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PDA Block 1 > Week 1 > Flashcards

Week 1 Flashcards

1
Q

Receptor

A

Binds drugs (ligands)

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2
Q

Ligand

A

drug that binds to receptor

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3
Q

Kd

A

Kd= Equilibrium Constant
Describes the goodness of fit between ligand and receptor
Kd=K2/K1
Kd= [L] *[R]/[LR]

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4
Q

Affinity

A

ability of drug to bind to receptor

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5
Q

Rt

A

Total number of receptors in a cell or tissue (bound and unbound)
Rt= [LR] + [R]

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6
Q

Intrinsic Activity

A

Measure of the ability of the LR complex to elicit the effect being measured

Ratio of Emax of the ligand of interest to the Emax of the full agonist

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7
Q

Agonist

A

alpha= 1

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8
Q

Antagonist

A

Alpha =0

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9
Q

Partial agonist

A

0 < alpha < 1

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10
Q

Spare receptors

A

increase the sensitivity of the cell to a low concentration of ligand

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11
Q

Potency

A 
Potency is the relationship between the amount of drug administered and its effect.
Potency inversely related ED50 
Determined by:
Affinity for the site of action
Ability to reach the site of action
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12
Q

Efficacy

A

Maximal effect that is produced by a drug.

On a graph, it is the maximum point on the Y axis that is reached
Determinants:
- intrinsic activity
-Characteristics of the effector
-limitations on the amount of the drug that can be administered

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13
Q

Maximal Efficacy

A

= maximal effect

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14
Q

ED50

A

Effective Dose

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15
Q

TD50

A

Toxic Dose

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16
Q

LD50

A

Lethal Dose

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17
Q

Therapeutic index

A

Ratio of TD50/ED50

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18
Q

Log normal distribution

A

Mean log dose vs. frequency of response

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19
Q

Hyporeactive

A

tail of the frequency distribution (frq of response vs mean log dose)

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20
Q

Hyperreactive

A

tail of the frequency distribution (frq of response vs mean log dose)

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21
Q

Hypersensitivity

A

allergic or inflammatory response to drug

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22
Q

Bioavailability

A

F= amount in the circulation/total amount administered

Fraction of the dose that reaches the systemic circulation

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23
Q

First pass effect

A

pass through the liver where metabolism can occur

if the metabolism of the drug by the liver is larger, the bioavailability is reduced substantially

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24
Q

Bioequivalence

A

two drug preparations with the same active ingredients at the same amount and delivered by the same route of administration are bioequivalent if the extent and rate of drug delivery to the circulation are the same

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25
Q

Redistribution

A

drug action is terminated because the drug redistributes from its site of action into other tissues

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26
Q

Therapeutic window

A

maintain a concentration of a drug that is high enough to produce desired effect with a minimum of toxicity

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27
Q

Volume of distribution

A

measure of the apparent space in the body available to contain a drug.

Disease states can alter Vd
Vd= Dose/C0

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28
Q

Clearance

A

rate of elimination from the body/concentration

Clearances are additive

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29
Q

Rate of Elimination

A

For most drugs, processes involved in elimination are not saturable in the range of the drug concentration used.

= CL x Concentration
-directly proportional to drug concentration

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30
Q

Half Life

A

time required to decrease the concentration of a drug by one half

T1/2= (0.69 xVd)/CL

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31
Q

Loading Dose

A

a larger dose of the drug that allows for therapeutic levels to be achieved immediately

Loading dose= (Vd xC0)/F
C0 is desired concentration

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32
Q

Maintenance dose

A

Maintenance Dose/Interval= (Css x CL)F

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33
Q

Intracellular steroid receptor

Where are they located/bind ligands?
What do they do?

A

Intracellular receptors for small hydrophobic molecules ( steroids)

  • bind ligands in cytoplasm
  • ligand activated transcription factors

Have a hormone binding site, DNA binding domain and transcription activating domain

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34
Q

Ion channel-linked receptor

A
  • composed of multiple subunits
  • receptor directly gates ion channels
  • rapid signaling

Ex: Nicotinic acetylcholine receptor, GABA receptor

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35
Q

GPCR

A
  • Single protein that spans membrane 7 times
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36
Q

Heterotrimeric G protein

G(alpha)

A

Guanine nucleotide binding proteins

  • link ligand activated G-protein coupled receptor to effector enzymes
  • cycles between two states and act as molecular switch (GTP and GDP)
  • consists of 3 different proteins (alpha, beta and gamma)
  • (alpha)s: stimulates adenylyl cyclase
  • (alpha)i:inhibits adenylyl cyclase
  • (alpha)q: stimulates phospholipase C
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37
Q

