Golan Pharm Chapter 1

Front 1

Symptomology of myeloid leukemia

Back 1

Fatigue, high WBC count, splenomegaly, no blast increase, Philadelphia chromosome

Front 2

Imatinib

Back 2

Highly selective inhibitor of BCR-abl tyrosine kinase. Used as treatment for myeloid leukemia

Front 3

Bond strength in drug-receptor interactions, in decreasing order of strength

Back 3

Covalent
Ionic
Hydrogen
Van der Waals

Front 4

Affinity

Back 4

The compatibility of a drug for its binding site on the receptor

Front 5

What is the pharmacological value of hydrophobicity?

Back 5

Since water is everywhere, it can "scare" hydrophobic drugs into hydrophobic protein pockets, enhancing interactions there.

Front 6

Are covalent drug-receptor bindings common?

Back 6

No. It is mostly irreversible and the body then has to synthesize new receptors

Front 7

Suicide substrate

Back 7

Another word for covalently bound drug molecules (the receptors that bind them only bind them once)

Front 8

Important attributes of a drug molecule that contribute to its binding strength

Back 8

Hydrophobicity, pKa, conformation, STEREOCHEMISTRY (remember that enantiomers can often have drastically different effects)

Front 9

Stereochemical effects on drug-receptor binding, using warfarin as an example

Back 9

warfarin is 50-50 racemic mixture of enantiomers, and the S is four times more potent than R. It would be too powerful on it's own, so the mix is necessary.

Front 10

Enantiomers

Back 10

Two arrangements of a drug molecule that can have drastically different effects). Sometimes they are synergistic, sometimes oppositional...as in one enantiomer can be toxic.

Front 11

Factors that determine drug-receptor specificity

Back 11

Structure (drug and receptor), chemical forces, solubility of the drug in water and membrance, function of receptor

Front 12

Rational drug design

Back 12

Using known receptor structure to manufacture a drug that interacts with it.

Front 13

Two mechanisms for drug selectivity

Back 13

1. Cell-type specificity of receptor subtypes
2. Cell-type specificty of receptor-effector binding

Front 14

Relationship of selectivity to therapeutic value?

Back 14

The more selective a drug, the more directed the therapy, and the less likely it is to have adverse, toxic, or unpredictable effects.

Front 15

Dogma of selectivity?

Back 15

The more restricted the cell-type distribution of a drug, the more selective the drug will be.

Front 16

While many cell may express a receptor for a given drug, why are the effects not the same for every cell?

Back 16

The function of the receptor may differ by cell type. Example, every cardiac muscle cell expresses calcium channels, but only pacemaker cells are really affected by CCBs because they are responsible for signal propogation.

Front 17

Second dogma of selectivity

Back 17

The more different the receptor-effect functions in cell types, the more selective the drug will be.

Front 18

Six major groups of drug-receptor interactions

Back 18

1. Transmembrane ion channels
2. Transmembrane G proteins
3. Transmembrane, cytosolic enzymatic domains
4. Intracellular receptors
5. Extracellular enzymes
6. Cell surface adhesion receptors

Front 19

3 main categories of transmembrane ion channels

Back 19

1. Ligand-gated (open/close on binding
2. Voltage-gated (open/close on change in membrane potential
3. Second messenger (think G proteins, open/close on second messenger interaction and concentration)

Front 20

Refractory or Inactivated ion channel state

Back 20

A period of time (milliseconds) in which a channel cannot be reopened no matter what the stimulus)

Front 21

State-dependent binding

Back 21

Drugs that bind with different affinities to different states (open/close/refractory) of the same ion channel. Consider arrythmia drugs

Front 22

Two drug classes that alter ion channel conductance

Back 22

1. Local anaesthetics - block Na through voltage gated channels
2. Benzodiazepines - increase ability of GABA to conduct Cl, thus "relaxing" the neuron, making it harder to activate.

Front 23

Characteristics of the G-protein coupled receptor

Back 23

7 transmembrane regions, all alpha helices, Upon binding of ligand, cytosolic domain binds GTP and alpha-subunit dissociates, effecting something else. The signal stops when GTP is hydrolyzed to GDP.

Front 24

Most common second messenger activated by G proteins?

