PHRM 3310 Test 1

Introduction to Molecular Pharmacology; Drugs, Receptors, & Pharmacodynamic Mechanisms; Pharmacokinetics & A.D.M.E

What is pharmacology?

the study of the actions & effects of drugs on living systems & the interaction of drugs with living systems

What are the two main divisions of pharmacology?

pharmacodynamics & pharmacokinetics

What is pharmacodynamics?

the study of drug actions at a target (receptor sites) & the physiological/chemical/behavioral effects they produce

What does pharmacokinetics study?

how drug concentration changes as it moves through the different compartments of the body

What is the classic difference between pharmacokinetics & pharmacodynamics?

• pharmacokinetics = what the body does to the drug

• pharmacodynamics = what the drug does to the body

What is pharmacodynamics also described as?

mechanism of action (MOA)

What is the mechanism of action of a drug?

how the drug produces its effects at the molecular level

Why is pharmacodynamics important?

it provides the basis for rational therapeutic uses & the design of therapeutic agents

What do most drugs interact with?

a specific target protein

What are the 4 groups of functional proteins?

• enzymes

• ion channels

• transporters

• receptors

How can drugs affect enzymes?

they can increase or decrease the rate of enzyme-mediated reactions

What are the 5 major types of drug effects/actions?

• stimulation

• depression/inhibition

• irritation/inflammation

• replacement

• cytotoxic effect

What is an example of a drug with stimulation effects?

adrenaline stimulates the heart

What are examples of drugs with depression/inhibition effects?

• quinidine depresses the heart

• barbiturates depress the CNS

• omeprazole depresses gastric acid secretion

What is meant by replacement as a drug effect?

replacing a missing substance in the body

What are examples of replacement therapy?

• levodopa in Parkinson’s disease

• insulin in diabetes mellitus

• iron in anemia

What is a cytotoxic effect?

a drug effect that kills cells/organisms

What are examples of drugs with cytotoxic effects?

• antiparasitics

• antibiotics

• anti-cancer

What does the magnitude of a drug’s response depend on?

the concentration achieved at the site of action/receptor

What factors influence the magnitude of drug response?

• dosage

• extent of absorption

• metabolism/distribution to the site

• rate/extent of elimination

What is the "site of action" relationship to drug response?

the higher the concentration at the site of action/receptor, the greater the potential response

What is absorption in pharmacokinetic terms?

how the drug gets into the body/blood

What is distribution in pharmacokinetic terms?

how the drug moves to different tissues or compartments

What is metabolism in pharmacokinetic terms?

how the drug is broken down

What is excretion in pharmacokinetic terms?

how the drug leaves the body

What is the receptor theory of drug action?

a drug binds to a receptor to form a drug-receptor complex that produces an effect

What are receptors?

proteins inside/on the surface of cells that mediate drug activity

What do receptors respond to?

specific ligands: neurotransmitters, hormones, antigens, chemicals, or other substances

What happens when a ligand binds to a receptor?

it triggers a response or signal in the cell

What is a ligand generally?

a molecule that binds to a receptor

What are the 2 general types of ligand function?

• agonist

• antagonist

What is an agonist?

a drug that mimics the endogenous/physiologic ligand to produce a similar response

What is an example of an agonist?

morphine→opioid receptors

What is an antagonist?

a drug that blocks the usual ligand & inhibits the physiologic response

What is an example of an antagonist?

naloxone→opioid receptors

What is receptor specificity?

the measure of a receptor's ability to respond to a single ligand

What can low specificity cause?

physiologic responses not targeted or intended by the drug, leading to side effects

What is receptor selectivity?

• the ability of the receptor to distinguish between drugs

• the drug's preference for one receptor type over another

What is receptor affinity?

the strength of attraction between the drug & its receptor

What does high affinity usually mean clinically?

a lower dose requirement

What is the occupancy theory?

the effect of a drug reflects the occupancy of its receptor site, sometimes

What does the occupancy model assume about drug-receptor binding?

one drug molecule combines reversibly with one receptor

What does the occupancy model assume about receptors?

all receptors are identical & equally accessible to the drug

What does the occupancy model assume about response?

the magnitude of the response is proportional to the number of receptors occupied by the drug

What does the occupancy model assume about drug concentration during the reaction?

the effective drug concentration does not change during the reaction

What is the relationship shown in the occupancy model diagram?

D + R ⇌ DR → Response

What is Kd in the receptor occupancy context?

the equilibrium dissociation constant, shown by the relationship [D][R]/ [DR] = k2/k1=Kd

What is the key idea linking pharmacokinetics & pharmacodynamics?

pharmacokinetics moves the drug to the site of action; pharmacodynamics begins when the drug binds to the target & produces a response

What does pharmacokinetics include?

• A.D.M.E.

  • absorption

  • distribution

  • metabolism

  • excretion

What are the 2 types of curves used to plot dose-response relationships?

