Pharmicokinetics

Question 1

Specificity

Answer 1

The drug only produces one effect on the body if it is very specific

Question 2

Selectivity

Answer 2

Drugs prefers to bind to one specific target (receptor) over others, most drugs are selective

Question 3

Agonist

Answer 3

Drugs fits the receptor and activates it

Question 4

Antagonist

Answer 4

The drugs fits the receptor but doesn’t activate it, just prevents its activation by another molecules

Question 5

What class of drugs have efficacy?

Answer 5

Agonists (efficacy is the ability to produce an effect)

Question 6

Law of mass action

Answer 6

Question 7

Affinity

Relationship to Kd

Answer 7

1/K_D

From law of mass action plot

Question 8

K_D

Definition

Answer 8

The drug concentration needed for 50% of receptors to be bound by the drug

Question 9

Potency

Answer 9

Used to compare binding affinities of drugs that bind to the same receptor site and work by the same mechanism

Question 10

Inverse agonists

Answer 10

Produce the opposite effect as the agonist. They still activate the receptor but instead of triggering a positive response, they cause a negative one.

Question 11

Dose response curves for different types of agonists

Answer 11

Question 12

Competitive antagonists

Answer 12

Bind to the same site on the receptor as the agonist

Can be overcome by increasing concentration of agonist

Question 13

Non-competitive antagonist

Answer 13

Bind to a different site on the receptor than where the agonist binds, but still prevent the agonist from activating the receptor

Question 14

Irreversible antagonists

Answer 14

Bind permanently to the receptor, often by forming covalent bonds

Question 15

Answer 15

X - agonist alone

Y - agonist with competitive antagonist

Z - agonist with an irreversible antagonist

Question 16

Quantal dose-response curves

Answer 16

Used to study how drugs affect a population - aka “all-or-none” curves = measure whether a drug causes a specific effect (yes or no) in a population of patients.

Question 17

Cumulative frequency distribution

Answer 17

Used to determine ED50 and TD50

When drugs TD50/ED50 <10 we say that the drug has a “narrow” therapeutic index - there is a small variation in drug dosage that causes desired effect vs. harmful effects

For humans we use TD50 (toxic dose in 50% of population)

Question 18

NSAIDs

Answer 18

Competitively bind cyclooxygenase (COX) preventing arachidonic acid from binding

Question 19

Aspirin

Answer 19

Non-competitively binds COX receptors (also irreversibly acetylates the enzyme) which prevents arachidonic acids from every binding

Question 20

Gs proteins

Answer 20

Stimulate adnylyl cyclase - increases cAMP

Question 21

Gi proteins

Answer 21

Inhibit adenylyl cyclase - reduces cAMP, often resulting in hyperpolarization of cells

Question 22

Gq proteins

Answer 22

Activate a different pathway using diacyglycerol (DAG) and inositol triphosphate (IP3) as second messengers. Typically when this pathway is activated there is an increase of calcium levels inside cells. When intracellular calcium levels increase, this can promote cell depolarization, release of neurotransmitters, or contraction depending upon the cell type.

Question 23

When receptors are exposed to continuous stimulation:

Answer 23

Desensitization - often because the receptors uncouple from their G-proteins

Down-regulate - few receptors available on the cell surface

Tachyphylaxis - decrease the situation in which there is a rapid or substantial decrease in the effect of a drug over time

(from AI - rapidly diminishing response to successive doses of a drug, rendering it less effective. The effect is common with drugs acting on the nervous system)

Question 24

What may occur when receptors are continuously blocked by an antagonist?

Answer 24

The receptors may become supersensitized and up-regulate making the cell more responsive to stimulation when the antagonist dissociates (or competitively displaced)

Question 25

Autoreceptors

Answer 25

Located on the presynaptic neuron Limits the release of neurotransmitters Drugs that act on autoreceptors can affect the amount of neurotransmitter reaching the postsynaptic neuron (leads to either up/down regulation - depending on whether drug is agonist/antagonist)

Question 26

Absorption

Answer 26

The process of moving a drug from its site of administration into the bloodstream

Question 27

PO absorption

Answer 27

1. Absorbed in the gut 2. Travels to the liver via the portal vein 3. First-pass effect in the liver

Question 28

Bioavailability

Answer 28

(F) - fraction (or percentage) of the drug that makes it into systemic circulation after the first-pass through the liver (i.e 40% of a drugs ia metabolized by first-pass metabolism, leaving 60% bioavailable - F=0.6)

Question 29

What enteral ROA(s) bypass the liver and avoid the first-pass effect?

