Pharmacokinetics 2 Flashcards
Drug Distribution Factors
Passive diffusion, tissue blood flow, macromolecule binding (more binding = less distribution (can’t bind to cells = no biological effect)), p-glycoproteins (more glycoproteins = less distribution) and ion trapping (gets stuck in 1 location, poor distribution)
Relationship between blood flow and distribution
better blood flow to area = better perfusion = better distribution
Binding To Macromolecules Outline
Bind to drug in blood for transport, there is competition for drug binding. Drugs can bind and dissociate indefinetly Multiple types: albumin, alpha1 acid glycoprotein, lipoproteins and beta glycoproteins
Albumin Outline
69,000 daltons. Bind anionic (mainly acidic) drugs (eg NSAIDs and diuretics). Multiple high capacity, low affinity binding sites (2 main ones). 40% in plasma and 60% extravascular
Alpha1 Acid glycoproteins
40,000 daltons. Binds cation (alkaline) and neutral drugs. Present in acute reactions
Lipoproteins/Globulins Outline
Macromolecules. Binds lipophilic weak bases (cations)
Plasma Protein Binding Outline
Hypoalbuminemia, uremia, age and binding displacement
Hypoalbuminemia Outline
low albumin levels = increase unbound substances = faster distribution = more unsustained metabolism. Eg liver cirrousis
Uremia Outline
Excess urea in blood = decrease in drug binding. Result of kidney binding
Age relationship to binding proteins
fetuses and neonatals (newborns a few weeks old) don’t have as many binding proteins
Displacement from binding outline
When a drug is outcompeted from a binding site by another drug
Clinical importance of protein binding
Free drug conc, therapeutic window (more free drug = narrower therapeutic window = more tissue-drug interactions) and drug displacement from binding sites
Narrow Therapeutic Window Outline
1 microgram - 50 micrograms
Wide Therapeutic Window Outline
1 microgram - 1,000 micrograms
Warfarin Binding relation to aspirin
Warfarin has a high % bound to protein (98%), in 5gs there’s 0.1g free. When administerd at the same time aspirin competes for the same receptors displacing some of the warfarin doubling the amount free (ie 0.1 to 0.2g)
Location of drug and macromolecule binding
Both in blood (drug-protein) and cell (drug-protein/lipid/nucleic acid)
What state are alkaline drugs in acidic enviorments
Neutralized (non-protenised). Means that alkaline substances don’t get absorbed in stomach (lipid cells are impermeable)
Volume of Distribution Def
Fluid volume a drug would occupy if drug concentration in body (as a solution) was the same as the drug concentration in the plasma. Measure of tendency for drug to leave plasma for another site
3 sites of body’s water
Interstitial (between cells), intracellular and plasma
Evan’s Blue Mode of Distribution Outline
Drug distribution only in plasma
Inulin Mode of Distribution Outline
Drug distribution from plasma to interstitial fluid
Ethanol mode of distribution Outline
Drug distributes to all water (plasma, interstitial and intracellular)
Quinicare Mode of Distribution Outline
Drug distributes to inside of cells
Volume of Distribution Calculation
Volume = Dose/Concentration. SI units: Liters (ensure all units agree)
Volumes of Distribution Low Number (eg <30) Meaning
Acting locally. More drug in plasma then in body tissues. Needs a lower dose to fill distribution space (doesn’t travel far)
Volumes of Distribution Medium Number (eg 30-200) Meaning
Equal drug concentrations in plasma and tissue
Volumes of Distribution Very High Numbers (eg 400+)
More drug in tissues then in plasma. Needs a larger dose to fill distribution space (travels far)
Metabolism Def
Drug broken down by enzymes to a metabolite (form more easily excreted) eg p. Metabolite has it’s own pharmacological properties (potentially toxic, eg prodrug to drug)
1st pass metabolism
Metabolism in liver. Only bypassed by buccal and IV administration. Anything absorbed in GIT is brought to liver via portal vein
Relationship between metabolism, bioavailability and therapeutic activity
Lower metabolism (less chemical conversion) = higher bioavailability = higher therapeutic activities. Same dose can result in therapeutic activity by 1 admin route and toxicity via another
Phase 1 metabolism Outline
Enzymes add functional groups (eg OH, NH2, COOH) to drug. Done via oxidation, reduction, monoamine oxidase (inactivating proteins) and hydrolysis. Prepares for phase 2
Phase 2 Metabolism Outline
Parts of drug molecules are conjugated with hydrophilic groups. Increases solubility = improving excretion = inactivation of molecules
Cytochrome P450 Enzyme System Outline
Group of related enzymes with distinct properties subdivided into subfamilies and individual proteins. Requires NADPH and O2 to function. Induced by dietary factors (brussels sprouts stimulate and grapefruit juice reduce). Part of 1st pass metabolism in liver and GIT (more active in liver)
Phase 1 Oxidation Reactions
Hydroxylation (add OH), deakylation (remove CH2) and dehydrogenation (remove H)
Glucuronic Acid Conjugation
Most common type (especially when OH, NH2 and COOH). Glucuronide group is added by glucorynyl transferase from uridine diphosphate glucuronic acid
Example of metabolism to toxic metabolites
paracetamol dehydrogenated to n-acetyl-p-benzo-quioine imine. Producing protein adducts resulting in hepatic cell death
Example of meatbolism from pro to active drugs
levodopa to dopamine
