pass liver BUCCAL approx 6 thin small Short unless controlled yes STOMACH 1 – 3 Normal Lipophilic,acidic and neutral drugs small 30 - 40 minutes, reduced absorption no DUODENUM 5 – 7 Normal Mainly lipohilic and neutral drugs large very short (6" long) no SMALL INTESTINE 6 -7 Normal All types of drugs very large 10 - 14 ft, 80 cm 2 /cm about 3 hours no LARGE INTESTINE 6.8 - 7 - not very large 4 - 5 ft long, up to 24 hr lower colon, rectum yes

INFLUENCE OF DRUG pKa AND GI PH ON DRUG ABSORBTION:

INFLUENCE OF DRUG pKa AND GI PH ON DRUG ABSORBTION 33 Drugs Site of absorption Moderately weak acids ( pKa 2.5 – 7.5 ) Unionized in gastric ph Ionized in intestinal ph Better absorbed from stomach Strong acids ( pKa <2.5) Ionized at all ph values Poorly absorbed from git Moderately weak bases ( pKa 5 – 11 ) Ionized in gastric ph Unionized in intestinal ph Better absorbed from intestine Strong bases ( pKa >11) Ionized at all ph values Poorly Absorbed from GIT

Parenteral :

Parenteral IV-100% IM> SC Faster and predictable than oral administration Application of heat muscular exercise Incorporation of hyaluronidase

Topical site:

Topical site Depends on lipid solubility E.g. hyoscine , fentanyl,GTN,nicotine,testosterone Abraded surface-readily absorb drug Cornea-permeable to lipid soluble drug

Bioavailabilty(F) :

Bioavailabilty (F) Rate and extent of absorption of drug from a dosage form as determined by its concentration time curve in blood or its excretion in urine

PowerPoint Presentation:

Fraction of administered -unchanged IV-100% Frequently lower after oral administration Incomplete oral administration First pass metabolism F= AUC (oral) X 100 AUC(IV)

PowerPoint Presentation:

Biologically inequivalent Bioequivalent Clinical significance Low safety margin eg.digoxin Drug intoxication Precise control-oral hypoglycemics,oral anticoagulants Therapeutic failure Drugs with mixed kinetics

Delay absorption:

Delay absorption Using appropriate dosage forms Changing the physical characteristics Adding vasoconstrictor drug Applying tourniquet

Facilitate absorption:

Facilitate absorption Addition of hyaluronidase Hot fomentation Hot massage

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