Pharmacology: Factors Affecting Drug Response

Pharmacodynamics of Drugs

• Pharmacodynamics is the study of the actions of drugs and their mechanisms of action.
• This includes the pharmacological actions of drugs and the mechanisms by which those actions occur.

Drug Actions

• Factors affecting drug action include:
  • Patient size (body weight or surface area): Larger body size results in lower plasma drug concentration and lower effect for a given dose.
  • Patient age: Drug response varies with age due to differences in absorption, metabolism, and excretion. Neonates and infants have undeveloped excretory and metabolizing systems, while older patients may have degenerative changes affecting these systems.
  • Patient gender: Doses of potent drugs for women may need to be reduced slightly due to higher percentage of fatty tissue compared to men. Oxidation of drugs is slower in fatty tissue than in skeletal muscle; therefore, drug effects might be more pronounced in women. During lactation, some drugs may be excreted in breast milk, potentially affecting the infant.
  • Genetic factors: Enzymes, mostly in the liver, break down drugs, ending their action. Congenital deficiencies in metabolizing enzymes can affect drug plasma levels and response.
  • Nutritional factors: Metabolic enzymes are made of protein. Severe malnutrition can decrease enzyme activity due to protein deficiency, impacting drug response.
  • Health conditions: Individuals with liver or kidney disease show different drug responses, often due to reduced drug metabolism and excretion.
  • Time of administration: Daylight enhances the effect of "stimulating drugs," while diminishing the effect of hypnotics. Darkness is a sedative; hypnotics are most effective at night.
  • Emotional status: A placebo can induce improvements in sleep, appetite, and well-being.
  • Drug interactions: Concurrent drug administration can impact the therapeutic value of each drug in various ways. Mechanisms include changes in drug metabolism, plasma protein binding, gastrointestinal tract uptake, renal clearance, or interactions at the receptor level.

Mechanisms of Drug Actions

• Drug-receptor interaction (receptor theory): Receptors are specific sites (inside or on the cell surface) that drugs bind to, mediating their actions. Drug fits into the receptor like a key into a lock (Key & Lock theory). Drugs can either stimulate (agonist) or occupy the receptor without action (antagonist).
• Enzyme inhibitors: Drugs can inhibit enzyme activity, affecting chemical reactions in the body.
• Action on cell membranes: Certain drugs, like local anesthetics, can affect ion movement across cell membranes, affecting nerve function.
• Antimetabolites: Drugs similar in structure to endogenous metabolites can disrupt cellular functions by interfering with the use of endogenous metabolites. For example, some anticancer agents work this way.

Dose-Response Relationships

• An agonist binds to a receptor and elicits a biological response. The magnitude of drug effect depends on drug concentration at the receptor site.
• As drug concentration increases, the magnitude of the pharmacologic effect also increases. Drug response is continuous and gradual.
• A graph of this relationship is a graded response curve.
• This curve often resembles a rectangular hyperbola.
• EC50 (Effective Concentration 50): The dose causing 50% of maximum response is useful in determining drug potency. The smaller the EC50, the more potent the drug.

Potency

• Potency is a measure of the amount of drug necessary to produce an effect of a given magnitude.
• Determined by the EC50 (the drug concentration needed to produce 50% of maximum effect).
• A lower EC50 indicates higher potency.

Efficacy (Intrinsic Activity)

• Efficacy is the ability of a drug to elicit a physiological response upon interacting with a receptor.
• It's dependent on the number and efficacy of drug-receptor complexes formed.
• Plotting the log of drug concentration creates sigmoid curves.

Drug Tolerance

• Tolerance is a decreased response to a drug after repeated administration; a form of desensitization or tachyphylaxis.
• Possible causes: changes or loss of receptors, mediator exhaustion, increased drug metabolism, or physiological adaptation by the body.

Drug Dependence

• Drug dependence describes the individual's reliance on a certain drug. Drug cessation may induce withdrawal symptoms.
• Two main types:
  • Psychological dependence: Individual cravings or psychological need for the drug (e.g. tobacco smoking)
  • Physical dependence: Body physically adapting to the presence of a drug. (e.g. morphine, alcohol, barbiturates)

Drug-Drug Interactions

• When two drugs are administered together, they may exhibit:
  • Additive effect: combined effect is equal to the sum of individual effects (1+1=2)
  • Synergism: combined effect is greater than the sum of individual effects (1+1>2)
  • Potentiation: a drug without effect enhances the effect of another drug (0+1>1)
  • Antagonism (drugs of opposite effects are given simultaneously)

Drug-Food Interactions

• Food may influence drug absorption in the gastrointestinal tract.
• Some drugs' absorption is reduced by stomach food; others might absorb quicker (e.g., ascorbic acid).
• The type of food can influence gastric emptying, impacting absorption rates (e.g., fats/sugars can reduce absorption).
• Certain food components can interact with drugs, reducing absorption (e.g., calcium in dairy products and tetracycline).

Therapeutic Index and Margin of Safety

• All drugs produce toxic responses at high doses.
• The therapeutic index is the ratio of the dose producing toxicity to the dose producing the therapeutic response.
• A higher ratio indicates higher safety of the drug.
• The therapeutic index is also determined by the ratio of the dose that kills 50% of the animals, to the dose that produces 50% of the therapeutic effect in animals.

Unwanted Drug Effects

• Adverse effects related to dosage: Most drugs have multiple effects, only one of which is the primary intended result. Unwanted secondary effects are called side-effects.
  • Toxic effects: Pathological or genotoxic (DNA-altering). Toxicity incidence and severity depend on the drug concentration. These effects frequently occur shortly after administration, but some, like cancer, take longer to manifest (e.g., 20-30 years).
• Adverse effects unrelated to dosage:
  • Idiosyncratic reactions: Reactions are genetically determined and qualitatively similar between individuals but different in their intensity (sensitivity or insensitivity). For instance, a serious hemolytic anemia can develop in response to primaquine, especially in certain populations. Also, genetically-linked resistance to warfarin.
  • Allergic reactions: A previous chemical exposure can trigger an allergic response towards structurally similar substances. Allergic reactions involve the immune system and can manifest in different ways (e.g., immediate hypersensitivity, delayed-type hypersensitivity).

Explore various factors influencing drug response in this pharmacology quiz. Delve into how body size, age, genetics, and nutritional aspects affect drug absorption, metabolism, and efficacy. Test your understanding of pharmacodynamics and the role of emotional status in medication response.