02- Drug Distribution, Metabolism and elimination Flashcards
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
What are some examples of phase 2 enzymes?
Glucouronyl transferase:
- Replaces -OH or -SH group with glucuronic acid
- Glucuronidation is the most common and most important conjugation reaction
N-acetyltransferase:
- Replaces an -OH, -SH or -NH2 group with an acetate
Sulfotransferase:
- Replaces an -OH or -SH group with sulfate
Glutathione S-transferase:
- Forms an adduct between the drug and glutathione
- Adds two molecules together to create a large H20 soluble molecule that cannot be reabsorbed
Why is oxidation of acetaminophen problematic during phase 1 reactions?
The product that is formed is very unstable. Its uncomfortable in its shape and its conformation shifts in a spontaneous reaction to become NAPQI. NAPQI binds to proteins irreversibly and cause permanent damage.
Which organ can NAPQI damage?
The liver
What is NAPQI?
Highly reactive free radical , binds to proteins irreversibly
What enzyme eliminates the reactivity of NAPQI?
Glutathione transferase, eliminates risk of damage and allows it to be excreted
How can acetaminophen overdose occur?
- Phase 2 reactions are overwhelmed, favours phase 1 reactions and then NAPQI levels begin to rise
- GT is overwhelmed, NAPQI causes damage
- NAPQI combines with sulfhydryl groups on hepatic cell proteins and this causes cell death
How soon do symptoms of liver failure appear?
Within 16-36 hours post overdose
How does alcohol contribute to acetaminophen overdose?
Ethanol is a phase 1 inducer, increases the level of NAPQI in the body, if the patient has poor liver function already (from alcohol abuse), then they will also have little glutathione and this can cause overdose
What drug can be administered in order to protect the liver in case of acetaminophen overdose?
Acetylcysteine:
- Acts like GT
- Binds to hepatocytes and prevents damage
- Binds to NAPQI to prevent damage
Why is Acetylcysteine given IV?
Patients cannot tolerate this medication orally
Excretion of drugs: KIDNEYS
- Primary site of excretion
- Drugs must be ionized and polar
- Urine pH low
- Weakly acidic drug –> fat soluble causes secondary absorption, this can be problematic for ASA overdose
- We can make the urine more basic with sodium bicarb so the drug stays h20 soluble and is excreted
Excretion of drugs: INTESTINES
- Feces can eliminate
- More fat soluble than H20 soluble even after metabolism
- Because they’re fat soluble they’re reabsorbed in intestines again into the system, this is problematic in case of an overdose
- Some drugs have long therapeutic effects because they’re very fat soluble, keep being reabsorbed until their water soluble enough to be excreted
Why is Acetylcysteine given IV?
Patients cannot tolerate this medication orally
Which organ can NAPQI damage?
The liver
What drug can be administered in order to protect the liver in case of acetaminophen overdose?
● Providing that there is sufficient undamaged liver tissue, (e.g. the overdose is identified within 8 hours of administration) we can administer a drug that quickly acts as a replacement for glutathione
● Acetylcysteine is an antidote and administered IV
○ This compound contains an -SH group similar to glutathione
○ Binds to NAPQI and prevents damage to hepatocytes
○ Product acts identically to glutathione to deal with oxidative free radical (NAPQI)
■ Makes it no longer reactive and damaging to the proteins
How does alcohol contribute to acetaminophen overdose?
- Ethanol speeds up phase 1 reactions
- Liver already stressed from drinking
- More acetaminophen is going to be oxidized
- More acetaminophen than normal is converted to NAPQi
- When drinking = do not take acetaminophen; take ibuprofen
- Liver is already stressed from the alcohol and then they take acetaminophen = alcohol speeds up phase 1 reactions
- More acetaminophen is going to oxidized = more is going to be converted to NAPQi
How soon do symptoms of liver failure appear?
16 – 36 hrs post-overdose
What enzyme eliminates the reactivity of NAPQI?
Glutathione s-transferase rescues the body from NAPQi by neutralizing it
What is NAPQI?
● NAPQi = red = meaning danger; spontaneously arises after acetaminophen has been oxidized
