Drug Action, Absorption, Distribution

Front 1

Most drugs produce effect by binding to _________ molecules

Back 1

Proteins

Front 2

Anti-tumor and antimicrobial drugs may not use proteins as targets and instead use _____

Back 2

DNA

Front 3

3 main types of target proteins

Back 3

1) Receptors
2) Enzymes
3) Carrier molecules

Front 4

K_d: defn

Back 4

Affinity. It measures the rate of DR formulation in the formula:

D + R ⇔ DR

Front 5

ε : defn

Back 5

Intrinsic efficacy. Measures effectiveness of the DR in producing desired effect.

Front 6

T/F Some drugs show affinity but not efficacy

Back 6

T

Front 7

Simple Occupancy Theory defn

Back 7

Intensity of response to a drug is proportional to the number of receptors occupied by that drug. This theory is not able to explain why one drug is more potent than another if they bind to the same receptor and both bind maximally to all receptors.

Front 8

Two Components of Modified Occupancy Theory

Back 8

a. Affinity binding- strength of the attraction between drug and receptor.
b. Intrinsic activity- ability of a drug to activate its receptor.

Front 9

strength of the attraction between drug and receptor

Back 9

affinity binding

Front 10

ability of a drug to activate its receptor

Back 10

intrinsic activity

Front 11

High intrinsic activity relates to high ______

Back 11

maximal efficacy

Front 12

Drugs with low affinity require ______concentrations to bind to receptor

Back 12

higher

Front 13

Which type of drug-receptor (DR) bond is strongest (ie, irreversible)?

Back 13

Covalent: sharing of electrons. Uncommon

Front 14

Van der Waals and Hydrogen bonds are examples of what type of DR bonds?

Back 14

Electrostatic - reversible.

Front 15

Affinity & efficacy are determined by ___________

Back 15

chemical structure

Front 16

Occupancy Theory of Drug Action: what is it?

Back 16

Receptors are fluid, flexible surfaces or pockets that can change shape when a ligand docks. Drugs can affect the probability that the receptor exists in the conformation that favors ligand binding.

Front 17

Drug favors active state of receptor

Back 17

Agonist

Front 18

Drug favors inactive state of receptor

Back 18

antagonist

Front 19

What is receptor-effector coupling?

Back 19

Transduction process between occupancy of receptors and drug response (amplification)

Front 20

What are spare receptors?

Back 20

Sometimes a drug's full effect is seen at a fractional receptor occupation. This is in contrast to the receptor theory which states that 100% receptor occupancy is required for an agonist to exert maximal effect.

Front 21

4 classes of receptors

Back 21

1) GPCRs
2) Tyrosine kinase coupled
3) Ligand-gated ion
4) Intracellular

Front 22

How do GPCRs activate G proteins?

Back 22

Upon activation the α subunit of the G protein exchanges GDP for GTP, then dissociates from the βγ subunits.

Front 23

A major role for G protein coupled receptors is to activate the production of second messengers. What are 3?

Back 23

1) cGMP
2) cAMP
3) IP3

Front 24

T/F Ligand-binding domain of a ligand-gated receptor can be extra or intra cellular.

Back 24

T

Front 25

Single membrane spanning protein forming dimers or multimers to transduce signals

Back 25

Tyrosine kinase linked receptors

Front 26

T/F Magnitude of drug effect (biochemical, physiological or clinical) is function of dose administered.

Back 26

T

Front 27

Type of Dose-Response Curve where the dose is related to magnitude of response on a graded scale

Back 27

Graded

Front 28

Type of Dose-Response Curve where the dose is related to percent of subjects showing a specific (all or none) response

Back 28

Quantal

Front 29

Potency: defn

Back 29

Amount of drug needed for effect. Expressed as ED50 weight of drug/weight of recipient (mg/kg). Not as important in clinical use.

Front 30

Efficacy: defn

Back 30

Magnitude of effect; Related to ability to activate receptors

Front 31

How do partial agonists differ from full?

Back 31

Partial agonist have lower maximal efficacy than full agonists

Front 32

Variability: defn

Back 32

Based on statistical distribution (usually normal distribution) of population; often expressed as 95% confidence limits around the ED50; Curves usually represent the mean response of a sample of population.

Front 33

Therapeutic Index

Back 33

LD50/ED50. Experimental value

Front 34

Certain Safety Factor

Back 34

LD1 (lowest lethal dose) / ED99

Front 35

Minimum lethal dose

Back 35

smallest dose observed to cause death in a human

Front 36

What happens to a full agonist in the presence of a partial agonist?

