PHARMACOLOGY 2 Flashcards
what are xenobiotics?
foreign compounds with no nutritional value
what is the overall repoonse of patients due to?
Pharmacodynamic effects
Pharmacokinetic effects
what does absorption, distribution and metabolism depend on?
Route of administration of drug
Physico-chemical properties of drug
how can things diffuse through the cell membrane?
through the lipid bilayer, aqueous channels or special transport proteins eg. carrier/channel proteins
what are chemical properties of drugs?
Drug Structure
Molecular Weight
Lipophilicity
Ionisation
what are physiological variables affecting drugs absorption?
pH of site Surface area of memb Mesenteric blood flow Gastric emptying Presence of food Efflux transporters
what is bioavailability?
% of the administered dose reaching the systemic circulation as unchanged drug (not as metabolites)
what is bioavailability governed by?
Absorption
First pass metabolism
where do most drugs need to be absorbed into?
the bloodstream, usually from the GI tract
where do enteral/oral go to?
to/through epithelium of G.I. tract (any location, from oral to rectal mucosa, could be many formulations
what does drugs given parenterally mean?
aside from intestine
where do drugs given parenterally cross and avoid?
may cross epithelium (e.g. skin, lung)
may avoid epithelium (e.g. subcutaneous, intramuscular, intrathecal, intraperitoneal injection)
what other ways are drugs administered?
directly into bloodstream
some drugs act locally at site of application, topical administration eg skin, eyes, vagina, nasal mucosa, airways
what do drugs given directly into the bloodstream allow?
absorption avoided by intravascular administration, e.g. intravenous, intra-arterial.
used for infusion, large volumes
what does ADME stand for?
absorption
distribution
metabolism
excretion
what is pharmacokinetics?
study of these processes to understand size and duration of response
what does distribution depend on?
on molecular size, ability to cross memb and extent of binding to plasma proteins.
what does plasma protein binding involve?
Loose electrostatic bonding, especially to albumin (for acidic drugs) and acid glycoprotein (for basic drugs)
what is equilibrium established between?
between bound & free form
what does equilibrium allow?
reduces free drug conc available in plasma to reach site of action
how does elimination occur?
Renal excretion
Liver metabolism Chemical transformation
what are the 2 compounds not metabolised, and cleared almost exclusively by glomerular filtration?
Small water-soluble molecules
Some complex carbohydrates
what drugs are extensively metabolised?
Lipophilic drugs
what would happen to lipophilic drugs if metabolism didn’t occur?
lipophilic drugs would be recycled endlessly through glomerular or enterohepatic re-absorption
what reactions are phase I metabolism?
Functionalisation reactions
what reactions are phase II metabolism?
Conjugation reactions
what reactions are phase III metabolism?
Formation of xenobiotic- macromolecule adducts
what is phase I metabolism?
Addition or unmasking of a functional polar group
give examples of phase I metabolism
Oxidation Reduction Hydrolysis Hydration Isomerisation Miscellaneous
what occurs to go from phase I to II metabolism?
Addition of a polar group
Catalysed by transferases
Cofactor donor
what are properties of drug-metabolising enzymes?
Low substrate specificity May have low reaction specificity Lower catalytic rates but may be present in high conc Substrates are usually lipophilic Enzymes are inducible
where does drug metabolism mainly occurs?
in 2 sub-cellular compartments in liver
Smooth Endoplasmic reticulum
cytosol
what is the Smooth Endoplasmic reticulum?
Continuous network of filamentous, memb bound channels
what happens when the drug reaches the Smooth Endoplasmic reticulum?
Cell disruption breaks the endoplasmic reticulum into small fragments which have metabolising enzymes
associated - Microsomes
give examples of Microsomal enzymes
Cytochrome P450
Flavin monooxygenase (FMO)
Glucuronosyl transferase
Epoxide hydrolase
give examples of Cytosolic enzymes
Aldehyde oxidase Aldehyde dehydrogenase Alcohol dehydrogenase Glutathione transferase Sulphotransferase
give examples of Mitochondrial enzymes
Aldehyde dehydrogenase
Monoamine oxidase
what are oxidation reactions catalysed by?
Cytochrome P450
give examples of factors that affect metabolism
Competition between substrates Inhibition of enzymes by drugs Induction of enzyme systems Age, nutritional status, liver disease Genetic polymorphism
how does induction of enzyme systems affect drug metabolism?
Inhibits function of repressor gene therefore operator gene active more mRNA more enzyme protein. rate of metabolism of barbiturates & other drugs increases and drugs become less effective
how does genetic polymorphism affect drug metabolism?
individuals or population groups may have less/more of particular enzymes & show slower/faster rates of metabolism
what is the role of the liver in drug metabolism?
Major site of drug metabolism & drug metabolising enzymes
what is first pass metabolism?
delivery of drug direct to liver after oral administration
what compromises metabolism/excretion of drugs?
Liver disease, liver function failure, reduction of synthesis of plasma proteins
give examples of inter-individual factors
species
sex
genetic factors
give examples of intra-individual factors
age pregnancy stress disease nutrition enzyme induction enzyme inhibition
what does drug effect in individual patient depend on?
Dose, potency, efficacy Mechanism of action Route of administration, extent of absorption Patient compliance Age, body weight, sex Rate of inactivation/excretion (liver, kidney function) Genetic factors Other drugs Placebo effect Disease Tolerance to drug