Answer 29

Sublingual and rectal

Question 30

Parenteral routes

Answer 30

All routes that do not involve the GI tract - IV, inhalation, transdermal...etc. ## Footnote Also bypasses first-pass metabolism

Question 31

Hydrophilic drugs

Answer 31

Need to be small enough to pass through aquaporins

Question 32

P-glycoprotein

Answer 32

Work to efflux drugs from cells.

Question 33

OATP1B1 and OATP1B3

Answer 33

Help transport drugs into cells

Question 34

Breast Cancer Resistance Protein

Answer 34

Pumps drugs out of cells

Question 35

Organic cation transporters and multidrug and toxin extrusion proteins

Answer 35

Move drugs in and out of renal cells

Question 36

Factors affecting absorption

Answer 36

1. Drug size 2. Formulation (i.e. tablet, capsule) 3. pk_a 4. pH of surrounding environment 5. Dose administered and resulting concentration gradient 6. Surface area and blood flow at absorption site

Question 37

Apparent volume of distribution (Vd)

Answer 37

Helps estimate how much of the drug is found in different areas (compartments) of the body. Vd assumptions: drugs is distributed equally throughout all body compartments and instantaneous distribution Vd = Dose/C₀ C₀ represents the drug's inital concentration in plasma.

Question 38

Properties that help drugs cross BBB and/or placental barrier

Answer 38

1. Low-ionization 2. High lipophilicity 3. Low amount of non-specific protein binding to ablumin 4. Small size ## Footnote If small enough (~equal to the mw of water) then things molecules will readily diffuse through the barrier with water, regardless of ionization state

Question 39

Enterohepatic recirculation

Answer 39

Acts like a resevoir for the drug After being metabolized by the liver, some drugs are excreted into the bile and then passed back into the instestines. Under favorable conditions, the drug may be reabsorbed from the intestines back into the bloodstream, extending its time in the body Estrogens (i.e. oral contraceptives) undergo enterohepatic recirculation - helps maintain their levels in body.

Question 40

Infants | Impact of age on drug absorption/distribution

Answer 40

Have **higher levels of extracellular fluid** compared to adults, which can change the distribution and plasma concentration of some durgs

Question 41

Older adults | Impact of age on drug absorption/distribution

Answer 41

Typically have more body fat than younger people, which can affect how fat-soluble drugs are stored and released Also tend to have less p-glycoprotein activity at the BBB, so more drugs may enter the CNS

Question 42

Main goal of biotransformation

Answer 42

To make drugs more water-soluble - allowing them to be more easily removed from the body

Question 43

Phase 1 rx'ns

Answer 43

Include oxidation, reduction, and hydrolysis Often referred to as unmasking or non-synthetic reactions because they expose or add a functional group to the drug, but they do not involve combining 2 large molecules to make a new one

Question 44

Phase 2 rx'ns

Answer 44

Involve conjugation - and are sometimes called synthetic rx'ns Combine the drug with another molecule like glucoronic acid, sulfate, or glutathione to form a new, more water-soluble compound

Question 45

Oxidation of phase 1 rx'ns

Answer 45

Most common type of phase 1 rx'n Often carried out by specific enzymes call ctyochrome P450 (CYP) enzymes in the liver

Question 46

P450 inhibitors

Answer 46

Cimetidine (OTC histamine-2 receptor antagonist), "azole" antigungals, some HIV medications

Question 47

P450 inducer

Answer 47

Increases the activity of the CYP enzyme, causing more enzyme to be made or stabilizing the mRNA that encodes for the enzyme. Leads to faster breakdown of other drugs that are metabolized by the same enzyme, may reduce other drug's effectiveness. Antiepileptic meds (**carbamazepine, phenobarbital, phenytoin**) and **rifampin** are potent P450 inducers

Question 48

Hydrolysis rx'sn

Answer 48

Peptidases/esterases/amidases | Phase 1 rx'sn

Question 49

Glucoronidation

Answer 49

Glucuronyl transferase adds glucoronic acid to the drug, making it easier to excrete Infants under 1 y/o have immature glucuronidation capabilities, and toxicities can result ## Footnote Phase 2 rx'ns Some drugs that are glucuronidated are excreted into bile and can undergo enterohepatic recirculation

Question 50

Glutathione conjugation

Answer 50

A small peptide added to detoxify harmful drug metabolites ## Footnote Phase 2 reactions

Question 51

Phase 2 rx'ns

Answer 51

Sulfation, acetylation, and methylation Along with glutathione conjugation and glucuornidation

Question 52

Two pathways of drug elimination

Answer 52

Metabolism - drug is chemically altered (mainly liver) and excretion (mainly kidneys)

Question 53

Drug clearance

Answer 53

Refers to the volume of fluid (usually plasma) from which a drug is completely removed over a given period of time - mL/min

Question 54

What factors influence hepatic clearance?

