Module 8 - Time Action

drug- receptor interaction happen via what interactions

ionic, hydrogen, van der waals, covalent

Drugs with short duration of action genrally have what type of bond

weak

Drugs with long-duration or irreversible interactions have what type of bond

stronger bond (covalent)

What are drug receptors

proteins that normally bind endogenous molecules to elicit physiological effects

Agonist

a chemical that activates a receptor to produce a biological response

Full agonist

activates a receptor with the maximum response that an agonist can elicit at the receptor

Partial Agonist

bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist, even at maximal receptor occupancy

Antagonist

blocks or dampens a biological response by binding to and blocking a receptor

What does pharmacodynamic relate

drug effect and concentration

What are pharmacokinetic properties related to

concentration and time

Time course of effect

the relationship of a drug’s effects over time

Time course of drug action

A function of drug absorption, distribution, metabolism and excretion

The intensity of a response elicited by a drug is a function of the dose administered and the concentration of the drug at the site where the action-effect sequence is initiated.

Absorption

The rate at which a drug leaves its site of administration and becomes bioavailable.

What factors affect transport across membranes and influences absorption

• Solubility, concentration, circulation to the site of absorption, the surface area of absorption, and the route of administration

• Binding to plasma proteins will increase the rate of passive absorption by maintaining the concentration gradient of free drugs

Distribution

• After a drug is absorbed or injected into the bloodstream, it may be distributed into interstitial and cellular fluids.

• Heart, liver, kidney, brain, and other well-perfused organs receive most of the drug during the first few minutes after absorption.

• Delivery to muscle, most other viscera, skin, and fat is slower, and these tissues may require several minutes to several hours before a steady state is attained.

• Binding to plasma proteins will decrease the distribution of drugs to other tissues.

Metabolism

Usually the body transforms drugs into more polar hydrophilic inactive compounds for elimination but sometimes the opposite occurs and you activate a drug.

Binding to plasma proteins will decrease the rate of metabolism.

The liver is the most important organ where most biotransformation/metabolism reactions take place.

Phase 1 Metabolism

biotransformation generally results in loss of pharmaceutical activity by the addition of a functional group

Phase 2 Metabolism

biotransformation is the conjugation of the parent compound / Phase I metabolite to glutathione, amino acid, sulfate, and glucuronic acid generally resulting incomplete inactivation of the drug

Excretion

Drugs are excreted either from the body unchanged or as metabolites.

Kidney is the most important organ for the excretion of water-soluble drugs and metabolites.

Oral drugs that are not absorbed by the GI tract are exreted in the feces. Some drugs (absorbed in the GI) and their metabolites are excreted in bile.

Renal excretion of drugs is dependent on several factors

protein binding, glomerular filtration (GFR), tubular secretion and reabsorption, blood flow.

Latency

The time between administration and the first measurable signs of a response

Time of onset

The time of the first measurable response

Time of peak effect

occurs when the drug concentration at the site of action has reached its maximum level

Duration of Action

from the time of onset to the time when the response is no longer perceptible (offset).

It depends on both the dose and rate of drug removal from the site of action.

Dose-response curve

Analyses the magnitude of drug effect by plotting magnitude of response as a function of dose of the drug.

The maximum effect

where the dose-response curve reaches a plateau

Affinity

The ability of a given drug to bind with a specific receptor.

Potency

The dose needed to produce a response/effect of given intensity.

• A shift to the right in the dose-response curve means a decrease in potency

• A shift to the left an increase in potency

Efficacy

The ability of a drug to produce the desired response/effect upon binding to the receptor. Describes the maximal response that can be created by the drug.

ED50 (50% effective dose)

The dose of a drug that produces an effect in 50% of the population (quantal) or causes 50% of maximal effect (graded). It is a convenient way to characterize a drug and a useful way to compare drug potency.

LD50

The dose that kills 50% of an exposed population.

The therapeutic index

A measure of a drug's safety and is equal to LD50/ED50. The higher the value, the safer the drug.

Barbiturates

Bind to the GABA_A receptors to increase GABA-induced chloride currents and result in CNS depressant effects. They are used as sedatives, hypnotics, anesthetics, and anticonvulsants.

Long-acting (over 6 hours)

Phenobarbital

Intermediate-acting (3-6 hours)

Amobarbital

Short-acting (Under 3 hours)

Pentobarbital

Ultra-short acting (30 min )

Thiopental

The onset and duration of a drug are dependent on

ADME

How does lipophillicity affect the onset of CNS effects

Thiopental is highly lipophilic and the brain is highly perfused and lipophilic. Hence thiopental very rapidly reaches effective blood levels. However due to its high lipophilicity, it also rapidly re-distributes into adipose and other tissues, the blood levels decrease rapidly to sub-therapeutic levels and as a result, its duration of action is ultra-short. Pentobarbital and Phenobarbital are less lipophilic, cross the brain barrier less rapidly and at the same time the drug is distributing to other tissues. It takes longer to reach the effective CNS levels.