Back 36

The partial agonist reduces the maximum response, acting as a competitive antagonist.

Front 37

Inverse agonist: defn

Back 37

Binds to same receptor binding site as an agonist for the receptor and exerts the opposite pharmacological effect of the agonist.

Front 38

Antagonist : defn

Back 38

Molecule inhibiting action of an agonist, but has NO EFFECT in absence of agonist

Front 39

Competitive Antagonist: defn

Back 39

binds reversibly to active site of a receptor and prevents binding of agonists to receptor.

Front 40

In presence of competitive antagonist, which direction the DR- Curve shift for the agonist?

Back 40

Shifted to right. NO CHANGE in slope or maximum.

Front 41

Non-competitive Antagonist: defn

Back 41

Binds go allosteric site of receptor, acting to prevent the receptor from being activated, even when agonist is bound to the active site.

Front 42

In presence of non-competitive antagonist, which direction the DR- Curve shift for the agonist?

Back 42

The efficacy is reduced/response is increased, so curve is not as tall.

Front 43

Competitive antagonist reduces agonist ___________ while non-competitive antagonist reduces agonist __________

Back 43

Potency (just need to add more agonist); Efficacy (Adding more agonist will not increase response)

Front 44

distinction between antagonist and inverse agonist effects

Back 44

in the absence of agonist, an antagonist will have no effect; however, an inverse agonist would be active which could lead to effects opposite of an agonist’s

Front 45

movement of the drug from its site of administration into the bloodstream.

Back 45

drug absorption

Front 46

Fick's Law of Diffusion

Back 46

-DA(ΔC)/Thickness

D = diffusion constant; A = Surface area

Front 47

measure of lipid solubility of a drug

Back 47

lipid partition coefficient, K

Front 48

Lipid Diffusion Eqn.

Back 48

-DAK(ΔC)/Thickness

Front 49

Highly polar or ionized molecules will have _____ lipid partition coeff, K; Nonpolar molecules will have ______

Back 49

Low; High

Front 50

Regarding weak acids and bases, which form will have a higher K?

Back 50

The unionized form will have a higher Lipid Partition Coeff, K. This is the acid form of weak acid and base form of weak base.

This reflects the fact that the uncharged form can diffuse across membranes more easily.

Front 51

Aspirin is a weak _____ while codeine is a weak _____.

Back 51

acid; base

Front 52

Henderson Hasselbach (HH) Equation

Back 52

pKa - pH = log ([Acid]/[Base]) aka (Protonated form/Unprotonated form)

Front 53

Absorption of acid drug is favored an _____ pH. Why?

Back 53

Acid. This is because more of the weak acid will exist in un-ionized form, and lipid partition coeff is higher for un-ionized molecules.

Front 54

Absorption of basic drug is favored an _____ pH. Why?

Back 54

basic. This is because more of the weak base will exist in un-ionized form.

Front 55

T/F The passive diffusion process is competitive and saturable.

Back 55

F. If two drugs are present and crossing a membrane by diffusion, the presence of one drug doesn't affect the diffusion of the other. Diffusion is always linear function of drug concentration.

Front 56

Carrier based transport requiring energy

Back 56

active transport

Front 57

Carrier based transport not requiring energy

Back 57

facilitated diffusion

Front 58

T/F The difference between active transport and facilitated diffusion is a concentration gradient

Back 58

T. Active transport moves molecules AGAINST concentration gradient.

Front 59

Maximal velocity of the carrier

Back 59

V_max

Front 60

Concentration of the drug resulting in 50% of the V_max. A measure of the affinity of the substrate for the carrier.

Back 60

K_m

Front 61

When does zero order kinetics typically occur?

Back 61

Zero order kinetics is the concentration of a drug is independent of the rate of transport. This occurs after saturation of the receptors is reached, typically.

Front 62

Refers to the bulk of fluid flow through a barrier, mechanism by which drugs can be transported

Back 62

Filtration.

Front 63

What is the driving force in the body

Back 63

Hydrostatic blood pressure

Front 64

Major mechanism by which drugs pass out of capillaries into interstitial fluid

Back 64

Filtration

Front 65

At low [S],
Rate =

Back 65

k * C (first order)

Front 66

At hi [S], Rate =

Back 66

k (zero order)

Front 67

3 main groups of factors that affect rate/extent of absorption

Back 67

Formulation, Drug itself, Biological

Front 68

Enteral administration: defn

Back 68

Oral ingestion, sublingual, recal

Front 69

Parenteral administration: defn

Back 69

IV, IM, subQ...usually involves injection.

