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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.

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

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?

Antacids reduce absorption of tetracycline (antibiotic)
Calcium supplements reduce absorption of thyroxine (hormone)
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?

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):

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


Summary for DDIs

Watch out for DDIs in:
The elderly
Receiving more than two drugs
Receiving warfarin, NSAIDs, antiplatelets, statins, thyroxine
New signs / symptoms after starting a new drug – investigate for DDI or ADR (adverse drug reaction)


What are the principles of drug administration during pregnancy?

-The first trimester is the most important when the fetal development is most sensitive to drugs
-Factors that affect drug transfer across the placenta:
- Molecular weight of the drug – drugs with a mol. Wt. > 500D have an incomplete transfer across the placenta. Note that most drugs have a mol. Wt. < 500D (most drugs cross over to the fetal circulation)
- pKa of the drug and degree of ionization – ionized drug transfers incompletely across the placenta (however, this may not always be true, e.g. ampicillin and methicillin are strong acids and are ionized but they have a bulky lipophilic group on their side chains which allows complete placental transfer)
- Protein binding of the drug
- Placental drug transporters



What are placental drug transporters?

Placental expression of drug transporters such as P-glycoprotein, breast cancer resistance protein (BCRP) and multidrug resistance protein (MRP) protects the fetus by efflux of drug from the fetal to maternal circulation


What is the summary of drug use during pregnancy?

The first trimester is most sensitive to drug effects on fetal development
Drug use during pregnancy is likely more prevalent than expected
Category D and X drugs are also used sometimes during pregnancy
Safety of many drugs during pregnancy is still not established
Consider the advantages and risks carefully for every drug prescribed or used during pregnancy


What is the effect of age on response to drugs?

Clinical trials are normally performed in young and middle aged adults – data on drug use in these age groups readily available
Pharmacokinetic and pharmacodynamic data in children and the elderly are not readily available
Patients at the two extremes of the age range differ markedly in their response to drugs, compared to adults and also compared to each other
One main reason is the differences in physiology (liver and kidney) at the extremes of the age range – dose adjustments are necessary


What are the principles of drug treatment in children?

- Pharmacokinetics of most drugs are not well defined in children
- Variability in pharmacokinetics can be expected to be greatest when the body physiology is changing – e.g. in the newborn or premature baby or during puberty
- In the premature and newborn babies dose adjustments and therapeutic drug monitoring for drugs with narrow therapeutic indices becomes necessary for safe and effective treatment
- Drug clearance values do not vary linearly with either body weight or body surface area – meaning that a one year old infant will not necessarily have lower clearance values compared to a ten year child for all drugs
- Hepatic drug metabolizing enzymes are not fully developed in infants, especially in premature infants
- Clearance values of most drugs are different in children than those in adults


What are metabolic enzymes like in infants?

Most drug-metabolizing enzymes are expressed at low levels at birth
Different isoforms start getting expressed at different times, e.g. CYP2D6 and CYP2E1 are expressed on the first day, whereas CYP3A4 is expressed within 1 week
So any drug that is metabolized by CYP3A4 is likely to produce toxicity if administered to a newborn or 1-2 day old infant
Similarly, newborns are unable to conjugate glucuronic acid during phase 2 metabolism


What is kidney function like in neonates?

Renal elimination of drugs is reduced in neonates
The GFR (glomerular filtration rate) is only 2 to 4 ml/min/1.73 m2 in neonates (in adults it is 100-130 ml/min/1.73 m2). It is further reduced in premature infants.
GFR increases to adult levels by 8 to 12 months of age
Dosing for drugs should be reduced to account for reduced renal clearance to avoid toxicity (e.g. aminoglycoside antibiotics)


What are pharmacodynamic differences in children?

Some examples:
Antihistamines and barbiturates cause sedation in adults but they cause “hyperactivity” in children
Children have increased sensitivity to sedating effects of propofol – this has resulted in cases of overdoses with myocardial failure, metabolic acidosis and multiorgan failure
Glucocorticoids can attenuate linear growth of bones


What do we need to remember about drugs in the elderly?

The percentage of elderly people is increasing with increasing life expectancy
About 15% of the population is over the age of 65 yrs
They take one third of drugs prescribed to all age groups
They take an average of 5 drugs per patient
They report 25% of drug adverse reactions of all age groups
Some common physiologic changes that take place in the elderly people affect pharmacokinetic and pharmacodynamic responses to drugs:
Reduction in lean body mass
Reduction in serum albumin – will decrease the amount of protein bound drug
Reduction in total body water
Increase in percentage of body fat – will increase the volume of distribution of lipid soluble drugs
- All of these factors alter the distribution of drugs depending on their degree of lipid solubility and protein binding


What is the GFR like in the elderly and how does this effect them?

The GFR, an indicator of renal function, declines at an average rate of 0.8 ml/min/1.73 m2 after the age of 30 yrs. The decline accelerates after age 65 to 70. (Davies DF, Shock NW. J Clin Invest 1950;29:496–507. Glassock RJ. Nephrol Times 2009;2:6-8. Glassock RJ and Winearls C. Trans Am Clin Climatol Assoc 2009;120:419-428)
An average 85 yr old male would be expected to have a GFR of around 55-60 ml/min/1.73 m2 (approximately 50% decrease compared to values at age 30 yrs)
Thus, elderly people over the age of 75 can be expected to have significantly reduced renal clearanxace of drugs and a carefully calculated dose reduction of drugs would be necessary


How does hepatic blood flow and drug metabolism change in the elderly?

Hepatic blood flow and drug metabolism are also reduced in the elderly with a great deal of variability between different individuals in this group
Hepatic CYP activity is reduced but conjugating enzymes are not much affected
Pharmacodynamically the elderly are more susceptible to CNS depressants, psychotropic drugs can produce more hypotension