Lecture 2 - Pharmacodynamics and Pharmacokinetics

Question 1

Define

Pharmacodynamics

Answer 1

The study of how a drug acts on a living organism

Interaction with receptors on a molecular level

Question 2

What does pharmacodynamics look at?

Answer 2

• Pharmacological response
• Duration and magnitude of response –> relative to the concentration of drug at the active site
• Affects efficacy and potency

Question 3

Drug-receptor interactions are dependent on:

Answer 3

• Receptor subunits
• Receptor confirmation
• Ionic concentration
• pH
• other interacting molecules

Question 4

Define

Pharmacokinetics

Answer 4

Study of the movement of drugs in the body
- Absorption, distribution, metabolism, and excretion (ADME)

Determines drug availability

Question 5

Define

Agonist

Answer 5

Molecule that binds to a receptor and stabilizes it in a particular conformation (usually activation)

Question 6

Define

Antagonist

Answer 6

Molecule that inhibits the action of an agonist, but generally has no effect in the absense of the agonist

Question 7

Define

Receptor antagonist

Answer 7

Binds to either the active site or the allosteric site on a receptor

Question 8

What happens to the active binding site when an antagonist binds to an allosteric site?

Answer 8

Kd is altered for the active site-agonist or the receptor is prevented from undergoing a conformational change

Question 9

Receptor antagonists

Binds to active site

Answer 9

• Reversible –> competitive
• Irreversible –> noncompetitive

Question 10

Receptor antagonists

Binds to allosteric site

Answer 10

Reversible and irreversible –> noncompetitive

Question 11

Nonreceptor antagonists

Chemical antagonist

Answer 11

• Uncompetitive
• sequester agonist and prevent it from interacting with the receptor

Question 12

Nonreceptor antagonists

Physiologic antagonist

Answer 12

• Uncompetitive
• Induces a physiologic response opposite to that of the agonist by a mechanism that does not involve the receptor for the agonist

Question 13

Define

Uncompetitive antagonist

Answer 13

A drug whose inhibitory action is contingent upon prior activation of the receptor by an agonist

Question 14

Kinetic profile

Uncompetitive antagonist

Answer 14

• Same amount of antagonist blocks higher concentrations of agonists better than lower concentrations od agonist
• Reduces both efficacy and potency of an agonist

Question 15

Kinetic profile

Competitive antgonist

Answer 15

• Reduces potency
• No effect on efficacy

Question 16

Kinetic profile

Noncompetitive antagonist

Answer 16

• Reduced efficacy
• No effect on potency

Question 17

Inverse agonist vs. Antagonist

Inverse agonist

Answer 17

• decreased receptor baseline activity
• produces an opposite effect compared to the natural ligand

Question 18

Inverse agonist vs. Antagonist

Antagonist

Answer 18

• Prevents receptor from being activated
• does not affect baseline activity
• no intrinsic effect itself

Question 19

Routes of Administration

Answer 19

• Enteral: oral, sublingual, rectal
• Parenteral: intrevascular, intramuscular, intraventrical
• Other: inhalation, intranasal, topical

Question 20

Define

Absorption

Answer 20

The enterance of a drug into the bloodstream

Question 21

Define

Bioavailability

Answer 21

The fraction of administered drug that reaches systemic circulation

Question 22

How does Absorption occur?

Answer 22

• Filtration
• Active transport
• Passive transport
• endocytosis

Question 23

General bioavailability equation

Answer 23

quantity of drug reaching systemic circulation / quantity of drug administered

max value = 1 (intravenous administration)

Question 24

Local bioavailability equation

Answer 24

Amount of drug at site of action / quantity of drug administered

always <1

Question 25

membrane diffusion is determined by what?

Answer 25

- lipid solubility - drug ionization - drug formulation - pH (pH trapping)

Question 26

What type of drugs can pass through the blood-brain barrier?

Answer 26

Hydrophilic, small molecules by active transport

Question 27

# Define Ph Trapping

Answer 27

Net diffusion of acidic and basic drugs across lipid bilayer membranes based on charge (noncharged molecules can pass through the membrane easier)

Question 28

What makes a drug slow to release and slow to eliminate?

Answer 28

Drug binds to Albumin or other plasma proteins in the vascular space

Question 29

# Define Fast-Pass metabolism

Answer 29

- All orally administered drugs travel to the liver via the portal system - Protects the body from the systemic effects of ingested toxins

Question 30

What are the phases of biotransformation?

Answer 30

Phase 1: reduction/oxidation reactions Phase 2: Conjugation/hydrolysis reactions

Question 31

What are the majority of oxidases?

Answer 31

Heme protein monooxygenases of the cytochrome p450 class - aka microsomal mixed-function oxidases - involved in the metabolism of about 75% of all drugs used today

Question 32

What are some factors that affect metabolism?

Answer 32

- Race - Age - Gender - Diet - Environment - Genetic background - Disease

Question 33

# Define Grapefruit Juice Effect

Answer 33

Psoralen derivatives and flavonoids in grapefruit juice inhibits P450 3A4 in the small intestine - significantly decreases fast-pass metabolism - if drank while on statins can cause kidney failure

Question 34

# Non P450 oxidative pathways Alcohol dehydrogenase

Answer 34

Oxidizes alcohols to their aldehyde derivatives as a part of the overall excretion process | Basis of methanol toxicity --> oxidized methanol to formaldehyde

Question 35

# Non P450 oxidative pathways Monoamine Oxidase (MAO)

Answer 35

Oxidation of amine-containing endogenous compounds such as catecholamines and tyramine

Question 36

Where does metabolism take place in the body?

Answer 36

- Liver (Most important) - intestine - blood - brain

Question 37

# Biotransformation (Phase 2) Hydrolysis and conjugation reactions

Answer 37

Converts drugs or phase 1 drug metabolites for excretion - most conjugation reactions increase drug hydrophilicity (except methylation)

Question 38

# Biotransformation (Phase 3) Drug transport

Answer 38

MDR1 or P-glycoprotein transport compounds back to the intestinal lumen

Question 39

# Biotransformation (Phase 3) How are compounds transported into hepatocytes from portal circulation

Answer 39

Organic anion transporting polypeptide (OATP) and Organic cation transporter (OCT)(responsible for renal secretion)

Question 40

# Structure P-glycoprotein (P-gp)

Answer 40

Consists of 2 nucleotide binding domains and 2 transmembrane domains

Question 41

# Structure Multidrug resistance-associated protein 1 (MRP1)

Answer 41

2 transmembrane domains, 2 nucleotide binding domains, a third transmembrane domain with 5 segments and an extra N-terminus

Question 42

# Structure Breast Cancer Resistance Protein (BCRP)

Answer 42

1 nucleotide binding domain and 1 transmembrane binding domain

Question 43

Modes of excretion

Answer 43

- Renal - GI - Respiratory - Sweat - Saliva - Breast milk - Feces

Question 44

# Define Enterohepatic circulation

Answer 44

Circulation of biliary acids, drugs, and other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte, and transport back to the liver | circulates fat-soluble substances until they become water-soluble

Question 45

# Define Drug interaction

Answer 45

Reaction between two drugs or between a drug and a food, beverage, supplement, or condition | ex. can't drink grapefruit juice with statins