Front 70

What is first pass metabolism?

Back 70

Some or all of the drug is eliminated during its original passage through the gastrointestinal tract to the portal blood to the liver
1) stomach acid/hydrolytic enzymes
2) enteric bacteria
3) gut mucosa rich in drug metabolizing enzymes
4) portal system drains to liver (rich source of drug metabolizing enzymes)

Front 71

T/F enteral absorption tends to be slower

Back 71

true

Front 72

What is bioavailability/F?

Back 72

A measure of the extent of absorption. The fraction of the dose that reaches the venous blood. (unitless).

F = Amount of drug reaching venous blood (mg)/Total drug administered (mg)

Front 73

What is the F for intravenous?

Back 73

1, by definition

Front 74

Calculation for Amount of drug reaching systemic blood

Back 74

= F x Dose

Front 75

Equation for F

Back 75

Amount of drug reaching venous blood/Amount given = AUC oral/AUC iv

Front 76

Sublingual administration of drugs: pros and cons

Back 76

Adv:
Good blood flow to vascular bed, avoids first pass effect Rapid absorption, rapid effect
Useful for nitroglycerin (vasodilator for angina), epinephrine (bronchodilator for asthma)


Disadv:
Few drugs can be given this way
Difficult to hold under tongue for extended time (saliva, bad taste)

Front 77

Rectal administration of drugs: pros and cons

Back 77

Adv: useful in unconscious or vomiting patients
avoids 90% of the first pass effect

Disadv: irregular and incomplete absorption

Front 78

What is difference between IM and subcutaneous injection?

Back 78

Subcutaneous is slower and more erratic. Tends to be used for local anesthesia or to limit rate of absorption

Front 79

When would a drug be given intraarterially?

Back 79

When a localized effect on a particular organ is desired, for example, delivery of chemo to tumors.

Front 80

What is intrathecal administration? Why would it be used?

Back 80

Into subarachoid space of brain or spinal column. Used when direct access to CNS is necessary, for example, spinal anesthesia during child birth, treatment of acute CNS infections

Front 81

What characteristics of a drug make it a good candidate for topical absorption?

Back 81

Potent, lipid soluble.

Front 82

Aspirin: action

Back 82

Antipyretic; analgesic; antiinflammatory

Front 83

Codeine: action

Back 83

analgesic; antitussive

Front 84

Epinephrine: action

Back 84

Bronchodilator, asthma

Front 85

Nitroglycerin: action

Back 85

vasodilator, angina

Front 86

Methoxyflurane: action

Back 86

inhaled anesthetic

Front 87

Nitrous oxide: action

Back 87

inhaled anesthetic

Front 88

blood-air partition coefficient: relationship with onset of action

Back 88

The higher it is, the slower the onset of action

Front 89

The passage of drugs from blood to tissues and from tissues back to blood

Back 89

distribution of a drug

Front 90

Volume of Distribution(V_d: defn

Back 90

Indicator of the extent of drug distribution in the body. Has units of volume (eg., mL).

Represents the apparent volume the drug dissolves in in order to account for observed plasma drug concentration.

Vd = Amt/C

Amt = amount of drug in body
C = plasma concentration

Front 91

Formula for V_d

Back 91

Q/C = Amount of drug in body/Concentration in plasma = g/(g/L) = L

Front 92

Drugs with HIGH V_ds are mainly found in what compartment? (Plasma or Rest of Body)

Back 92

Rest of the body. That means they're likely to be fat soluble/nonpolar.

Front 93

Drugs with LOW Vds are mainly found in what compartment? (Plasma or Rest of Body)

Back 93

Plasma.

Front 94

Provides clinician with a way to estimate the amount of drug that needs to be in the body to obtain a certain desired plasma drug concentration.

Back 94

Volume of distribution

Front 95

How and why does binding to plasma proteins affect drug distribution?

Back 95

Reduces extent of drug distribution because proteins are too large to pass thru capillary membrane.

Front 96

How are plasma-bound drugs a drug reservoir?

Back 96

Because the binding is reversible and saturable, the bound drug is in equilibrium with the free. As free drug goes into the tissues more bound drug dissociates.

Front 97

Why should sulfonamides not be given to infants?

