lectures 5 and 6 Flashcards
What is first order rate of elimination?
First-order rate of elimination - A constant fraction of drug is eliminated per unit of time.
4 molecules out of 20 are metabolized. 4/20 or 1/5th of drug is metabolized
If you give 40 molecules, 8 molecules will reach the enzyme in the liver after equilibrium and 8/40 or still 1/5th of drug will be metabolized
What is zero order elimination?
The metabolic mechanism for most drugs will be saturated only at very high concentrations – doses not commonly used therapeutically
The metabolic capacity for very few drugs becomes saturated at concentrations within the therapeutic range: e.g. phenytoin, aspirin (acetylsalicylic acid -ASA), carbamazepine, ethanol
In zero-order rate process a constant amount of drug is eliminated per unit of time (e.g., 10 g/hr) because that is the maximum rate of elimination when the pathway for elimination is saturated.
What is half-life and its clinical significance?
Half-life is the time required for the blood (or plasma) concentration of a drug to be reduced by 50%
This applies to drugs that are eliminated by the first order rate of elimination
For practical purposes, it takes about 5 half-lives for more than 90% of a drug to be effectively eliminated from the body.
If a fixed dose of a drug is given repeatedly at fixed intervals, it takes about 5 half-lives for that drug to achieve steady-state concentrations in the plasma
E.g. if the half-life of a drug is 20 hours, then it will reach a steady concentration (where the elimination rate equals the administration rate) after 5 x 20 = 100 hours.
The table shows the amount of drug eliminated after each half-life and the amount remaining. It does not matter how drug is present initially. E.g. the table shows 100 mg of drug A and 500 mg of drug B. In each case after 5 half-lives about 3% of the original amount of drug remains in both cases.
What is the significan of clearance and Vd? What are they combine dto find?
Clearance and volume of distribution are independent variables.
They determine the half-life (Cl = k x Vd)
k = rate constant of elimination
t1/2 = 0.693/k or k = 0.693/t1/2
Cl = (0.693/t1/2 ) x Vd
t1/2 = 0.693 x Vd / Cl
t1/2 is proportional to Vd/Cl
What is loading dose?
Loading Dose (DL) = a dose of drug sufficient to produce a plasma concentration of drug that would fall within the therapeutic window after only one or very few doses over a very short interval. It is larger than the dose rate needed to maintain the concentration within the window and would produce toxic concentrations if given in repeated doses.
WE DON’T NEED TO KNOW THESE EQUATIONS. BUT KNOW WHAT WE NEED TO KNOW FOR EXAMPLE WE NEED TO KNOW C AND VD.
If we know the target plasma concentration, and the Vd, we can calculate the i.v.loading dose:
L = C(Vd)
For the oral loading dose we have to take the fraction bioavailable into account (0-1)
L = C x V / F
What is the maintenance dose?
Maintenance Dose (M) = The dose needed to maintain the concentration within the therapeutic window when given repeatedly at a constant interval Maintenance Dose = Steady-state plasma concentration (Css) x Clearance (Cl) If not administered by constant infusion, divide the dose by dosing interval M = Cldrug.Css For oral dosing M = Cldrug.Cp/F
DON’T NEED TO KNOW THESE JUST NEED TO KNOW WHAT WE NEED TO KNOW FOR THE EQUATIONS IF WE WERE TO CALCULATE THEM.
Steady-state is reached when the rate of administration = the rate of elimination
Steady-state concentration = Rate of administration / Clearance
If clearance does not change, than doubling the dose will double the blood concentration of the drug
summary card
A knowledge of concepts of pharmacokinetics and drug metabolism is important to help prescribe drugs for optimum therapeutic response and avoid drug-drug interactions
Drug dosing should aim for the target plasma concentration.
The volume of distribution is useful in calculating the loading dose
The clearance is useful in calculating the maintenance dose
The time to reach steady state depends only on the half life
What is drug interactions?
Drug interactions - a situation in which a substance affects the activity of a drug
Drug A + Drug B = increased effect, of one of the drugs and therefore possible toxicity.
Drug C + Drug D = drug C or D decreased effect treatment failure.
Drug E + Drug F = new effect?
Drug interactions cause up to 2.8% of hospital admissions
Among people ≥ 65:
> 90% use ≥ 1 drug/week
> 40% use ≥ 5 different drugs/week, and
12% use ≥ 10 different drugs/week – an open invitation for drug interactions?!
Women take more drugs - particularly psychoactive and arthritis drugs
Drug use is greatest among the frail elderly, hospitalized patients, and nursing home residents
typically, a nursing home resident is given 7 to 8 different drugs on a regular basis
What are the different drug interactions that may occur?
The interaction can be between two drugs - drug-drug interaction (DDI)
Between a drug and a food item - drug-food interactions
Between a drug and herbs - drug-herb interactions
Other interactions
Regarding drug-drug interactions, what are the two types?
Pharmacodynamic interaction
Two drugs affecting the same system (effect on the organism) - e.g. Two sedative drugs will produce more sedation
Pharmacokinetic interaction
One drug changes the absorption, distribution, metabolism, excretion (ADME) of another
What are two examples of both absorption and distribution being affeted by drug-drug interaction?
Absorption
Antacids reduce absorption of tetracycline (antibiotic)
Calcium supplements reduce absorption of thyroxine (hormone)
Distribution
Competition for plasma protein binding by non-steroidal anti-inflammatory drugs (NSAIDs) and warfarin (anticoagulant)
What are two examples of excretion and metabolism being affeted by drug-drug interaction?
What is the most common reason for drug-drug interactions?
Excretion
Probenecid reduces excretion of penicillin by competition for the kidney tubule transport system. This was good because less penicillin could be used or it could have an effect for longer periods of time so during WWII when they needed more this was very beneficial.
Metabolism – one drug affecting the metabolism of another drug is the most common reason for drug-drug interactions
Two drugs metabolized by the same enzyme can compete for the enzyme (e.g. CYP3A4)
What are the 4 mechanisms by which NSAIDs interact with warfarin?
An NSAID greatly increases risk of warfarin toxicity because of multiple interactions:
1) Protein bound warfarin is displaced by the NSAID - ↑ free plasma warfarin and causes toxicity
2) NSAIDs suppress platelet function (anticlotting action) that adds to anticoagulant action of warfarin
3) Some NSAIDs prevent metabolism of warfarin by competition for the metabolizing enzyme - ↑ plasma warfarin and toxicity
4) NSAIDs directly cause gastric injury and warfarin can cause gastric bleeding
What is the clinical significance of drug metabolism interactions?
When a patient is taking two or more drugs, the possibility of drug interactions resulting from metabolism should be considered
When a patient is taking a single drug metabolized by the cytochrome P450 enzymes, interactions with food items or herbal medicines should be considered
In cases of drug toxicity or treatment failure genetic variation of metabolizing enzymes should be considered
Look out for these patients (at risk patients for DDIs):
elderly
comorbidities/polypharmacy
reduced kidney or liver function
What advice should be given for patients regarding drug - drug interactions?
Report any herbal or OTC medicines (e.g. omeprazole) they are taking
Other commonly prescribed medications written for by other physicians
Ask them about regular grapefruit juice consumption
When a patient starts on a new drug, he/she should report any new sign/symptom that develops – rule out DDI or ADR
Educate patients
- On drugs with narrow therapeutic window
