Chapter 5 Stoelting Basic Pharm Principles

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Pharmacokinetics describes

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the absorption, distribution, metabolism, and excretion of inhaled or injected drugs (i.e., what the body does to the drug).

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what the drug does to the body is

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Pharmacodynamics

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what the body does to the drug is

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Pharmacokinetics

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Pharmacodynamics describes

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the responsiveness of receptors to drugs and the mechanism by which these effects occur (i.e., what the drug does to the body).

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Receptors are the

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components of the cell that interact with drugs to initiate a sequence of events leading to pharmacologic effects.

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Ternination of a drug's effect depends of 3X

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occurs by metabolism, excretion, or redistribution to inactive sites.

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The nonionized drug fraction tends to be

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pharmacologically active and lipid-soluble

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the ionized fraction is

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inactive and water soluble.

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The degree of ionization of a drug is a function of its

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pK and the pH of the surrounding fluid. When the pK and pH are identical, 50% of the drug exists in the ionized form.

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small changes in pH can resslt in

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large changes in the degree of ionization, especially if the pH and pK : values are similar.

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Absorption is

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defined as the rate at which a drug leaves its site of administration.

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Membrane transport occurs when

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drugs cross cell membranes by simple diffusion, by facilitated or carrier-mediated transport, and by active (energy- I dependent) transport.

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first pass effect

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Drugs absorbed from the gastrointestinal tract (principally the small intestine) enter the portal venous blood and pass through the liver before entering the systemic circulation for delivery to tissue receptors.

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The pKa of a drug is

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the pH at which the nonionized and the ionized drug concentrations are equal.

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PROTEIN BINDING
The binding of a drug to proteins determines the

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concentration of the drug in the plasma and various other tissues.

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ION TRAPPING is

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The lower pH of the fetal blood means that drugs, such as local anesthetics and opioids, that cross the placenta in the nonionized form I will become ionized in the fetal circulation. Because an . ionized drug cannot readily cross the placenta back to the maternal circulation, it accumulates in the fetal blood against I a concentration gradient.

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This transfer of drugs to inactive tissue sites

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as redistribution.

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Metabolism (principally in the liver, but to some extent also in the kidneys, lungs, and gastrointestinal tract) converts

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pharmacologically active, lipid-soluble drugs to watersoluble and often inactive metabolites.

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phase I reactions are

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oxidation, reduction, and hydrolysis)

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Conjugation reactions involve

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coupling of a drug with an endogenous substrate, such as glucuronate, acetate, or an amino acid, so that I they can be excreted. .

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phase II reactions are

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conjugation-

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The rate at which the plasma concentration of a drug decreases with time (i.e., elimination half-time) is determined by

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Vd and clearance of the drug. Context sensitive half-time and effect-site equilibration time are more useful than elimination half-time in characterizing the clinical responses to drugs.

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The first (alpha) phase is designated the

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distribution phase, corresponding to the initial distribution of drug from the circulation to tissues (i.e., peripheral compartments).

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The second (beta) phase is designated the

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elimination phase. This phase is characterized by a gradual decrease in the plasma concentration of drug and reflects its elimination from the central vascular compartment by renal and hepatic mechanisms.

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Clearance is

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the volume of plasma (i.e., central compartment) cleared of drug (mL/min) by renal excretion or metabolism, or both, in the liver or other organs

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V d is a calculated by

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V d is a calculated number (i.e., dose of drug administered intravenously, divided by the plasma concentration) that . reflects the apparent volumes of the compartments that I constitute the compartmental model for that drug

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Elimination half-time

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is the time necessary for the plasma concentration of drug to decrease 50% during the elimination phase

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_____ elimination half-times are required for almost complete elimination of a drug.

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Five

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Bioavailability is defined as

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the amount of active drug that is absorbed and reaches the systemic circulation.

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The most important mechanism by which drugs exert pharmacologic effects is

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by the interaction of the drug WIth a specific protein molecule in the lipid bilayer of cell membranes

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Receptors are

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excitable transmembrane proteins that are responsible for transduction of biologic signals.

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Voltage-sensitive ion channels depend on ...

examples are

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cell membrane voltage to open and close, and they are represented by classic ion channels, such as sodium, chloride, potassium, and calcium channels.

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Ligand-gated ion channels, receptor ion channel complexes are,

2 examples

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such as nicotinic cholinergic receptors and amino acid receptors (e.g., y-aminobutyric acid [GABA]) function as receptorion channel complexes in which the ion channel is an integral part of a larger and more complex transmembrane protein.

