Pharmacology: Dose-Concentration-Effect Relationship

DOSE-CONCENTRATION-EFFECT RELATIONSHIP

• Effect: Changes caused by the drug in relatively simple systems, such as cells, tissues, and organs.
• Influence: Changes in organs or the whole organism that can be directly observed or measured.
• Result: Combination of effect and influence.

DOSE-CONCENTRATION RELATIONSHIP

• A minimum concentration of the drug is required at the site of action for it to have an effect.
• The effect increases in a dose-dependent manner, but plateaus when the maximum effect is reached.
• Increasing the dose beyond this point can increase side effects.

PLASMA CONCENTRATION-TIME CURVE

• Measures the concentration of the drug in plasma over time.
• The curve varies depending on the dose, route of administration, and other factors.
• Key points on the curve include the peak concentration (Cmax), time to reach peak concentration (tmax), and area under the curve (AUC).

ADMINISTRATION OF SINGLE DOSE

• Complete absorption of the drug leads to 100% bioavailability.
• Fractional absorption equals systemic bioavailability (F).

ADMINISTRATION OF REPEATED DOSES

• Drugs are administered in repeated doses to maintain a continuous effect.
• The plasma concentration fluctuates around the average steady-state concentration (Css).
• Factors affecting the fluctuation include the dose interval (T) and the elimination half-life (t1/2).

TARGET CONCENTRATION APPROACH IN RATIONAL DOSING

• Loading dose: given to quickly reach the desired concentration in patients with a long elimination half-life.
• Maintenance dose: continued to maintain the desired concentration.

ADMINISTRATION OF THE DRUG BY INTRAVENOUS INFUSION

• The drug enters the body at a constant rate, and its elimination follows first-order kinetics.
• The concentration of the drug in plasma at steady-state is directly proportional to the infusion rate.

DOSE-EFFECT AND CONCENTRATION-EFFECT RELATIONSHIPS

• Gradual dose-effect curve: shows the effect of increasing doses of the drug.
• Concentration-effect curve: shows the effect of increasing concentrations of the drug.
• Important parameters include Emax (maximum effect), EC50 (concentration producing 50% of Emax), and IC50 (concentration inhibiting 50% of Emax).

POTENCY AND EFFICACY

• Potency: the dose or concentration of the drug required to produce a certain effect.
• Efficacy: the maximum effect that the drug can produce.

QUANTAL DOSE-EFFECT RELATIONSHIP

• Used to study the effect of the drug on a large population.
• The dose that produces the desired effect in 50% of individuals (ED50) is an important parameter.

THERAPEUTIC INDEX

• Compares the dose required to produce the desired effect with the dose that produces an undesirable effect.
• A higher therapeutic index indicates a safer drug.

RELATIONSHIP BETWEEN DURATION OF ACTION AND DOSE

• The duration of action depends on the dose, with higher doses leading to longer durations.
• This relationship can be influenced by the drug's pharmacokinetics and pharmacodynamics.

TIME-DEPENDENT VARIATION OF DRUG EFFECT

• Immediate effects: the effect of the drug changes over time, depending on the concentration and pharmacokinetics.
• Delayed effects: the effect of the drug is delayed due to factors such as slow synthesis of physiological substances.
• Cumulative effects: the effect of the drug accumulates over time, leading to a delayed but prolonged effect.

Area Under the Curve (AUC)

• AUC is a measure of the total exposure of a drug to the body
• It is calculated by plotting the concentration of the drug against time
• Peak concentration (tmax) reflects the absorption rate of the drug

Single Dose Administration

• When a drug is given orally or intramuscularly, complete absorption results in AUCs equal to 100% bioavailability
• Fractional absorption is equal to systemic bioavailability (F)

Repeated Dose Administration

• Drugs are administered in certain doses and at intervals to achieve a continuous effect
• The interval (T) is determined so that the doses after the first dose are given long before the plasma level provided by the previous one approaches zero
• The newly added drug is added to the remaining drug concentration
• The plasma concentration at steady-state does not follow a constant course, but fluctuates around the average steady-state concentration (Css)
• Cssmax is the peak concentration, and Cssmin is the bottom concentration
• The amplitude of the fluctuation varies with the ratio between the dose interval (T) and the half-life of the drug (t1/2)

Accumulation of the Drug

• The rate of attainment of steady-state is not dose-interval-dependent, but depends on the elimination rate constant and thus on the half-life of the drug (t1/2)
• The drug is considered to have reached steady-state in plasma at 4 elimination half-times, at which point it has reached 94% of the plateau level

Target Concentration Approach

• A loading dose is given to patients with a long elimination half-life, followed by a maintenance dose
• Examples of drugs that require a loading dose include digoxin and theophylline

Administration of the Drug by Intravenous Infusion

• The drug enters the body at a constant rate (zero-order kinetics)
• Its elimination is according to first-order kinetics
• The concentration of the drug in the plasma at steady-state is directly proportional to the infusion rate
• The time taken to reach steady-state depends on the half-life of the drug (t1/2)

Dose-Effect and Concentration-Effect Relationships

• Gradual dose: the effect increases with the increasing dose
• Quantal dose: the effect is all or nothing (e.g. relieving headaches, preventing convulsions)
• Emaks: the maximum effect that the drug can create
• EC50: the molar drug concentration that creates an effect equal to 50% of the Emax
• IC50: the concentration that inhibits an inhibition equal to 50% of Emax

Potency and Efficacy

• Potency: the ability of a drug to produce a certain effect at a smaller dose or concentration
• Efficacy: the maximum effect value of the drug
• A drug with a low EC50 value is stronger

Therapeutic Index

• The therapeutic index is the ratio of the LD50 (median lethal dose) to the ED50 (median effective dose)
• It is a measure of the safety of a drug

Relationship Between Duration of Action and Dose

• The effect of the drug begins when it reaches the minimum effective concentration (MEC) and continues as long as it remains above this level
• The dose is not increased to prolong the duration of action; instead, the drug is re-dosed at certain intervals or slow-release modified-release tablets are used

Time-Dependent Variation of Drug Effect

• Immediate effects: the effect is directly proportional to the concentration, and the time-dependent variation of the effect depends on the exponential decrease in concentration
• Delayed effects: the effect is delayed due to the dispersion time it takes for the drug to reach the site of action or the slow synthesis rate of physiological substances responsible for the emergence of the drug effect
• Cumulative effects: the effect depends on the accumulation of effects, as opposed to their rapidly rotating effects