pharmacokinetics- a detailed and easy way to learn
- 1. pharmacokinetics - Sowmiya s MDS- 1st yr.
- 2. • Pharmacokinetics is the quantitative study of drug movement in the body. • It is the process by which a drug is absorbed, distributed, metabolized & eliminated by the body.
- 3. What is Pharmacokinetics…? • Pharmacokinetics refers to what the body does to the drug. • It controls the dose concentration relationship of the drug. • Pharmacokinetics determines: - Onset - Intensity - Duration of the drug action. • The four cornerstones of pharmacokinetics: - Absorption - Distribution - Metabolism - Elimination.
- 4. ABSORPTION: • Transfer of drug from the site of administration. • The rate and efficiency of absorption depends on the : - route of administration - Drug nature - Formulation of the drug. • IV drugs – complete absorption.
- 5. • Higher to lower concentration • Does not require any carrier or energy source • Most of the drug absorption occurs by passive diffusion • Lipid soluble drugs move faster than the water soluble drugs 1.PASSIVE DIFFUSION: TYPES OF ABSORPTION:
- 6. 2. FACILITATED DIFFUSION: • Specialized transmembrane carrier protein that facilitate the passage of the drug molecules • Can be inhibited by the compounds that compete for the carrier • Higher to lower concentration • Does not require energy 3. ACTIVE TRANSPORT: • Specialized trans membrane carrier protein is required • Drugs move against the concentration gradient (i.e from lower concentration to higher concentration) • Energy is required – obtained by ATP hydrolysis
- 7. 4. ENDOCYTOSIS AND EXOCYTOSIS: • This type used to transport large size molecule across the cell membrane • Endocytosis Involves engulfment of drug by the cell membrane and transport into the cell by pinching off the drug filled vesicle • Example: vitamin B12 –transported across gut wall- by endocytosis neurotransmitters intracellular vesicles in the nerve terminal &released by exocytosis • Exocytosis is the reverse of endocytosis 5.FLITRATION • Small drug molecules move along fluid through pores in cell walls. • No passage through the lipid matrix of cell. • Capillary membrane pores act as barriers to only very large drug molecules. • Water soluble drugs and some electrolytes are absorbed through tissue pores.
- 8. FACTORS AFFECTING DRUG ABSORPTION 1. IONIZATION 2. SOLUBILITY OF THE DRUG 3. BLOOD FLOE TO THE ABSORPTION SITE 4. SURFACE AREA AVAILABLE FOR ABSORPTION 5. CONTACT TIME AT THE ABSORPTION SURFACE 6. ROUTE OF ADMINISTRATION
- 9. 1.IONIZATION • Most drugs are weak acids & base • Unionized molecules -more lipid soluble & pass easily through membrane • Ionized molecules - low lipid solubility • THE EXTENT OF IONIZATION depends on pka (ionization constant) of drug & the pH at the site of absorption Pka – is the pH at which half the drug is in its ionized form, a measure of the extent of dissociation at any given pH • ↑ value of pka , ↓ extent of dissociation at given pH Lipid soluble drugs cross lipid cell membranes more rapidly. In Tablets disintegration and dissolution are the rate limiting step for absorption. 2.SOLUBILITY OF THE DRUG:
- 10. 3. BLOOD FLOW TO THE ABSORPTION SITE • Blood flow to small intestine is higher than stomach. • Absorption from intestine is more than stomach. 4.SURFACE AREA • More surface - more absorption • Microvilli in intestine increases surface area to 1000 folds that of stomach. 5.ROUTE OF ADMINISTRATION • Important factor to determine the rate of absorption • Some drug only absorb only from parenteral route. • Example : INSULIN 6.CONTACT TIME AT THE TIME OF ABSORPTION • More time in GIT - More absorption • In severe diarrhea – drug moves fastly in git tract parasympathetic activity ; not well absorbed • Anything delays the transport of drug from stomach to intestine delays absorption sympathetic activity anticholinergics & food
- 11. BIO AVAILABILITY • Is the fraction of unchanged drug reaching the systemic circulation following administration by any route • Example: 100mg drug administered orally , 70mg absorbed unchanged, bioavailability 70% • IV dose - 100% bioavailability (unity) • ORAL DRUG – bioavailability is less than 100% • Incomplete extent of absorption across the gut wall • First pass elimination • Bioavailability is determined by comparing plasma levels of drug after a particular route of administration (eg: oral) and after IV inj. • AREA UNDER THE CURE (AUC) - By plotting plasma concentration of the drug vs time • TOTAL AUC reflects the extent of absorption of the drug
- 12. FIRST PASS METABOLSM: • It is the process of drug metabolism before entering into systemic circulation. • during this process , certain drugs gets metabolized and are removed before they reach the systemic circulation. • This results in reduced therapeutic response of the drug
- 13. • Process by which a drug reversibly leaves the bloodstream and distributed throughout the body. • Drugs can be distributed to WATER COMPARTMENTS: plasma, interstitial fluid & intracellular fluid CELLULAR COMPARTMENTS: binding to lipids, proteins & nuclei acids • A prerequisite for most of drug to reach target organs in therapeutic concentrations. • Distribution plays a significant role in onset, intensity and some times duration of action. Factors influencing Distribution ➤Blood flow ➤Capillary permeability ➤Protein binding ➤Lipophilicity Affecting Rate of Distribution • Membrane Permeability • Blood Perfusion ■ Affecting extent of distribution • Extent of plasma protein binding • Regional differences in pH • Lipid solubility • Available transport mechanisms Intracellular Binding DISTRIBUTION:
- 14. The rate of blood flow to tissues vary widely ➤ Well perfused tissues: kidney, heart, liver, brain → ↑ blood flow faster uptake, receive the drug within minutes. ➤ Poorly perfused tissues: muscle, adipose tissue, skin⇒ ↓ blood flow slower uptake, require longer time REDISTRIBUTION: Drug effects may also be terminated by redistribution from its site of action to other tissues or sites A highly lipophilic-drug may: • Rapidly partition into the brain • Act briefly and then redistribute into other tissues often ultimately concentrating in adipose tissue
- 15. PHYSIOLOGICAL BARRIERS: Drugs, once again, must overcome these barriers • Simple capillary endothelial barrier • Simple cell membrane barrier • Blood-brain barrier» Blood-placental barrier • CSF barrier • Blood-testis barrier BLOOD BRAIN BARRIER: • Capillary boundary present between blood and brain • Drugs that are SMALL, lipid soluble and poorly bound to plasma proteins can cross BBB and produce effects in the CNS. • Highly ionized and protein bound drugs cannot enter CNS PLACENTAL BARRIER: • Lipid membrane between the mother and fetus . • Non-ionized, lipid soluble drugs readily reach fetus through maternal circulation. • Fetus is exposed to same drug concentrations as those in the mother, possibly higher.
