Week 1 Flashcards
(123 cards)
1
Q
Receptor
A
Binds drugs (ligands)
2
Q
Ligand
A
drug that binds to receptor
3
Q
Kd
A
Kd= Equilibrium Constant
Describes the goodness of fit between ligand and receptor
Kd=K2/K1
Kd= [L] *[R]/[LR]
4
Q
Affinity
A
ability of drug to bind to receptor
5
Q
Rt
A
Total number of receptors in a cell or tissue (bound and unbound)
Rt= [LR] + [R]
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
7
Q
Agonist
A
alpha= 1
8
Q
Antagonist
A
Alpha =0
9
Q
Partial agonist
A
0 < alpha < 1
10
Q
Spare receptors
A
increase the sensitivity of the cell to a low concentration of ligand
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
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
13
Q
Maximal Efficacy
A
= maximal effect
14
Q
ED50
A
Effective Dose
15
Q
TD50
A
Toxic Dose
16
Q
LD50
A
Lethal Dose
17
Q
Therapeutic index
A
Ratio of TD50/ED50
18
Q
Log normal distribution
A
Mean log dose vs. frequency of response
19
Q
Hyporeactive
A
tail of the frequency distribution (frq of response vs mean log dose)
20
Q
Hyperreactive
A
tail of the frequency distribution (frq of response vs mean log dose)
21
Q
Hypersensitivity
A
allergic or inflammatory response to drug
22
Q
Bioavailability
A
F= amount in the circulation/total amount administered
Fraction of the dose that reaches the systemic circulation
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
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
25
Redistribution
drug action is terminated because the drug redistributes from its site of action into other tissues
26
Therapeutic window
maintain a concentration of a drug that is high enough to produce desired effect with a minimum of toxicity
27
Volume of distribution
measure of the apparent space in the body available to contain a drug.
Disease states can alter Vd
Vd= Dose/C0
28
Clearance
rate of elimination from the body/concentration
Clearances are additive
29
Rate of Elimination
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
30
Half Life
time required to decrease the concentration of a drug by one half
T1/2= (0.69 xVd)/CL
31
Loading Dose
a larger dose of the drug that allows for therapeutic levels to be achieved immediately
Loading dose= (Vd xC0)/F
C0 is desired concentration
32
Maintenance dose
Maintenance Dose/Interval= (Css x CL)F
33
Intracellular steroid receptor
Where are they located/bind ligands?
What do they do?
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
34
Ion channel-linked receptor
- composed of multiple subunits
- receptor directly gates ion channels
- rapid signaling
Ex: Nicotinic acetylcholine receptor, GABA receptor
35
GPCR
- Single protein that spans membrane 7 times
36
Heterotrimeric G protein
| G(alpha)
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
37
Enzyme Linked receptor
receptors with different enzymatic activities
| - tyrosine -kinase linked receptors
38
Tyrosine Kinase Linked receptor
- 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
39
Epidermal Growth factor receptor
Epidermal growth factor
40
Transcription factors
DNA binding proteins that regulate transcription of specific genes
41
Protein Kinases and protein Phosphatase
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
42
Second messengers
small diffusable signaling molecules that are generated in response to ligand-receptor binding and activate other downstream signaling molecules
43
cyclic adenosine monophosphate
cAMP: generated by adenylyl cyclase (which is activated by Galpha (S)--> activates PKA
44
Diacylglycerol
DAG: generated when PLC cleaves PIP2--> IP3 and DAG
activates PKC
45
Inositol Triphosphate
IP3: generated when PLP cleaves PIP
binds to IP3 receptors on ER --> causes ca2+ to be releases from ER
46
Calcium
generated by opening of ion channels
activates PKC and other protein kinases
47
Signaling pathway
1. Cyclic nucleotide pathways (cAMP)
2. Phospholipid hydrolysis pathway (IP3)
3. Monomeric G proteins (Ras)
48
Monomeric G protein
Ras
aka: small G proteins, small GTPases
- activated by direct interacting with GEF
49
GEF
Guanine nucleotide exchange factor
- activates monomeric G proteins
(Ex: Ras-GTP)
50
GAP
GTPase-activating protein
turns off monomeric G proteins
51
MAP kinase signaling
MAPKKK-->phosphorylates MAPKK---> phosphorylates MAPK--> phosphorylates a transcription factor --> increase gene expression
52
Gefitinib/ Erlotinib
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
Adaptation
modulation of signals in response to intensity and frequency of stimulation
54
Receptor mediated endocytosis
