02- Drug Distribution, Metabolism and elimination Flashcards
(43 cards)
Roughly how much drug remains free and unbound at physiological pH?
About 20%
How does P-Gp work with the blood-brain barrier?
Works against us, we need drugs to move past P-Gp without issue. Makes disease states of the brain difficult to treat
How does P-Gp work with the fetal-placental barrier?
Works with us, protects the baby from medications that could harm it
What is the first pass effect?
Before entering systemic circulation, drugs first go through the hepatic portal circulation and some drug is inactivated by the liver
How do you avoid the first pass effect?
- Parenteral administration, goes directly into systemic circulation
- Rectal administration, partial avoidance of the first pass effect
Define metabolism:
Process by which drugs are biotransformed into water soluble compounds that are easily excreted by the kidneys
What are some of the consequences of metabolism?
- Biologically active drug is metabolized into one or more inactive, water soluble metabolites, terminating the therapeutic response
- Biologically active drug yields metabolites that are still active, prolonging the therapeutic response
- The biologically inactive drug (prodrug) is metabolized and activated, initiating the therapeutic response
What happens to codeine when its metabolized?
Turns into morphine
What happened when mothers were given codeine after labour?
Neonates were dying of respiratory distress because drug morphine was coming through their mother’s breast milk
Neonates were dying of respiratory distress because drug morphine was coming through their mother’s breast milk
If the liver isn’t functioning properly then there won;t be any metabolites and therefore no therapeutic effect. Prodrugs rely on the patients body functioning properly
What has to happen to lipid soluble drugs in order for us to excrete them?
Must be converted to their polar form
What does a phase 1 reaction involve?
- Hydrolysis
- Oxidation
- Reduction
Following phase 1 metabolism, the drug may be…
- Unchanged
- Activated
- Inactivated
Why do phase 1 reactions occur?
Convert non-polar molecules into polar molecules via the addition of a polar functional group, make the drug more water soluble. Makes it easier for them to be excreted.
- Oxidation: catalyzed by oxidative enzymes (ex. CYP-450)
- Reduction: Addition (gain) of electrons
- Hydrolysis: A chemical decomposition process that uses water to split the chemical bonds of a drug
What occurs during phase 2 metabolism?
Drugs are conjugated, usually become inactive but occasionally yields active metabolites (Ex. morphine)
What does the cytochrome P450 (CYP-450) do?
Replaces a -CH or -NH group in a molecule with an -OH group
What does the cytochrome P448 (CYP-448) do?
Inserts an oxygen atom between two carbons that are connected with a double bond
What are some factors that can influence enzyme activity?
- Concentration of enzymes will vary with ethnicity, age and health of the patient
- Enzyme activity also affected by other drugs, chemicals (smoking) and food (grapefruit juice)
What are the microsomal mixed function oxidases?
- Cytochrome P450
- Cytochrome P448
What is Rifampin? What does it do?
- Antibiotic
- Increases metabolism of itself and any other administered drugs (ex. antidepressants, estrogen’s, anti-arrhythmic’s
- Increases the synthesis of CYP enzymes, this increased metabolism decreases the plasma concentrations of co-administered drugs
What is Erythromycin? What does it do?
- Macrolide antibiotic
- Decreases the metabolism of itself and other co-administered drugs
- This can cause issues because a lot of the drug is left free and able to produce toxic effects (ex. antidepressants, statins)
- Inhibits activity of the CYP enzymes
- Decreased metabolism increases the plasma concentrations of co-administered drugs
What other enzymes can catalyze phase 1 reactions?
- Liver alcohol dehydrogenase (LADH)
- Aldehyde oxidase (Can only oxidize alcohols)
- Monoamine oxidase (critical in termination of monoamine neurotransmitters, ex. dopamine, norepinephrine, serotonin)
What do phase 2 reactions do?
Conjugate a drug with a very water soluble compound to form a highly water soluble metabolite
- Product is readily excreted by the kidney
- Conjugated drug is inactivated
Do all drugs need to undergo both phase 1 and phase 2 reactions?
Some drugs will only undergo phase 1 reactions, as this produces a sufficiently water soluble molecule which can be excreted
