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pharmacokinetics ppt
pharmacokinetics - pharmaco: drug kinetic: movement The study of drug movement through the body; or "what the body does to the drug" how does a drug reach the sites of action within the body? - the four pharmacokinetic processes - ADME administration/absorption distribution metabolism excretion drug absorption definition - time from administration to entrance into the bloodstream!
- onset of action is largely determined by the rate of absorption [onset of action = time it takes for a patient to feel the smallest amount of relief]
- intensity of effect determined by the extent of absorption
- bioavailability = % of dose that enters the blood --> IV 100% [entering directly into the bloodstream] PO < 100% absorption -
- extent of movement depends on the ability of drugs to pass to and from the major spaces of the body: intracellular, intravascular, and interstitial
- diffusion of a molecule from area of high concentration to low concentration
- in many cases, drugs can pass freely between wide junctions, or gaps, in a capillary wall [Hydrophobic, small, non-polar, lipid soluble - pass through passive diffusion, easily in and out]
- at other times drugs must pass across membranes via
channels or pores transport systems direct membrane penetration [drug must be lipid soluble, nonpolar, or nonionized] Some drugs may need help from active transporters if they are larger or charged in order to get to the site of action pH partitioning (ion trapping) - Ionized acid attaches to a weak, nonionized acid Traps it Can't go back - stays in the blood stream Important for absorption and excretion Drugs that are toxic - blood needs to be alkalinize the blood - drug gets inactivated mechanisms of drug transport - Passive Diffusion •Lipophilic •Small size Active Transport •Electrolytes Carrier Proteins •Structurally selective •Hormones Endocytosis •Immune Complexes
Expensive, inconvenient, cannot take it back, infection, fluid overload, embolism Route of Administration: Intramuscular (IM) and subcutaneous (SC) - •Barriers to absorption None: easily passes through spaces of capillary wall •Patterns of absorption Rapid or slow Water solubility of the drug Blood flow to the site of injection •Advantages Good for meds with poor water solubility Used for administration of depot preparations •Disadvantages Discomfort, inconvenient, can be painful, infection, nerve damage Routes of Administration: Oral (PO) - Advantages •Easy, convenient, safe Barriers to absorption •Requires patient cooperation, epithelial cells ling the GI tract, •Patterns of absorption are highly variable Solubility/Stability of the drug Gastric and intestinal pH Gastric emptying time
Presence of food Co-administration of other drugs Coatings on the drugs First pass metabolism à Passes the liver before it gets to the plasma Only happens with PO Additional routes of administration - •Topical •Transdermal •Sublingual •Inhalation •Suppository •Direct injection to the site of action Factors Affecting Absorption - •Route •Formulation (chemical makeup) •Dyes, binders, coatings •Solubilizers •Liposomal preparation •Particle size •Acid-base properties •Temperature •Blood flow The goal of drug therapy is to provide maximum benefit with minimum harm - •Administration Medication Errors
Dependent on blood flow: if it is slower/not adequate, the drug will not be distributed in the way that it is supposed to Ex. Doing compressions after administering a drug during CPR entering cells - -Some drugs must enter cells to reach their sites of action, and most must enter to undergo metabolism and excretion -Lipid solubility -Transport system exiting the vascular system -
- capillary beds
- blood brain barrier ^ tight junctions ^ not fully developed in infants
- placental drug transfer ^ not an absolute barrier
- protein binding ^ plasma albumin ^drugs can form reversible bonds ^ bound molecules cannot reach their sites of action, metabolism, or excretion ^ drugs with the ability to bind to albumin will compete for sites and may displace other drugs causing increased levels of the free drug protein binding - Medication that is bound to plasma will stay there and act as a drug reservoir Drugs that are highly protein bound will stay in the plasma longer (longer half life) Free drug exits out easily
All the protein bound still in the vasculature; they will start to reverse once all the free drug is gone (binds will break and they will become free drugs) plasma binding proteins - Albumin •Most abundant, low affinity •Least selective Globulin •Low concentration, high affinity •Selective binding to sex steroids Alpha 1 glycoproteins Lipoproteins process of protein binding -
- Only free drug is active!!
- Bound drug is inactive because of the large size •Drug Reservoir •Released as free drug is utilized
- Bound drugs have a longer half-life •Epinephrine 0% bound •T ½= 15 seconds •T1/2= 6 hours •Binding can result in drug interactions •Warfarin 99% bound •Aspirin 50% bound
•E.g procainamide, voriconazole Potential site for drug interactions •E.g. Quinidine displaces Digoxin from muscle deposits leading to digitoxicity Barriers to distribution - •Blood brain barrier •Blood testes barrier •Placental barrier
- Most drugs cross placenta
- Many can enter breast milk as well metabolism - BIOTRANSFORMATION - the chemical alteration of the drug structure
- main site of metabolism is the liver [cytochrome p450 system) first pass effect -
- rapid inactivation of some oral drugs as the pass through the liver after being absorbed
- parenteral administration will bypass this effect nutritional status - adequate nutritional status provides the required cofactors for the hepatic drug metabolizing enzymes to function competition between drugs - two or more drugs that use the same metabolic pathway may cause a decrease in metabolism of one or more
Metabolism: Special Considerations - Age •Infants - liver is not fully developed. Toxicity can build up Induction of drug metabolizing enzymes •Some drugs can cause the liver to synthesize more drug metabolizing enzymes •Increases metabolism of the drug •Increases metabolism of other drugs Inhibition of drug metabolizing enzymes •Decrease rates of drug metabolism CYP 450 inducers - speed up metabolism •Rifampin •Rifabutin •Carbamazepine •Phenobarbital •Phenytoin •Nevirapine, efavirenz •St. John's wort •Troglitazone, pioglitazone •Cruciferous veg, char-broiled foods, nitrates •Cigarette smoking, chronic alcohol consumption ex - birth control will not be as effective if pt is also taking an inducer CYP 450 inhibitors -
-Drugs going from the blood into the glomerulus -Glomerular filtration rate will tell us how well the drug can be eliminated from the body -You can only excrete water soluble drugs -Lipid soluble drugs go back into the blood stream to go back to the liver to get biotransformed (metabolized) - now water soluble and can go to the kidneys to get excreted factors that modify renal drug excretion - •pH-Dependent Ionization •Competition for Active Tubular Transport non-renal routes of drug excretion - •Breast milk •Bile (Stool) •Lungs (Exhalation) •Sweat and saliva time course of drug response - Serum/Plasma Drug Levels Drug levels are highly predictive of therapeutic and toxic responses minimum effective concentration (MEC) - the minimum plasma drug level at which therapeutic effects will occur toxic concentration - the level at which toxic effects can occur therapeutic range - falls between the MEC and toxic concentration
- enough drug is present to produce a therapeutic response narrow vs. wide & safety implications Narrow range: a lot easier to reach toxic concentration Wider range: harder to reach the MEC drug half life - the time required for the amount of drug in the body to be decreased by half dependent on plasma binding proteins plateau - •When a steady level of drug has been achieved •When the amount of drug eliminated between doses equals the dose administered •It takes 4-5 half-lives to achieve plateau!! Reducing fluctuations in drug levels - •Administer a continuous infusion •Administer a depot preparation •Reduce the size of a dose and the dosing interval peak and trough - peak - the highest blood level of drug trough - the lowest blood level of drug
- for trough lab, •draw serum level immediately before administration of next dose Draw level right before you give the next dose of medication Med due at 6, draw trough at 5:59. this tells us the lowest amount of drug concentration in the blood. This tells how the body is metabolizing and eliminating the drug High trough - pts body is not doing a good job