- 16. BINDING TO PLASMA PROTEINS: • Reversible binding of drug to plasma proteins slows drug distribution • As the concentration of the free drug decreases due to elimination, the bound drug dissociates from the protein • This maintains the free-drug concentrations a constant fraction of the total drug in the plasma CAPILLARY PERMEABILITY : • Depends on capillary structure and the chemical nature of the drug • In liver, capillaries are discontinuous having large slit junctions between endothelial cells • Lipophilic drugs can pass through the endothelial cell membrane while hydrophilic substances pass through the slit junctions
- 17. VOLUME OF DISTRIBUTION: • Drug may distribute into any of the following components of body water: Plasma compartment Extracellular fluid Total body water
- 18. Calculating Volume of Distribution… • Volume of distribution (Vd) is the apparent fluid volume required to contain the entire amount of drug homogenously in the body at the same plasma concentration. Vd = Q/Cp (Q) = the total body content of the drug (Cp) = concentration equal to that present in the plasma - increase Vd - increase concentration in extravascular tissue & decreased plasma concentration (retention outside plasma) - decrease Vd - decreased concentration in extravascular tissue & increased plasma concentration (retention within plasma)
- 19. METABOLISM - BIOTRANSFORMATION: • Chemical alteration of the drug in the body. • Metabolism of a drug usually converts the lipophilic drugs into more ionized compounds and hence they are readily excreted • Liver is the main site for drug metabolism . • The end result of drug metabolism is inactivation. • Active drug to inactive metabolite: eg : phenobarbitone hydroxyphenobarbitone. • Active drug to active metabolite: eg : codeine morphine • Inactive drug to active metabolite: (PRODRUG) eg : levodopa dopamine
- 20. PATHWAYS OF DRUG METABOLISM: • Drug metabolic reaction grouped into 2 phases • Phase 1 or non synthetic phase • Phase 2 or synthetic phase
- 21. MICROSOMAL ENZYMES • They are located in the lipophilic membranes of endoplasmic reticulum (microsomes) of liver and other tissues. • These enzymes catalyse oxidative, reductive, hydrolytic and glucuronidation reactions. • Microsomal enzymes convert lipid soluble drugs into water soluble metabolites and readily excreted. • Non microsomal enzymes present in soluble form in cytoplasm, attached to mitochondria not to endoplasmic reticulum. • These are non specific enzymes that catalyse few oxidative, reductive, hydrolytic, and conjugation reactions other than glucuronidation. • These enzymes act on relatively water soluble drugs. DRUG METABOLIZING ENZYMES : NON MICROSOMAL ENZYMES :
- 22. ENZYME INDUCTION: • An enzyme inducer is a type of drug that increases the metabolic activity of the enzyme . • This occurs by either binding to the enzyme and activating or by increasing the expression of gene coding. • Agents which cause this effect are enzyme inducers
- 23. ENZYME INHIBITION: • Certain drugs inhibits the activity of drug metabolizing enzymes and are known as enzyme inhibitors. • Rapid process • May lead to drug toxicity
- 24. EXCRETION: • Removal of the drug and its metabolites from the body is known as drug excretion or elimination • Main site of drug excretion is kidneys • Renal elimination is the most important route for drug removal from the body into urine • Glomerular filtration: drugs with smaller molecules are readily filtered filtration directly proportional to GFR and to the fraction of the unbound drug in the plasma . • passive tubular reabsorption: reduces the drug excretion, • PH of the renal tubular fluid and degree of ionization affects the passive reabsorption. • Active tubular secretion: it is carrier mediated and requires energy
- 25. HALF LIFE • The time required to eliminate (metabolize and excrete) 50% of the drug from the body. • Determines the frequency of dosing required to maintain therapeutic plasma levels of a drug • Half-life depends on clearance (CL) and volume of distribution (Vd) t1/2 = 0.693 Vd/CL CLEARANCE • Clearance is hypothetical volume of body fluid from which the drug is removed/cleared completely in a specified period of time (ml/min) Rate of elimination • CL = drug concentration (c) • CLsystemic = CLKidney + CLliver + CLothers • Maintenance dose of a drug depends on total body clearance • CL is inversely related to Vd