BASIC PRINCIPAL PART III IV

Pharmacodynamics

Definition: Plots of drug dose (or log dose) versus response for drugs (agonists) that activate receptors.
Characteristics revealed by D-R curves include:
- Affinity: The strength of binding between a drug and its receptor. A higher affinity indicates a drug that binds more effectively at lower concentrations.
- Potency: The amount of drug required to produce a specific effect; a more potent drug achieves its effects at lower doses.
- Efficacy: The maximum effect a drug can produce, regardless of dose; related to the drug's intrinsic activity at the receptor.

Figure Analysis: Comparison of D-R Curves for two different drugs acting on the same (left panel) versus different (right panel) receptors can illustrate varying pharmacodynamic profiles. Nonparallel curves can indicate possible receptor interactions or differing mechanisms of action.

Full Agonists: Produce a maximal response and possess maximal efficacy by fully activating the receptor.
Partial Agonists: Unable to elicit a maximal response; therefore, they are less effective than full agonists and may even act as antagonists in the presence of a full agonist due to their lower efficacy.

Emax: Maximum effect achievable by a drug, often related to the number of receptors activated.
Bmax: Maximum binding capacity, representing the total number of available receptors.
EC50 and Kd: Concentrations at which effects are observed; EC50 is the concentration producing 50% of Emax, while Kd is the concentration required for 50% receptor occupancy.

Role of Receptor Antagonists: Bind but do not activate receptors; reduce the effects of agonists, thus altering the dose-response curve.
Classification of Antagonists:
- Competitive Antagonists: Compete with agonists for receptor binding, effects can be overcome by increasing agonist concentration.
- Irreversible Antagonists: Bind permanently to receptors, preventing agonist effects and cannot be displaced by increasing agonist concentrations.

Interactions: Agonist actions can be modified by competitive and non-competitive antagonists, changing the pharmacological effect. Dosing effects are influenced by the log dose of the agonist and the presence of inhibitors, which can shift or change the shape of the dose-response curve.

Application: Plots the percentage of a population responding to drug effect versus dose. It is useful for estimating ED50, the effective dose for 50% of the population, which helps assess drug safety and efficacy.

Potential Individual Variations in Response Include:
- Idiosyncratic Reactions: Unusual responses that cannot be predicted based on the drug's known pharmacology.
- Hyporeactive/Hyperreactive: Individual variations in drug sensitivities; hyperreactive individuals may require lower doses to achieve desired effects.
- Tolerance: Decreased response over time with repeated doses due to adaptation mechanisms within the body.
- Tachyphylaxis: A rapid decrease in response to a drug after initial administration, often due to receptor desensitization.
- Consider age, sex, body size, genetic factors, and simultaneous drug administration, which can dramatically affect individual responsiveness.

General Characteristics: No drug causes only a single, specific effect.
Selectivity in Actions: Drugs exhibit selectivity by binding more tightly to specific receptor types, which allows for therapeutic efficacy while minimizing adverse effects. Effects can be categorized into:
- Beneficial/Therapeutic Effects: Desired outcomes of drug therapy.
- Toxic/Adverse Effects: Undesired, harmful outcomes that can cause harm to the patient.

Key Processes: Concern the processes of absorption, distribution, metabolism, and excretion (ADME) that determine the drug's bioavailability and pharmacologic effectiveness.
Permeation: Affects the biodisposition of drugs and depends on:
- Solubility: The importance of both lipid and water solubility for effective diffusion across biological membranes.
- Concentration Gradient: The effect of free drug forms that influence the rate of absorption.
- Surface Area & Vascularity: Impact the efficiency of absorption into systemic circulation.

Dose of Drug Administered: Affects drug levels in the body; routes of administration and elimination processes influence drug concentration and pharmacologic effects.
- Absorption: Process by which a drug enters circulation, influenced by previous permeation factors.
- Intravascular Administration (IV): Direct; involves no absorption loss.
- Extravascular Administration: Such as oral, intramuscular (IM), and subcutaneous (SC) routes may not achieve 100% systemic circulation due to bioavailability variances.

Key Timepoints:
- Cmax: Maximal drug level achieved in the plasma, critical for understanding maximum exposure.
- tmax: Time at which Cmax occurs; important for determining onset of action.
- Lag Time: The period from administration to detection in blood, indicative of absorption delay.
- Onset of Activity: Time until drug effect reaches the minimal effective concentration (MEC).
- Duration of Action: The time the drug concentration remains above MEC; essential for dosing schedules.

Definition: The fraction of administered dose that reaches systemic circulation.
- IV Administration: Always demonstrates 100% bioavailability; hence, f = 1.
- Calculating Bioavailability: Uses area under the curve (AUC) calculations from oral (po) and intravenous (iv) administration.
- First-Pass Effect Concept: Oral drugs absorbed into portal circulation may undergo significant metabolism in the liver before reaching systemic circulation, which can drastically reduce bioavailability.

Drug Distribution Processes: Depends on drug solubility, blood flow to tissues, and plasma protein binding, which affect the extent and rate of distribution.
Plasma Protein Binding: Drugs equilibrate between free and bound states; only unbound drugs can cross cell membranes and exert pharmacological effects.

Definition and Implications: Vd correlates dose with plasma concentration at time zero. Higher Vd values indicate extensive distribution into the tissues rather than remaining in the circulation, which may imply potential for displacement effects by other drugs or agents.