Enzyme Linked receptor

A

receptors with different enzymatic activities

- tyrosine -kinase linked receptors

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38
Q

Tyrosine Kinase Linked receptor

A
  • single protein with one transmembrane domain which dimerizes upon binding
  • activation by cross phosphorylation
  • binding of intracellular signaling molecules
  • regulate cell proliferation and differentiation in response to hormones or growth factors
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39
Q

Epidermal Growth factor receptor

A

Epidermal growth factor

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40
Q

Transcription factors

A

DNA binding proteins that regulate transcription of specific genes

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41
Q

Protein Kinases and protein Phosphatase

A

Protein kinase: catalyze the addition of phosphate group to side chain of amino acids of proteins and peptides

Protein phosphatase: catalyzes the cleavage of phosphate groups from side chain of amino acids of proteins and peptides

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42
Q

Second messengers

A

small diffusable signaling molecules that are generated in response to ligand-receptor binding and activate other downstream signaling molecules

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43
Q

cyclic adenosine monophosphate

A

cAMP: generated by adenylyl cyclase (which is activated by Galpha (S)–> activates PKA

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44
Q

Diacylglycerol

A

DAG: generated when PLC cleaves PIP2–> IP3 and DAG

activates PKC

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45
Q

Inositol Triphosphate

A

IP3: generated when PLP cleaves PIP

binds to IP3 receptors on ER –> causes ca2+ to be releases from ER

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46
Q

Calcium

A

generated by opening of ion channels

activates PKC and other protein kinases

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47
Q

Signaling pathway

A
  1. Cyclic nucleotide pathways (cAMP)
  2. Phospholipid hydrolysis pathway (IP3)
  3. Monomeric G proteins (Ras)
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48
Q

Monomeric G protein

A

Ras

aka: small G proteins, small GTPases
- activated by direct interacting with GEF

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49
Q

GEF

A

Guanine nucleotide exchange factor
- activates monomeric G proteins
(Ex: Ras-GTP)

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50
Q

GAP

A

GTPase-activating protein

turns off monomeric G proteins

51
Q

MAP kinase signaling

A

MAPKKK–>phosphorylates MAPKK—> phosphorylates MAPK–> phosphorylates a transcription factor –> increase gene expression

52
Q

Gefitinib/ Erlotinib

A

tyrosine kinase inhibitor that targets EGFR–> inhibits signaling

efficacy of drug is enhanced by presence of mutations in EGF receptors expressed by a tumor

53
Q

Adaptation

A

modulation of signals in response to intensity and frequency of stimulation

54
Q

Receptor mediated endocytosis

A

regulates the number (amount) of receptors (sensitivity for ligand)–> promote degradation of both receptor and ligand

55
Q

Prodrug

A

Some drugs are converted to their active form by metabolic enzymes

56
Q

Phase I Metabolism

A

Phase I: oxidation reduction , dealkylation or hydrolysis reactions

  • often introduce or reveal a functional group
  • enzymes are usually in Smooth ER
57
Q

Phase II metabolism

A

Phase II

  • conjugation of the drug or drug metabolite to an endogenous substrate molecule
  • enzymes are cytosolic
58
Q

First Pass effect

A
  • applies to orally administered drugs
  • following absorption from GI tract, portal venous system transports them to liver
  • significant metabolism can occur prior to reaching the general circulation due to drug metabolizing enzymes in the liver or intestine

-lowers the oral bioavailability of a given drug

59
Q

Cytochrome P450

A

Phase I drug metabolism

- Hemeprotein that are major catalysts of Phase I biotransformation reactions

60
Q

P450 Reductase

A

flavoprotein

catalyzes NADPH reduction reaction

61
Q

Monooxygenase

A

adds one oxygen at a time

62
Q

CYP 3A

A

50% of drugs

-GRAPEFRUIT juice

63
Q

CYP 2D6

A

25% of drugs

64
Q

CYP 2C9

A

15% of drugs

65
Q

CYP 2C19/ CYP 1A1/ 2E1

A

<5% each

66
Q

Flavin containing monooxygenase

A

FMO

  • Phase I enzyme
  • catalyzes mono-oxygenation reactions of soft nucleophiles (N and S oxidation reaction)
67
Q

UDP glucuronosyl transferase (UGT)

A

Glucuronidation

-High energy intermediate: UDP Glucuronic acid

68
Q

N-acetyltransferase (NAT)

A

Acetylation

-High energy intermediate: Acetyl-CoA

69
Q

Sulfotransferase (SULT)

A

Sulfation

-High energy intermediate: PAPS

70
Q

Glutathione S-Transferase (GST)

A

Glutathione conjugation

-High energy intermediate: drug itself, arene, oxide, epoxide

71
Q

Enzyme Induction

A

exposure to some drugs and environmental chemicals can markedly upregulate amount and or activity

