Metabolism and Excretion Flashcards
Metabolism and excretion together are called?
drug elimination
What is biotransformation?
metabolism or degradation of a drug from an active form to its inactive form
What is clearance (Cl)?
removal of the drug from the body?
What is the first pass effect?
oral drug passes through the liver for degradation before distribution into tissues
What is Half-life (t½)?
time required for total drug concentration in the body to be reduced by 50%
What is a prodrug?
precursor to an active drug
What is pKa?
describes how acidic (or not) a given hydrogen atom in a compound is
What is metabolism?
2
Change drug into water-soluble form
Promotes excretion
What is excretion?
removal of drug from the body
What organs are involved in metabolism?
4
(whats the main one?)
Liver
Kidneys
Intestines
Enzymes in blood (e.g., esterases)
What are the funciton of these organs involved in metabolism?
2
- Detoxify drugs and other foreign substances
- Active to less active/inactive forms (i.e. metabolites) - Activation of prodrugs
- Inactive precursor or “parent drug” to active metabolite or “active drug”
What is the primary means of metabolism and where does it occur?
enzyme reactions and they occur in the liver
Describe phase I of metabolism?
Drugs become more polar and water-soluble. This makes them more prone to renal elimination
What kind of reactions are phase I reactions?
Oxidation, hydrolysis, reduction
Describe phase II of metabolism
Drugs are conjugated and are usually inactivated or become more water-soluble. This makes them more prone to renal elimination
What kind of reactions are phase II reactions?
Formation of glucuronides, acetates, sulfates
What are active metabolites?
Ex?
Possess ability to exert effects on body
codeine to morphine
Active forms: Clarinex and prednisolone
What are inactive metabolites?
Ex?
No appreciable function
Plavix to carboxylic acid metabolite
What are toxic metabolites?
Two ex?
Lead to cell damage or other adverse effects
Demerol can cause a build up of its metabolite normeperidine
which can lead to seizures
Acetaminophen can cause a build up of NAPQI
What enzymes are involved in phase I metabolism?
CYP enzymes
What can CYP enzymes do?
They can either induce or inhibited by other drugs or substances
What detemines the amount of CYP enzymes you have?
2
- geneotype variations
2. disease-induced changes can affect CYP enzymes availability
What is induction?
And what does it result in?
Drug or substance increases enzyme expression (e.g., caffeine)
Results in faster metabolism
Activates the enzymes itself
What is activation?
And what does it result in?
Drug or substance binds to enzyme to increase the activity of the enzyme
Results in faster metabolism
Works on the activated enzyme
What is inhibition? 2
What does this result in?
- Drug or substance with greater affinity for the enzyme competes with a drug or substance with less affinity
OR
- Enzyme expression is reduced (enzymes are not activated e.g., cirrhosis)
Results in slower metabolism
What do plasma esterases do?
3
- Catalyze the hydrolysis of ester groups
- Usually leave drugs inactive
- Can activate some prodrugs
How to plasma esterases relate to organ function?
They are ubiquitous, independent of organ function
What organs are involved in drug excretion? 5
And what is the main organ?
Kidneys – primary Lower gastrointestinal (GI) tract Lungs Skin Glands (sweat, mammary, and salivary)
What is the forcible removal of drugs called?
Dialysis
What the most important organ for elimination?
kidneys
What are the three things drugs entering the nephron might end up doing?
- Exert an action (such as diuretics)
- Be reabsorbed into the bloodstream
- Progress to the collecting duct and be excreted from there
What are the three processes by which a drug can be excreted?
Glomerular filtration
Active tubular secretion
Passive tubular reabsorption
What is glomerular filtration and what kind of compounds is it best for?
Unbound drug is filtered into tubule
Best for hydrophilic, ionized compounds
Describe active tubular secretion
2
Transporters move conjugated metabolites into the tubule
Separate systems for organic acids and bases
Describe passive tubular secretion
Some non-ionic drug passively diffuses out of the tubule
Weak acids are excreted faster in what form of urine?
alkalized. Because weak acids cannot be reabsorbed in a basic environemt?
Weak bases are excreted faster in what form of urine?
acidic. Because weak bases cannot be reabsorbed in an acidic environment
Where are weak acids better absorbed?
In the stomach where its more acidic/pH is low
Where are weak bases better absorbed?
In the intestine where its more basic/pH is high
The pKa is what in terms of pH?
the pH at which concentration of ionized and non-ionised forms is equal.
If an acid is in an alkaline environment what will happen in terms of protons?
There are few protons in an alkaline environment so it will donate them
What will a weak acid dissocaite into?
a negatively charged ion (anion)
and a proton (that is donated)
So in an alkaline environment weak bases will be what?
2
ionized and water soluable!
-not absorbed (need to be neutral and lipid soluble)
If an acid is in a acidic environment what will happen in terms of protons?
There are many protons so the weak acid will not dissociate, and keep its proton.
This means it will be non-ionized and lipid soluble and will absorb.
If a base is in an acidic environment what will happen in terms of protons?
The acidic environment is proton rich so the base will accept protons.
So in an acidic environment weak bases will be what?
2
Ionized and water soluble
-not absorbed (need to be neutral and lipis soluble)
If a base is in an alkaline environment what will happen in terms of protons?
There are few protons in an alkaline environment so the base will not accept any protons, will not become ionized, and stay lipid soluble so it can be absorbed.
if you are trying to prevent reabsorption, how do we want our urine?
MAKE THE URINE pH OPPOSITE to the drugs acidity.
A base with a high pKa will clear faster or slower into acidic urine than a base with a low pKa?
why?
