Flashcards in ADME Deck (58):
How does one typically get a drug past all of the barriers within the body?
LARGE drug dosage
What is albumin?
What is the organ associated with the metabolism of drugs?
What is the organ associated with the excretion of drugs?
4 mechanisms of transport across a membrane.
Passive diffusion, facilitated diffusion, active transport and endocytosis.
What type of drug is usually taken up via endocytosis?
Those with a high molecular weight (>1000)
Including cytokines, GF's, hormones, etc.
What is the most important mechanism of transport?
Can active transport become saturated?
Name two sites where filtration occurs.
Blood capillaries and glomerular capillaries.
The area under the concentration-time curve indicates what?
Describe how a drug tablet is absorbed into the body.
2. Dissolution (dissolved)
4. Metabolism (and remainder distributed to body tissue - bioavailability).
Factors influencing oral bioavailability of drugs.
Acidic gastric juices
Hydrolytic gut enzymes
Gut wall enzymes
Liver enzymes before reaching blood
In absorption, what is the rate limiting step?
Emptying of the stomach to the intestines
When taken with milk, the bioavailability of a drug ___ .
True or False. Brain capillaries have pores.
False. Blood brain barrier (additional layer of glial cells). Only lipid soluble drugs diffuse across BBB.
How many litres of ICF, ECF and plasma is there?
Therefore total body water = 42L
Perfused organs (muscle, skin and fat) receive what blood flow rate?
A SLOW blood flow rate
Esterases in the plasma are important for which stage of ADME?
A metabolising enzyme helps to make a drug more water soluble, which in turn means what?
Less likely to enter cells
Inc. excretion favoured
Usually terminates drug action
it can promote activity (prodrug)
There could be no change in activity
It could produce toxic metabolites
What is phase 1 of metabolism?
addition or uncovering of reactive group
(oxidation, reduction, hydrolysis)
oxidation is most important (CYP450)
What is phase 2 of metabolism?
Conjugation of endogenous molecule (with large charge) with drug. This makes the molecule more POLAR.
Where are CYP450's located?
What 3 things do CYP's require?
oxygen, NADPH and cytochrome 450 reductase
What happens during the metabolism of phenytoin?
Highly lipophilic -> PHASE 1 -> Slightly soluble -> PHASE 2 -> Very soluble
What is the common endogenous conjugate protein during drug metabolism?
When >600 daltons, molecules are excreted how?
Neonates (new borns) have a reduced capacity to metabolise what?
When is enzyme synthesis initiated during the induction of metabolism?
within 24 hours, increasing over 3-5 days at plateau
BBQ meat can induce the metabolism of what drug?
Phenacetin (pain relief)
How long does the onset of inhibition of drug metabolism last?
Rapid (1 day)
What type of inhibitor is grapefruit juice?
Why can heavy metals inhibit drug metabolism?
Forms complex with CYP450 (located on smooth endoplasmic reticulum)
What percentage of blood is filtered at the glomerulus of the kidney during excretion?
10%, at about 130ml/min
What are the 3 stages of kidney excretion of a drug?
1. Glomerular filtration
2. Active secretion of free and protein-bound drugs
3. Reabsorption by passive diffusion
How do you calculate exposure?
Area under time-concn curve (mg.h/L)
What are the 4 parameters of pharmacokinetics?
Bioavailability, volume of distribution, CL and plasma half life
How do you calculate volume of drug distrib?
Amount of drug in body divided by plasma drug conectrations
Loading Dose (LD) = ?
LD - V x target concn
What parameter is associated with drug elimination (but not total elimination)?
What is clearance?
- = dose / AUC
- elimination rate = CL x concn
What does half life depend on?
Volume and clearance. Larger the volume, larger the half life
How to calculate half life?
= 0.7 V/CL
4 half lives is equal to how much elimination?
>90% drug elimination
What is accumulation?
A drug accumulates in body till input rate = elimination rate. Steady state occurs when accumulation is complete and concentrations have plateaued.
What is the use of a loading dose?
Targets concentration/steady state faster!
What is the effect of smoking on theophyline?
It lowers plasma concentration of the drug.
What happens when you take grapefruit juice with Felodipine?
The grapefruit juice inhibits the enzyme that breaks down Felodipine so you overdose on the drug. Results in an increase in the bioavailability of Felodipine.
What are 4 main factors that influence renal drug excretion?
What are 3 things that can alter renal excretion of drugs?
Competitive inhibition of tubular secretion
Urinary flow rate
How does competitive inhibition effect renal excretion of drugs?
Some drugs may have a higher affinity for active transport than the 'normal' target drug, so the 1/2 life of the 'normal' drug increases, taking longer to excrete.
How does pH influence renal excretion?
If ionisation occurs, substrates are not actively absorbed and so there is more excretion.
How does urinary flow rate effect renal excretion?
If you are to drink more water, urinary flow rate increases, diluting the drug along the tubule, therefore a decrease in conc gradient for passive readsorption of the drug and enhanced excretion.
How does pH effect the excretion of methamphetamine?
Ionisation reducing the pH (acidic) increases the excretion (e.g. treat with ammonium chloride).
Ionisation increasing the pH (basic) decreases the excretion (e.g. treat with baking soda). --> Prolongs the effect.
What is the first-pass effect?
Loss of the drug occurring before the drug reaches the systemic circulation.
How do you calculate the volume of distribution (V)?
V = (amount of drug in body) / (plasma drug conc)
What 3 factors determine V?
Drug binding to plasma elements
What is maintenance dose rate (MD)?
Dose rate to achieve and maintain a target concentration.