  • usually transcriptional increases
  • can increase or decrease drug effects
  • because of broad specificity of many substrates, single inducer will simultaneously upregulate ability to metabolize several drugs
  • inducers may or may not be substrates
72
Q

Enzyme Inhibition

A

Drug or environmental chemical may inhibit the metabolism of several drugs

  • usually activity decreases
  • competitive: substrates are major cause of drug-drug interactions
  • non-competitive: disrupt function/conformation
73
Q

Acetaminophen

A

dependent on various drug metabolism mechanisms

  • most common cause of acute hepatic failure
    SULT, UGT, CYP2E1

Tylenol overdose
- CYP2E1–> induced by alcohol–> GST is slow to replenish–> leads to hepatotoxicity

74
Q

Pharmacogenetics

A

Genetically controlled variations in drug response

Genetic factors that alter an individual’s drug response to a drug

75
Q

Genotype

A

Genotype: an individual’s composition at the gene level ( specific genes that they have)

76
Q

Phenotype

A

an individual’s composition at the gene level

77
Q

Genetic Polymorphism

A

Mendelian trait that exists in the population in at least two phenotypes, neither of which is rare ( variant that represents greater than 1% of total pool)

78
Q

Single Nucleotide Polymorphism (SNP)

A

a change in a single base pair in the DNA sequence that differs from the wildtype or predominant sequence

79
Q

Haplotype & Halotype

A

Haplotype: closely linked genetic markers on a chromosome that tends to be inherited together (often within a gene or on closely linked gene)

Halotype: Cluster of SNPS that occur together in an individual ( and are of interest to a phenotype)

80
Q

Autosomal co-dominance

A

Each allele contributes to phenotype

81
Q

Autosomal Recessive

A

Wild type allele has predominant effect: takes two recessive alleles to see the effect

82
Q

x-linked inheritance

A

genes inherited on X chromosome, all makes will express these traits (males are hemi-zygous)

83
Q

NAT-2 polymorphism

A

Responsible for metabolizing Isoniazid ( anti-TB)
Fast vs slow polymorphism
Autosomal recessive trait

84
Q

CYP 2D6 polymorphism

A

Anti-depressants

First identified from those who suffered severe hypotension following administration.
- linked to “poor metabolizer” variant ( mutant allel)

Ultrafast metabolizer
- duplication of normal allele

Metabolizes 25% of metabolized prescription drugs including Anti-depressants and Beta blockers

85
Q

CYP 2C19 polymorphism

A

Omeprazol: proton pump inhibitor
Phenytoin: anti-convulsants
Clopidogrel: anti-platelet drugs** (activated by 2C19)

Poor metabolizer phenotype

86
Q

CYP 2C9 polymorphism

A

Warfarin (anti-coagulant)

Poor metabolizer phenotype: 2 variants (*2 and *3)

  • decrease clearance
  • increase warfarin half life
  • increase risk of serious bleeding
87
Q

Vitamin K receptor polymorphism

A

Subunit of vitamin K epoxide reductase complex
Warfarin: a vitamin K antagonist, inhibits activity of this complex
A Clade: require lower warfarin dose (bc lower expression of VKORC1)

B Clade: require higher warfarin dose (higher expression of VKORC1)

88
Q

Pseudocholinesterase polymorphism

A

Succinylcholine ( depolarizing muscle relaxant)

- due to reduced activity variants of pseudocholineresterase

89
Q

TPMT polymorphism

A

Mercaptopurine
6 M–> 6methyl-MP (inactive)

presents as increased risk for life threatening bone marrow suppression in cancer patients treated with thiopurine drugs

Due to variants with decreased activity of TPMT

90
Q

P-glycoprotein polymorphism

A

Pgp polymorphism: ATP binding protein that effluxes drugs from GI
Pgp polymorphism results in increased net uptake of digoxin due to decreased levels of Pgp protein
(low expression alleles)

91
Q

Acetylcholine

A

Neurotransmitter in peripheral nerves

Synthesis: choline is taken up into nerve terminals (rate limiting step)
Synthesized from acetyl choline and choline (choline acetyl transferase)

Transported into vesicles by VAChT
Released into synaptic cleft by exocytosis (inhibited by botulinum toxin)

AcH receptors: Nicotinic and Muscarinic

92
Q

Norepinephrine

A

Neurotransmitter in peripheral nerves

Tyrosine–> l-DOPA–> NE
Dopamine synthesized in nerve terminals–> transported into storage vesicles ( VMAT2)

Adrenergic receptors

93
Q

Epinephrine

A

Neurotransmitter in peripheral nerves

94
Q

Tyrosine Hydroxylase

A

rate limiting step of Norepi synthesis

95
Q

Cocaine

A

blocks Norepi uptake from nerve terminal

96
Q

Reserpine

A

Blocks VMAT2

97
Q

Botulinum Toxin

A

Inhibits acetylcholine release

98
Q

VMAT2

A

Vesicular monoamine transporter 2

Dopamine synthesized in nerve terminals are transported into storage vesicles via VMAT2-> converted to norepinephrine.