• graded dose-response curve

• sigmoid curve

What is a graded dose-response curve?

a plot of response vs. the drug concentration/dose

What is a sigmoid curve?

a plot of the same data of a graded dose-response curve, but on a logarithmic concentration axis

What is the value associated with Bmax?

the maximal number of receptors bound

What does Emax measure?

efficacy

What does EC50/ED50 measure?

potency

What is the value associated with EC50/ED50?

the dose/concentration at which effect is half maximal

What is the value associated with Emax?

maximal effect

What is the relationship between efficacy & potency?

the smaller the EC50/ED50, the greater the potency

What is the value associated with Kd?

the concentration at which 50% of receptors are bound

What does Kd mean?

dissociation constant

What does Kd measure?

the affinity of a drug to its binding site

What is the relationship between Kd & affinity?

the smaller the Kd, the greater the affinity of the drug for its receptor

What is efficacy?

the greatest effect (Emax) an agonist can produce if the dose is taken to the highest tolerated level

What is potency?

the amount of drug needed to produce a specified effect

What is the therapeutic window?

the safe range between the minimum therapeutic concentration & the minimum toxic concentration of a drug

What is a full agonist?

a drug capable of fully activating the effector system when it binds to the receptors

What kind of affinity & concentration do full agonists have for the activated receptor conformation & what is the result?

high affinity & sufficiently high concentrations, resulting in all the receptors achieving the activated state

What is a partial agonist?

a drug that is not capable of producing the full effect, even when it has saturated the receptors

What kind of affinity do inverse agonists have for the inactive state of a receptor?

higher than for active state

What happens when an antagonist binds to receptors?

it prevents agonists binding & block their actions

Antagonists bind to receptors, but produce what kind of effect?

none

What do neutral antagonists do?

bind with equal affinity to the Ri (inactivated) & Ra (activated) conformation; prevent binding by an agonist & any deviation from the level of constitutive activity

What are a competitive antagonists?

drugs that bind to, or very close to, the agonist receptor site in a reversible way without activating the effector system for that receptor

What is a noncompetitive antagonist?

a drug that binds reversibly/irreversibly at an allosteric site on the receptor

What is a neutral antagonist?

a drug that binds to the receptor w/o shifting the ratio of activated receptor to inactivated receptors

When do spare receptors exist?

when maximal drug response (Emax) is reached at less than 100% occupation of receptors (Bmax)

What is the relationship between EC50 & Kd in a system with spare receptors & what does this indicate?

the EC50 is lower than the Kd, indicating that to achieve 50% of the maximal effect, less than 50% of the receptors need to be activated

What does EC50 < Kd mean?

the full effect can be reached with <100% occupancy

What are the relationships when the full effect can be reached with <100% occupancy?

• duration of effector activation > duration of drug-receptor interactions

• number of receptors > number of effector molecules

What is pharmacokinetics (PK)?

the study of the disposition of a drug in the body; what the body does to the drug; includes ADME: absorption, distribution, metabolism, & excretion

What does ADME stand for?

absorption, distribution, metabolism & excretion

Why does pharmacokinetics (PK) matter?

• safety: toxic drugs may accumulate

• dosing: doses may be too low to work effectively

• effectiveness: patients may metabolize drugs at different rates, leading to different responses

What is absorption?

the process by which a drug moves from the site of administration into the bloodstream

Why is absorption important?

it is usually necessary to produce a therapeutic effect, especially for non-IV drugs

Which route of administration BYPASSES absorption?

IV (intravenous) administration; drug goes directly into the bloodstream

What is bioavailability?

the fraction of the administered dose that reaches systemic circulation

Which route has 100% bioavailability?

IV (intravenous) administration because it bypasses absorption

What is the first-pass effect?

the process in which an oral drug is metabolized in the gut wall & liver before reaching systemic circulation, reducing the amount of active drug that enters the body

How does first-pass metabolism affect oral drugs?

it reduces the concentration of the drug before it reaches the rest of the body, which can lower drug effect & bioavailability

What are the MAIN routes of administration?

• intravenous (IV)

• oral (PO)

• sublingual/buccal

• inhalation/topical

What is special about IV administration?

• immediate effect

• complete absorption

• 100% bioavailability

What is special about oral administration?

• slower onset

• possible first-pass metabolism

• incomplete absorption

Why can sublingual or buccal administration act faster than oral swallowing?

because the drug dissolves under the tongue or in the cheek & is absorbed directly into systemic circulation, avoiding much of the first-pass effect

What is passive diffusion?

the movement of small, lipid-soluble drugs across membranes from high to low concentration WITHOUT using energy

What is facilitated diffusion?

the movement of water-soluble drugs across membranes using carrier proteins, but WITHOUT energy use

What is active transport?

the movement of drugs against a concentration gradient & REQUIRES ATP energy

Which type of drug movement is energy-dependent?

active transport

Which type of drug movement is most associated with small, lipid-soluble drugs?

passive diffusion

Which type of drug movement uses carrier proteins but NO energy?

facilitated diffusion

What are the key factors affecting absorption?

• drug form: liquid absorbs faster than solids

• pH environment

• blood flow

• surface area (SA)