Answer 54

Factors that influence: 1. Enzyme induction or inhibition 2. Liver blood flow 3. Protein binding

Question 55

Renal clearance | Equation

Answer 55

CI_renal = UV/P U = concentration of drug in urine V = urine volume formed per minute P = concentration of drug in plasma

Question 56

Main processes of renal clearance

Answer 56

Glomerular filtration - passive procces where small, unbound drugs are filtered from the blood into the renal tubule (creatinine clearance used to estimate kidney function) Active secretion - some drugs are actively transported from the blood into the urine using ATP. Involves protein carriers, which can be saturated and lead to drug interactions Reabsorption - drugs that are lipid-soluble can passively diffuse back into the bloodstream from the renal tubules. However, polar or ionized drugs are more likely to stay in the urine and be excreted. ## Footnote Making urine more acidic (with Vit C) or more alkaline (NaHCO₃) can help excrete certain drugs faster by preventing their reabsorption

Question 57

Gray baby syndrome

Answer 57

Due to immature hepatic enzymes needed for glucoronidation of chloramphenicol

Question 57

Antagonism | Drug interactions

Answer 57

Pharmcologically: at the receptor level, where two drugs compete for the same receptor Physiologically: When drugs act through different body systems but have opposing effects Chemically: two drugs form a chemical complex

Question 58

Synergism | Drug interactions

Answer 58

Combining antigoagulants and antiplatelets can increase overall blood-thinning effects

Question 59

Pharmacokinetic drug interactions

Answer 59

Absorption: one drug can interfere with the absorption of another, either by altering the stomach's pH or forming complexes that reduce absorption Distribution: Drugs can compete for binding sites on proteins like albumin, affecting how much of each drug is "free" to act in the body Metabolism: some drugs speed up or slow down liver enzymes - this can lead to one drug being metabolized too quickly or slowly Elimination: drugs can affect each other's clearance, especially through the kidneys, either by competing from transport proteins or altering pH of urine

Question 60

Time-response curves

Answer 60

Useful for calculating bioavailability Area under the curve represents total drug exposure over time

Question 63

Zero-order elimination kinetics

Answer 63

Alcohol is the key example Enzyme(s) responsible for eliminating drugs are sturable (i.e. alcohol DH)

Question 64

First-order elimination kinetics

Answer 64

Applies to most drugs Rate of elimination is proportional to the drug concentration A constant fraction of the drug is eliminated per unit of time - rate of elimination depends on how much drug is in the body

Question 65

Calculation of V_d

Answer 65

Question 66

Formula for calculating steady-state concentration

Answer 66

Cpss = MD/Cl MD = the maintenance dose Cl = clearance

Question 67

How long does it take to reach steady state plasma concentration?

Answer 67

4-5 half lives if a drug is administered once every half-life This is regardless of ROA ## Footnote Once steady state is achieved it takes 4-5 half-lives to completely clear the drug from the body

Question 68

How to calculate the elimination constant

Answer 68

Question 69

One vs. two compartment models

Answer 69

Question 70

Calculate bioavailability of oral drug

Answer 70

F = AUC_oral/AUC_IV

Question 71

What increases serum concentration fluctuation?

Answer 71

Extended dosing intervals ## Footnote Cl = clearance

Question 72

Most drugs gain entry into cells by?

Answer 72

1.Passive diffusion with zero order kinetics 2.Passive diffusion with first order kinetics 3.Active transport with zero order kinetics 4.Active transport with first order kinetics 5.Passive diffusion through membrane pores

Question 73

Elimination half-life

Answer 73

t_1/2 = 0.692 (V_d)/Cl ## Footnote Vd = L Cl = mL/min.

Question 74

An elderly patient is prescribed a beta receptor antagonist to treat his atrial fibrillation. These drugs act at post-synaptic receptors of the heart. Which of the following changes do you expect within the first 2 weeks of therapy?

Answer 74

Beta-receptor numbers increase

Question 75

Which of the following provides information about the variation in sensitivity to a drug within a population being studied?

Answer 75

Quantal dose-response curves

Question 76

Which of the following is correct about the concept of volume of distribution?

Answer 76

This is a value that remains relatively constant in a specific person who is taking a specific drug.

Question 77

Which of the following processes accounts for MOST movement of drugs across biological barriers?

Answer 77

Passive diffusion

Question 78

Efficacy vs. potentcy

Answer 78

Efficacy - considers response Potency - considers binding affinity

Question 79

What aspect of the cell contains steroid receptors?

Answer 79

Cytoplasm, receptor is then translocated into the nucleus