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Flashcards in 1: Pharmacodynamics 2 Deck (31):
1

description of intracellular receptors

-lipid-soluble ligand crosses the cell membrane and acts on an intracellular receptor
ex: corticosteroids, mineralocorticoids, sex steroids, vitamin D, thyroid hormone

-stimulate the transcription of genes in the nucleus by binding to specific DNA sequences near the gene whose expression is to be regulated

2

therapeutic significance of intracellular receptor binding

-drugs produce their effects after a characteristic lag period
-cannot be expected to alter a pathologic state w/i minutes
-effects of these agents can persist after the [agonist] has been reduced to zero due primarily to the relatively slow turnover of most enzymes and proteins (or due to high affinity of receptors for the hormone)
-no simple temporal correlation b/w plasma levels of the hormone and its effects

3

protein tyrosine kinases: what type of enzymes are they, what is their mechanism of action, examples

-ligand-regulated transmembrane enzymes
-adds a phosphate group to substrate
-ex: insulin, EGF, PDGR

4

protein tyrosine kinases: describe the receptor

-extracellular hormone-binding domain
-cytoplasmic enzyme domain with protein tyrosine kinase activity
-spans lipid bilayer once

5

protein tyrosine kinases: how do they work

-usually act as dimers
-hormoen binds to extracellular domain -> conformational change
-receptor molecules associate -> brings together protein tyrosine kinase domains
-kinase becomes capable of autophosphorylation
-tyrosine residues in both cytoplasmic domains are phosphorylated -> activates enzymatic activity -> phosphorylation of substrate proteins
-P-substrate proteins become signal for the effects of the ligand

6

how is the process initiated by protein tyrosine kinases turned off/regulated?

-duration and intensity of the action is limited by receptor down regulation
-upon ligand binding, endocytosis of the receptor is stimulated

7

how can ligand-gated channels be utilized by drugs?

drugs can mimic or block the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels -> transmits signal across by increasing transmembrane conductance of the relevant ion -> alters electric potential across membrane

8

speed of ligand-gated channel interactions

-often milliseconds -> rapidity is crucially important for extremely rapid transfer of signals across synapses

9

calcium and phosphoinositides

-effector enzyme = PLC
-releases phosphoinositides and diacylglycerol
-results in release of Ca2+ --> increase cytoplasmic [Ca2+]
-diacylglycerol can activate PKC

10

speed of ligand-gated channel interactions

-often milliseconds -> rapidity is crucially important for extremely rapid transfer of signals across synapses

11

GPCRs action

-ligands acts by increasing intracellular concentrations of second messengers
-generally signaling system has 3 components:
-extracellular ligand is detected by cell-surface receptor
-receptor triggers activation of G protein on cytoplasmic
face of plasma membrane
-changes activity of an effector element
-effector changes [second messenger] --> effect

12

cAMP

-effector enzyme = adenylyl cyclase (ATP --> cAMP)
-stimulates cAMP-dependent protein kinases (also EPAC)
-specificity due to distinct substrates of the kinases that are expressed in different cells

13

definition of therapeutic index/ratio

-relative safety of a drug expressed as LD50/ED50 or TD50/ED50
-larger the ratio --> greater the relative safety

14

cGMP

-effector enzyme = guanyl cyclase
-activates cGMP-dependent protein kinase
-much more specific than other messenger systems

15

quantal drug responses vs. graded drug responses

-quantal is all or none (binary response)
-threshold: minimum effective dose of the drug which evokes an all-or-none response
-normal frequency distribution

16

definition of median effective dose (ED50)

-the dose required to produce the stated effect in 50% of the population

17

tachyphylaxis

-acute development of tolerance following rapid, repeated administration of a drug
-the first administration produces a much larger response than subsequent doses, when given after a breif interval
-CANNOT overcome this type of tolerance with increasing dose
-ex: ephedrine (NE release - indirect mechanism)

18

drug adverse effect

an adverse response to a foreign chemical resulting from previous exposure to the substance
-involves an immune response to the drug
-at initial exposure, drug or metabolite acts as a hapten and combines with a protein to generate an Ag
-Ag induces latent synthesis of Ab's
-subsequent exposure to the drug results in an Ag-Ab response

19

drug allergy

-seen in a small fraction of the population
-no apparent dose-response - a minute amount of drug results in response
-effects not related to pharmacologic activity
-sensitizing period required b/w 1st and 2nd exposure
-circulating Abs can be found after 1st exposure

20

two ways to develop drug tolerance

1. decrease in effective concentration of the agonist at the site of action
-drug disposition tolerance
-end result is decreased effect of drug

2. decrease in the normal reactivity of the receptor
-cellular or pharmacologic tolerance
-downregulation of receptors
-change in receptor affinity
-most often seen with CNS drugs, such as narcotics, depressants, and stimulants

21

cross tolerance

-tolerance develops to one drug that is also seen with drugs belonging to the same class
-ex: an individual tolerant to morphine develops tolerance to all narcotics

22

tachyphylaxis

-acute development of tolerance following rapid, repeated administration of a drug
-the first administration produces a much larger response than subsequent doses, when given after a breif interval
-CANNOT overcome this type of tolerance with increasing dose
-ex: ephedrine (NE release - indirect mechanism)

23

drug allergy

an adverse response to a foreign chemical resulting from previous exposure to the substance
-involves an immune response to the drug
-at initial exposure, drug or metabolite acts as a hapten and combines with a protein to generate an Ag
-Ag induces latent synthesis of Ab's
-subsequent exposure to the drug results in an Ag-Ab response

24

drug allergy

-seen in a small fraction of the population
-no apparent dose-response - a minute amount of drug results in response
-effects not related to pharmacologic activity
-sensitizing period required b/w 1st and 2nd exposure
-circulating Abs can be found after 1st exposure

25

pharmacogenetics

genetic variation within humans that affects responsiveness to drugs
-can affect drug target or metabolism of drug
-can alter both therapeutic and adverse effects
-can result from polymorphisms in coding and non-coding regions of genes
-may be the result of SNPs

26

T2HS

Ab-dependent cytolytic rxn
-drug binds to surface component of cell causing the cell to appear foreign (tissue antigens)
-IgG and IgM Ab's produced
-Ab's activate the complement system
-cell lysis results
-blood cells are primary target tissues
-subsides within months after removal of drug

27

T3HS

immune complex formation
-drug reacts in blood with soluble Ab (IgG)
-resulting immune complex deposited in vascular endothelium
-cell mediated immune response (T-cells) causing local inflammation and complement activation
-serum sickness, hemolysis and allergic nephritis
-subsides 1-2 weeks after drug is removed

28

T4HS

delayed hypersensitivity (cell mediated)
-hours or days after exposure before rxn occurs
-mediated by antigen contact with sensitized T cells and macrophages
-interaction causes release of lymphokines/cytokines
-subsequent influx of neutrophils and macrophages
-ex: contact dermatitis with topical drugs

29

idiosyncratic reaction

-a genetically-determined abnormal reactivity to a drug
-may be extreme sensitivity to low doses or insensitivity to high doses
-often a difference in drug metabolizing enzymes

now referred to as pharmacogenetics

30

pharmacogenetics

genetic variation within humans that affects responsiveness to drugs
-can affect drug target or metabolism of drug
-can alter both therapeutic and adverse effects
-can result from polymorphisms in coding and non-coding regions of genes
-may be the result of SNPs

31

companion diagnostics

a way to ID which patients will benefit from very specific cancer therapies (drugs only work for certain mutations)