Unit 4: Clinical Pharmacology

Question 1

The Half Life

Answer 1

• Drug half-life is calculated from a plasma concentration (Cp) versus time curve.
• Note the curve shape after IV injection - this “first-order” elimination curve applies to most drugs.
• The shape of the Cp-time curve depends on the Vd, Cl, t1/2, dose size and dose interval.

Question 2

t1/2, Vd & Cl (The Half Life)

Answer 2

The half-life (t1/2) is a dependent variable, dependent on the 2 independent variables Cl and Vd.

t1/2 = 0.693 x VD/CL

Question 3

t1/2, Dose Size & Interval (The Half Life)

Answer 3

Either dose or the dose interval can be adjusted to get a curve appropriate to the MEC, MTC.

Question 4

Dosing by Injection

Answer 4

The mode of drug administration influences the rate at which effective plasma concentrations are achieved. A loading dose also allows earlier achievement of effective concentrations

Question 5

Dosing by Pill or Slow Release Pills

Answer 5

The mode of drug administration influences the rate at which effective plasma concentrations are achieved. A loading dose also allows earlier achievement of effective concentrations.

Observe how the drug concentration-time profiles for IV versus oral dosing, with and without loading doses.

-Slow release pills allow longer dose intervals. A loading dose can also be used with slow release pills.

Question 6

Oral Availability (F)

Answer 6

-The fraction of drug that reaches the systemic circulation after oral ingestion. It is determined by ‘absorption’ and ‘first-pass’ metabolism.

Absorption refers to the ability of a drug to cross the gut wall into the portal vein.

First-pass metabolism describes presystemic drug elimination and can occur in the gut wall, portal vein or liver. The liver is usually the most important contributor.

Question 7

First Pass Metabolism (Oral Availability)

Answer 7

• Can occur in the gut wall, portal vein (uncommon) and in the liver.
• Note that high rates of metabolism at either site result in low oral availability.

Question 8

AUC (Oral Availability)

Answer 8

Oral availability defines how much drug gets ‘on board’ after oral ingestion. It is determined by ‘absorption’ and ‘first pass’ metabolism.

Oral availability is usually defined by comparing the fraction (F) of drug that gets into the body after oral (po) versus IV administration.

The total amount of drug in the systemic circulation is defined by the area under the concentration-time curve (AUC).

Question 9

Linear vs. Log Graphs (Pharmacodynamics)

Answer 9

• As concentration increases, the effect approaches a maximum, e.g. a blood vessel cannot dilate forever or it will explode!
• The maximum effect is called the Emax. The concentration at which the effect is 50% of the maximum is called the EC50.
• The shape of the linear graph is called a rectangular hyperbola. The shape of the log graph is called a sigmoid curve.

Question 10

Potency (Pharmacodynamics)

Answer 10

• An index of the concentration required for a given effect - usually the EC50. It is not the same as effect.
• Drugs that are highly potent require only small doses (concentrations) to achieve their effects.
• High potency is often considered desirable because less drug (in molar terms) is available to cause adverse effects.

Question 11

Efficacy (Pharmacodynamics)

Answer 11

• The desired effect (e.g. analgesia). Some drugs (e.g. morphine) have greater analgesic effect than others (e.g. paracetamol).
• Each drug has its own Emax and EC50. The Emax of paracetamol is lower than the Emax of morphine.

Question 12

Therapeutic Index (Pharmacodynamics)

Answer 12

• Represents the relationship between concentrations causing adverse effects and concentrations causing desired effects.
• It is usually EC50 (adverse effect)/EC50 (desired effect)
• Drugs with a high or large therapeutic

Question 13

Pharmacogenetics

Answer 13

• Sometimes people have different drug clearances because their genetics (genotypes) differ.
• Each genotype has a phenotype (e.g. enzyme activity) that has its own normal distribution.The different normal distributions are termed polymorphisms.
• NB: The ‘normal’ status is the EM, which is sometimes called the ‘wild type’.

Question 14

General Principle of Saturable Drug Metabolism

Answer 14

• Some drugs at therapeutic concentrations overwhelm the metabolising enzymes (i.e. saturation).
• Adjust drug dose to see that enzymes can eventually become saturated and no further increase in the rate of metabolism can occur.

Question 15

Cp-dose Effect (Saturable Drug Metabolism)

Answer 15

• When metabolism becomes saturated the relationship between dose and Cp is no longer linear (see graph).
• Adjust dose and observe how after saturation small increases in dose then result in large increases in Cp.

Question 16

Cp-Time Effect (Saturable Drug Metabolism)

Answer 16

• When metabolism becomes saturated, drug elimination changes from “first-order” (exponential decline in Cp) to “zero-order” (linear decline in Cp).
• Most drugs have first-order elimination at therapeutic Cp. Drugs that have enzyme saturation at or near the therapeutic Cp include phenytoin, aspirin, alcohol, fluoxetine and verapamil.

Question 17

Protein Binding and Clearance

Answer 17

• When the amount of binding protein is reduced, (e.g. in liver or renal disease) the free drug concentration is not altered.
• Commonly quoted drug concentrations include both bound and free drug i.e. total drug.
• When Cl is altered, the ratio of free to bound drug does not change. This can occur in renal or liver disease or with drug interactions.

Question 18

Effect of Altering pH

Answer 18

If acid is added, eg. H⁺Cl⁻, the equilibrium moves to the right. If alkali is added, eg. Na⁺OH⁻, then OH⁻ ions and H⁺ ions neutralise each other to form water, and the equilibrium moves to the left.

Unionized drug crosses lipid biological barriers (e.g. membranes) better than ionized drug.

Question 19

Dosing and Age

Answer 19

Drug clearance increases and decreases markedly during a lifetime. Drug dosing needs to be appropriate for each age group.

Question 20

Dose Adjustment in Children

Answer 20

Clearance changes dramatically in the first year and then stays high until puberty.

Question 21

Dose Adjustment with Age

Answer 21

Because dose rate = Cpss x CL, the dose rate should be appropriate to the age of the patient.

Question 22

Effects of Drugs on Pregnancy

Answer 22

In the first 4 weeks, prior to implantation, drug exposure is relatively safe as the foetus is not exposed to the mother’s blood supply. An adverse effect at this time is likely to result in spontaneous abortion (all or nothing effect).

Post-partum, drugs with a long half-life may continue to affect the baby. Drugs with a short half-life may result in neonatal withdrawal symptoms. After implantation, foetal drug concentrations are similar to those in the mother. Adverse effects depend on both drug toxicity and the developmental stage of the foetus.

Question 23

Effects of Pregnancy on Drugs

Answer 23

Drug clearance increases during pregnancy as a result of increased cardiac output (hence renal elimination) and rate of metabolism. Doses of drugs often need to be higher in the 2nd and 3rd trimesters.

Question 24

Pharmacodynamic (Drug Interactions)

Answer 24

A competitive inhibitor “competes” with the primary drug at effect receptors.

Therefore a higher dose of the primary drug is needed to obtain the desired effect. Emax can theoretically still be achieved.

Non-competitive inhibitors decrease the Emax by reducing the number of functional receptors. This cannot be overcome by increasing the concentration of the primary drug.

Question 25

Pharmacokinetic (Drug Interactions)

Answer 25

• A standard drug dose assumes normal clearances. If clearance is altered in a drug interaction, the steady state concentration will change.
• An enzyme inducer will increase the clearance, by providing more enzyme. Drug concentrations will decrease.
• An enzyme inhibitor will decrease the clearance by making less enzyme available. Drug concentration will increase.