Back 97

It binds tightly to plasma proteins, and can displace bilirubin, causing an increase in free bilirubin, resulting in bilirubin - induced encephalopathy.(kernicterus)

Front 98

What will the Vd of a highly-protein bound drug be?

Back 98

Pretty low, reflecting most of the drug is int he plasma

Front 99

What 3 things affect the rate of drugs moving through capillary walls?

Back 99

lipid solubility (decreased lipid solubility lowers distribution rate)
molecular size (increased size reduces distribution rate)
protein binding (reduces drug distribution)

Front 100

T/F Heparin can pass freely into tissues

Back 100

False. Heparin is too large and polar of a molecule. It's restricted to plasma.

Front 101

Capillary beds in testes, brain, and placenta are alike how?

Back 101

They prevent easy passage of substances from the blood into tissue. The endothelial cells have tight junctions here

Front 102

Cocaine, cigarette smoking, thalidomide, alcohol, diethylstilbestrol have what in common?

Back 102

teratogenicity

Front 103

Cocaine, Tamoxifen: teratogenic effects

Back 103

Abortion and abnormal development

Front 104

Thalidomide, Methotrexate, Isotretinoin: teratogenic effects

Back 104

malformation

Front 105

Alcohol, Cocaine, Amphetamines: teratogenic effects

Back 105

alter behavior and intelligence

Front 106

Diethylstibesterol: teratogenic effects

Back 106

vaginal cancer later in life

Front 107

Heroin, Morphine and Cocaine: Teratogenic effects

Back 107

Withdrawal after birth

Front 108

Smoking: teratogenic effects

Back 108

Intrauterine growth retardation, prematurity, SIDS

Front 109

The primary mechanism of cell membrane permeability of drugs

Back 109

lipid diffusion

Front 110

Where is cloroquine concentrated and what are the consequences?

Back 110

This antimalarial drug is concentrated in the liver and slowly released due to high protein binding

Front 111

Drugs that chelate with ions are usually concentrated where?

Back 111

tissues that are enriched in these minerals like Ca or Mg, eg bones and teeth

Front 112

What is the pH trapping effect?

Back 112

Basic drugs become trapped in stomach fluid

Front 113

What occurs in phenobarbital poisoning and how is it treated?

Back 113

It's a weak acid with pKa of 7.2. These patients have metabolic acidosis (from decreased respiration)

ECF pH is lowered to 7.0 or even lower (acidic).

This increases the fraction of total PB in the ECF that is in the unionized state -> more PB enters brain cells because it's more soluble unionized -> respiration decreases even further


Treatment is to give sodium bicarb to alkalinize the blood, ionize the barbiturate and prevent further entrance into brain.

Front 114

How does the rate of perfusion/blood flow into an organ influence drug effect?

Back 114

Organs that are more rapidly perfused (brain, kidney, etc) respond more quickly whereas those less rapidly perfused (e.g., fat) respond more slowly.

Front 115

Why is the anesthetic affect of thiopental lost so quickly?

Back 115

It gets into the brain quickly, then it more slowly gets redistributed to fat

Front 116

Some formulations of local anesthetics (procaine or lidocaine) or antiinfectives (penicillin) contain vasoconstrictor substances (epinephrine). What does this do?

Back 116

helps prevent the drug from redistributing to the rest of the body

Front 117

What does it mean for a drug's distribution if it had a Vd close to water?

Back 117

Drugs with Vds approaching extracellular water (0.2 L/kg) –can leave blood to reach interstitial fluid but can’t cross cell membranes to reach intracellular water space
(example: highly polar, large or charged drugs such as the aminoglycosides)

Front 118

How does aging change drug distribution?

Back 118

1) Increased fat and decreased lean mass result in higher Vd for some drugs

2) Serum albumin is lowered in elderly, resulting in more free drug

Front 119

Digoxin is used for what?

Back 119

Congestive heart failure

Front 120

Thalidomide used for what?

Back 120

Anti-leprosy

Front 121

Sulfonamides: used for what?

Back 121

antibiotics

Front 122

bronchospasm and hypotension is most likely to be caused by what NM blocker?

Back 122

Tubocurarine

Front 123

What is Hoffman degradation and why is it advantageous?

Back 123

Spontaneously decomposes without needing anything. (major advantage of cisatracurium)

Front 124

T/F In myasthenia gravis, a higher dose of succinylcholine is required to produce muscle relaxation

Back 124

T. This is because succinylcholine binds to nicotinic receptors, and there are FEWER receptors to bind to.