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Activation of GABA-chloride channels results in

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cell hyperpolarization or an increase in ion conductance that prevents depolarization, thereby inhibiting neuronal activity.

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Approximately one third of all synapses in the central nervous system are responsIve to ___ .

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GABA

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An agonist is a

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drug that initiates pharmacologic effects after combining with the receptor.

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Agonist drugs, when bound to a receptor, ...

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induce I stimulatory or inhibitory effects that mimic endogenous hormones and neurotransmitters. .

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partial agonist.

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A drug with an affinity equal to or less than that of the agonist but with lesser efficacy is called a partial agonist.

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The number of receptors in lipid cell membranes is

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dynamic, increasing (upregulation) or decreasing (downregulation) in response to specific stimuli.

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Dose-response curves depict the relationship between

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the dose of drug administered (or the resulting plasma concentration) and the resulting pharmacologic effect.

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ceiling effect

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the degree of effect produced by increasing doses of a drug eventually reaches a steady level. This phenomenon is called the ceiling effect, and the dose at which it is obtained is called the ceiling dose. If the dose of '" .~ drug exceeds the ceiling dose, there is no further increase in the therapeutic effect, and undesirable effects . may predominate.

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The therapeutic index of a drug is the ratio between

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the lethal dose (LD50) in 50% of patients and the effective dose (ED50) in 50% of patients.

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When the pharmacologic effect of two or more drugs administered together is equivalent to the summation of their individual effect

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additive effect

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occurs when the pharmacologic effect of two or more drugs administered concomitantly is greater than the sum of the individual pharmacologic effects.

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synergistic response

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Agonist and antagonist drugs compete for the same

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receptors.

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competitive antagonist usually can be displaced from the receptor sites by

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administration of high doses of the agonist.

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Competitive antagonism is

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reversible.

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a noncompetitive antagonist produces a

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conformational change in the receptor that results in a diminished receptor response when exposed to an agonist, even at high doses.

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Drug tolerance is present when

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a large dose of a drug is required to elicit an effect that is usually produced by the smaller (therapeutic) dose of the drug.

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TACHYPHYLAXIS

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Tachyphylaxis (i.e., acute tolerance) to the pharmacologic effects of certain drugs (e.g., ephedrine, amphetamine) may occur when they are administered at short intervals. The mechanisms responsible for tachyphylaxis are unclear but may reflect depletion of norepinephrine stores or altered dissociation of drug from its receptor sites.

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Selectivity of drug action is determined by

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receptors that recognize specific drugs.

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A drug may be defined as

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a chemical compound that produces pharmacologic effects as determined by its pharmacokinetics and pharmacodynamics.

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When the pK and pH are identical,

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50% of the drug exists in the ionized form.

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Simple diffusion is a

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bidirectional process ill which the rate of transfer of the drug is proporoonal to the concentration gradient.

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Highly lipid soluble and small-molecular-weight and cell membranes.

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drugs diffuse passively across cell membrane

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Large molecular-weight drugs and cell membranes

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Large-molecular-weight drugs are transported across cell membranes by a carrier-mediated process or an active transport system that requires energy ti

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The first-pass pulmonary effect may influence

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the peak arterial concentration of these drugs, and the lungs subsequently can serve as a reservoir to release drug back into the systemic cirrulation.

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After absorption, the drug circulates in the plasma in the

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unbound (free) form and in the form bound to protein, which is usually albumin (acidic drugs) or acid glycoprotein (basic drugs).

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Protein binding acts as a__________ that prevents large fluctuations in the concentration of the unbound or free drug.

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temporary reservoir for a drug

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A.. lipid-soluble drug undergoes minimal renal crcretion because

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of the ease of reabsorption from the lumens of renal tubules into pericapillary fluid.

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Microsomal enzymes that participate in the metabolism of many drugs are located principally in

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hepatic smooth endoplasmic reticulum.

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The microsomal fraction contains the cytochrome P4\O system, which

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most likely constitutes a large number of protein enzymes responsible for metabolism of many foreign compounds.

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Drugs are excreted as

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unchanged or as metabolites.

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Context-sensitive half-time describes the

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time necessary for the drug concentration to decrease to a predetermined percentage (e.g., 50%,60%,80%) after discontinuation of a continuous intravenous mfusion of a specific duration;

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Antagonist drugs bind

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to receptors but are not capable of eliciting a pharmacologie response

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The dose required to produce a specified effect is designated as

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the effective dose (ED) necessary to produce that effect in a given . percentage of patients (e.g., EDso, ED90).