Back 24

cAMP, and cGMP. The rest of the cascade is reviewed on page 10.

Front 25

Action of Gs protein

Back 25

Activate Ca channels, activate cAMP

Front 26

Action of Gi protein

Back 26

Activate K channels, inhibit cAMP

Front 27

Action of Go protein

Back 27

Inhibit Ca channels

Front 28

Action of Gq protein

Back 28

Activate phospholipase C

Front 29

Example of G protein coupled receptors

Back 29

The Beta=adrenergic family, whose endogenous activators are norepi and epi.

Front 30

Locations and actions of beta-1-receptors

Back 30

SA node = Inc. heart rate
Cardiac muscle = Inc. contractility
Adipose tissue = Inc. lipolysis

Front 31

Locations and actions of beta-2-receptors

Back 31

Bronchial smooth muscle = dilation
GI smooth muscle = close sphincter, relax gut
Uterus = relax uterine wall
Bladder = relax bladder
Liver = stim. metabolism
Pancreas = Inc. insulin release

Front 32

Location and action of beta-3-receptors

Back 32

Adip. tissue = inc. lipolysis

Front 33

Major structure and function of transmembrane receptors with cytosolic enzymatic activity

Back 33

Single-span proteins and mainly, phosphorylation. Example, receptor tyrosine kinases, ex., insulin receptor

Front 34

"Gain of function" mutation

Back 34

Typically, when a phosphorylating receptor gains activity even when not bound to a ligand. Commonly cancerous. The BCR-abl kinase encoded by the Philadelphia chromosome is a good example.

Front 35

Effect of Imanitib on BCR-abl kinase?

Back 35

Prevents the kinase from phosphorylating, like other tyrosine kinase inhibitors, very effective against myeloid cancer.

Front 36

Major classes of transmembrane receptors with cytosolic enzymatic activity

Back 36

1. Tyrosine kinase
2. Tyrosine phosphorylase
3. Non-receptor tyrosine kinases
4. Serine/threonine kinases
5. Guanylyl cyclases

Front 37

Family of serine/threonine kinases

Back 37

TGF-Beta superfamily, responsible for growth. Often gain function in cancer.

Front 38

Nesiritide

Back 38

Used for decompensated heart failure, activates Guanylyl cyclase receptor.

Front 39

Target of Warfarin

Back 39

Vitamin K epoxide reductase, thus preventing clotting.

Front 40

Common target of intracellular drugs

Back 40

Transcription factors which then dimerize to affect DNA.

Front 41

Angiotensin Converting Enzyme (ACE)

Back 41

Converts the relatively weak angiotensin I to the ridiculously strong angiotensin II.

Front 42

ACE inhibitors

Back 42

Prevent the formation of angiotensin II from I, thus promoting vasodilation and a lowering of systemic blood pressure.

Front 43

Cell adhesion inhibitors

Back 43

For example, preventing the adhesion of integrins to other extracellular macromolecules

Front 44

Tachyphylaxis

Back 44

The diminished effect of a drug on the body over time. Also called desensitization

Front 45

Homologous versus heterologous desensitization

Back 45

Homologous: Only one type of receptor shows diminished activity
Heterologous: Two or more receptors show coordinate loss of function

Front 46

Inactivation

Back 46

An extreme form of desensitization where the receptor function is completely blocked or stopped by molecular mechanisms

Front 47

Refractoriness

Back 47

A receptor characteristic, example in neurons, that causes a lack of function for a period of time, usually due to voltage dependence.

Front 48

Down-regulation

Back 48

After prolonged stimulation, the cell will endocytose the receptor until the stimulus stops, and only then will it return the receptor to the surface

Front 49

Which is on a longer time scale, phosphorylation or down-regulation?

Back 49

Down-regulation. Often takes hours to reverse, while a phosphorylating stimulus will only take a few milliseconds to occur.

Front 50

Diuretic family of drugs

Back 50

Change fluid balance in the body by affecting the water/ion absorption in the kidneys. Most are ion channel effectors, but some affect osmolarity directly, like mannitol (sugar).

Front 51

Two examples of drugs that do not fit the drug-receptor model

Back 51

Some diuretics and some antacids. The diuretic mannitol is an osmolarity effector, while antacids directly neutralize pH in the stomach solution.