  • blocked by reserpine
99
Q

Norepinephrine Transporter

A

NET: re-uptake into nerve terminal. primary mechanism by which the actions of norepi are terminated

100
Q

Extra-neuronal transporter

A

ENT: uptake Nor-epi

101
Q

Monoamine oxidase

A

oxidatively deaminates catecholamines.
found on outer surface of mitochondria

Intraneuronal Norepi not taken up into storage granules is metabolized by MAO. metabolizes diffused from nerve terminals

102
Q

Catechol O Methyltransferase

A

transfer a methyl group to 3 hydroxy position of phenyl ring

- cystolic enzyme

103
Q

Acetylchoinesterase

A

AcH is rapidly metabolized and inactivated by acetycholinesterase

104
Q

Nicotinic Receptors

A

Nm: NMJ: end plate depolarization
Nn: Autonomic ganglia: depol. of post ganglionic neuron

105
Q

M1 Receptor

A

Gq (peripheral and central nerves)

Depolarization of nerves
Activates PLC

106
Q

M2 Receptor

A

Gi (heart nerves and smooth muscles)

Decrease electrical conductance
Inhibits AC

107
Q

M3

A

Gq (glands, smooth muscle)
increased secretion and muscle contraction
Activates PLC

108
Q

M4

A

Gi (CNS)

inhibit depolarization
Inhibit AC

109
Q

M5

A

Gq (CNS)
Depolarization
Activated PLC

110
Q

Alpha 1

A

Gs (vascular, smooth m.)
contraction and secretion from glands

Activated PLC

111
Q

Alpha 2

A

Gi (Nerve Terminals)

Decrease NE release
Inhibit AC

112
Q

Beta 1

A

Gs: activate AC
(cardiac m)- increased force and rate of contraction
Glands: increased secretion

113
Q

Beta 2

A

Gs- activate AC
(vascular, smooth m): relaxation
(Skeletal mu): Glycogenolysis
(Liver): glycogenolysis

114
Q

Beta 3

A

Gs- Activate AC

Adipose tissue: lipolysis

115
Q

Characteristics of monoclonal antibodies

A

Homogenous for antibody type, amino acid sequence. affinity and specificity

High specificity, monospecific
High affinity
Long half life

116
Q

How are antibodies administered?

A

Parenterally
IV: 100% bioavailability
SQ or IM: 24-95% bioavailability (absorbed through lymph and diffusion into blood vessels)

117
Q

Neonatal Fc Receptor (FcRn)

A

Transfers passive immunity across placenta from mother to fetus

protects IgG from degradation

Binds Fc region at acidic pH
IgG undergoes endocytosis in low pH–> promotes binding of IgG to FcRn ( bound form–> returned to cell surface)–> dissociates–> IgG can move across placenta

118
Q

Metabolism & elimination of therapeutic Ig

A
  • presystematic catabolism by proteolysis
  • metabolism
    • Ig binding results in endocytosis and catabolism
    • phagocytic cells have Fc receptor promoting antibody phagocytosis and degradation
    • elimination influenced by FcRn
  • Renal elimination unimportant
  • Secretion into bile eliminated IgA but not IgG
119
Q

Mechanism of Therapeutic Ig

- targets?

A

Ig binds to specific site at variable Fab

Targets soluble antigens or cell surface proteins ( act extracellularly)

120
Q

Mechanism from antigen-Ig binding:

Antagonism/ Neutralization

A

Ig binding inactivates antigen

acts as a competitive inhibitor blocking interaction of a soluble antigen with its ligand (anti-ligand)

decreases concentration of unbound soluble antigen in plasma

121
Q

Mechanism from antigen-Ig binding:

Cell signaling inhibition

A

Ig binds surface signaling molecule to inhibit cell activation or signaling function

  • may function as an agonist
  • acts as a competitive inhibitor
  • promotes ACDD (activates complement–> MAC attack complex).

CDC: complement dependent cytotoxicity
+ FAB regions bind FcY on NK cell–> activates–> release cytotoxins
+ Fc regions bind FcY receptors on macrophages–> phagocytosis

122
Q

Mechanism from antigen-Ig binding:

delivery of toxins

A

toxins or radionuclids are conjugated to an Ig

Ig binds to surface protein–> selectivity delivers toxins or radionuclid

123
Q

Mechanism from antigen-Ig binding

A

Radiocontrast agent
Ig binds to cell surface protein–> targets delievery of imaging agent
Radiocontrast agent imaged

PDA Block 1 (3 decks)

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