Faster
Gradient is higher to excrete it
How are biles excreted?
4
From the liver
To the gallbladder
and then empties into the intestines which forms feces and its excreted in that form
Liver>Gall bladder>intestines>feces
Other excretion routes you should know?
4
Sweat, tears, saliva
Hair, skin
Breast milk
Expiration
Factors affecting metabolism and clearance?
6
1. Genetic variance Presence/absence of enzymes 2. Induction/inhibition of enzymes 3. Competing/complementary pathways 4. Disease factors 5. Age and gender 6. Pregnancy
What is a half life?
Time required for serum concentration to decrease by ½ after absorption and distribution
One half life=100% to 50%
Two half lives= 50% to 25%
What does half life determine?
Determines time to reach steady-state
How many half lives does it usually take to reach steady state?
4-5 elimination half lives
What is steady-state?
equilibrium between amount of drug entering body and amount of drug leaving the body
What is the half life dependent on?
3
Volume of distribution
Clearance
Amount of drug
Drug X works best with a maximum steady-state concentration of 20 mg/L and a minimum steady-state concentration of 10 mg/L. What would be an ideal dosage interval?
- One elimination half-life
- One hour
- One day
- 4-5 elimination half-lives
- one elimination half life
What is the removal of the drug from the body and the final element of the elimination process?
clearance
What are the three ways drugs can be cleared by?
biliary means
renal means
hepatic means
What is clearance directly dependant on?
and inversely related to?
directly to apparent volume of distribution and inversely related to the elimination half-life
Equation for drug clearance?
How is it measured?
Clearance (Cl) = 0.693 x Vd/
t½
Measured as volume over time (L/hr)
What is creatinine?
Byproduct of continual muscle breakdown
What is creatinine eliminated by?
glomerular filtraiton
Is it secreted or reabsorbed in the kidney?
no
What is creatinine a good indicator of?
2
Good surrogate marker for estimating
1. glomerular filtration rate (GFR) 2. renal clearance
How is creatinine usually measured and what are the normal lab values?
Usually measured through a blood test looking at serum creatinine
Normal value: 0.8 – 1.2 mg/dL
What is the cockcroft-gault equation?
Creatinine clearance equation
CrCl = [(140-age)X(IBW)] / (SrCrX72) then times all that by 0.85
Whats the rule of thumb for creatinine testing?
patients 65 or older
patients with a creatinine level of more than 1.5mg/dL
What would we do if the creatinine levels was abnormal in the blood test?
24 hour urine study
What is a loading dose?
Large amount given to reach desired serum drug concentrations quickly
What is the loading dose based on?
WHAT IS IT NOT BASED ON?
Based on volume of distribution (Vd)
Independent of half-life (t½)
Why are maintenance doses given?
And what are they based on?
Given to replace the amount of drug being eliminated
Based on half-lives
What does a steady state graph look like?
Goes up fairly quickly at first but will eventually level off
What are the two types of pharmacokinetics?
linear and non-linear
Describe linear pharmacokinetics?
1st order pharmacokinetics
These are dose-independent kinetics (non-saturable)
Describe non-linear pharmacokinetics.
What are the types?
Zero Order Pharmacokinetics
Michaelis-Mentin Kinetics
Non-linear protein binding
Dose-Dependent
Kinetics(saturable)
In 1st order pharmacokinetics
if the dose is doubled what happens to the serum drug concentration?
it is also doubled
They are proportional
In 1st order pharmacokinetics, elimination rate is dependent on drug concentration. What does this result in?
2
- Constant proportion is eliminated from body
- Body is able to keep up with dose increases & prevent accumulation in normal course of therapy
THESE ARE MOST DRUGS IN CLINICAL PRACTICE
Describe continuous infusions/dosing with linear pharmacokinetics?
Serum concentrations increase until drug infusion rate equals drug elimination rate
Example: Drug X infusing IV at 10 mg/hr would eliminate at 10 mg/hr once the equilibrium or steady-state concentration was achieved
Describe intermittent dosing with linear pharmacokinetics?
Steady-state occurs when previous dose curve matches next curve
How are drugs eliminated in nonlinear zero order pharmacokinetics?
eliminated at a constant X mg/hr (amount)
In zero order kinetics how is elimination dependant on drug concentration?
its not. its independant of it
What is the risk with a zero order kinetic drug?
2
Can lead to accumulation
Mechanism responsible for metabolism/ excretion is saturated so the drug accumulates in the serum (blood)
Example of zero order kinetic drug?
ethanol
Describe Michaelis-Menten Kinetics?
4
Below a given serum concentration, elimination follows 1st order kinetics
Above the given serum concentration, elimination follows zero order kinetics
Steady-state concentrations increase greater than expected with dose increases
Also called saturable metabolism or capacity-limited metabolism
Example of Michaelis-Menten Kinetics?
phenytoin (dilantin)
Describe Nonlinear Protein Binding?
5
- Binding of drugs to plasma proteins is capacity-limited
- Plasma proteins become saturated - Steady-state concentrations increase less than expected with dose increases
- Unbound drug concentration increases linearly with dose increases
- Total drug concentration increases less than proportionally to dose increases
- More unbound/free drug results in greater rate of elimination
Where does nonlinear protein binding occur more often?
Proteins with fewer binding sites
- like α1 acid glycoprotein (Norpace)
Why do you monitor drug levels?
2
- Correlate drug levels with response/efficacy
2. Prevent toxicity
What kind of drugs are we wantinng to monitor more closely?
drugs with a narrow therapeutic index
What is the difference in a normal therapeutic dosing graph compard to one with a loading dose?
Shoots immediately up to therapeutic range with the loading dose