regulates the number (amount) of receptors (sensitivity for ligand)--> promote degradation of both receptor and ligand
55
Prodrug
Some drugs are converted to their active form by metabolic enzymes
56
Phase I Metabolism
Phase I: oxidation reduction , dealkylation or hydrolysis reactions
- often introduce or reveal a functional group
- enzymes are usually in Smooth ER
57
Phase II metabolism
Phase II
- conjugation of the drug or drug metabolite to an endogenous substrate molecule
- enzymes are cytosolic
58
First Pass effect
- 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
Cytochrome P450
Phase I drug metabolism
| - Hemeprotein that are major catalysts of Phase I biotransformation reactions
60
P450 Reductase
flavoprotein
catalyzes NADPH reduction reaction
61
Monooxygenase
adds one oxygen at a time
62
CYP 3A
50% of drugs
-GRAPEFRUIT juice
63
CYP 2D6
25% of drugs
64
CYP 2C9
15% of drugs
65
CYP 2C19/ CYP 1A1/ 2E1
<5% each
66
Flavin containing monooxygenase
FMO
- Phase I enzyme
- catalyzes mono-oxygenation reactions of soft nucleophiles (N and S oxidation reaction)
67
UDP glucuronosyl transferase (UGT)
Glucuronidation
-High energy intermediate: UDP Glucuronic acid
68
N-acetyltransferase (NAT)
Acetylation
-High energy intermediate: Acetyl-CoA
69
Sulfotransferase (SULT)
Sulfation
-High energy intermediate: PAPS
70
Glutathione S-Transferase (GST)
Glutathione conjugation
-High energy intermediate: drug itself, arene, oxide, epoxide
71
Enzyme Induction
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
Enzyme Inhibition
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
Acetaminophen
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
Pharmacogenetics
Genetically controlled variations in drug response
| Genetic factors that alter an individual's drug response to a drug
75
Genotype
Genotype: an individual's composition at the gene level ( specific genes that they have)
76
Phenotype
an individual's composition at the gene level
77
Genetic Polymorphism
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
Single Nucleotide Polymorphism (SNP)
a change in a single base pair in the DNA sequence that differs from the wildtype or predominant sequence
79
Haplotype & Halotype
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
Autosomal co-dominance
Each allele contributes to phenotype
81
Autosomal Recessive
Wild type allele has predominant effect: takes two recessive alleles to see the effect
82
x-linked inheritance
genes inherited on X chromosome, all makes will express these traits (males are hemi-zygous)
83
NAT-2 polymorphism
Responsible for metabolizing Isoniazid ( anti-TB)
Fast vs slow polymorphism
Autosomal recessive trait
84
CYP 2D6 polymorphism
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
CYP 2C19 polymorphism
Omeprazol: proton pump inhibitor
Phenytoin: anti-convulsants
Clopidogrel: anti-platelet drugs** (activated by 2C19)
Poor metabolizer phenotype
86
CYP 2C9 polymorphism
Warfarin (anti-coagulant)
Poor metabolizer phenotype: 2 variants (*2 and *3)
- decrease clearance
- increase warfarin half life
- increase risk of serious bleeding
87
Vitamin K receptor polymorphism
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
Pseudocholinesterase polymorphism
Succinylcholine ( depolarizing muscle relaxant)
| - due to reduced activity variants of pseudocholineresterase
89
TPMT polymorphism
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
P-glycoprotein polymorphism
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
Acetylcholine
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
Norepinephrine
Neurotransmitter in peripheral nerves
Tyrosine--> l-DOPA--> NE
Dopamine synthesized in nerve terminals--> transported into storage vesicles ( VMAT2)
Adrenergic receptors
93
Epinephrine
Neurotransmitter in peripheral nerves
94
Tyrosine Hydroxylase
rate limiting step of Norepi synthesis
95
Cocaine
blocks Norepi uptake from nerve terminal
96
Reserpine
Blocks VMAT2
97
Botulinum Toxin
Inhibits acetylcholine release
98
VMAT2
Vesicular monoamine transporter 2
Dopamine synthesized in nerve terminals are transported into storage vesicles via VMAT2-> converted to norepinephrine.
* blocked by reserpine
99
Norepinephrine Transporter
NET: re-uptake into nerve terminal. primary mechanism by which the actions of norepi are terminated
100
Extra-neuronal transporter
ENT: uptake Nor-epi
101
Monoamine oxidase
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
Catechol O Methyltransferase
transfer a methyl group to 3 hydroxy position of phenyl ring
| - cystolic enzyme
103
Acetylchoinesterase
AcH is rapidly metabolized and inactivated by acetycholinesterase
104
Nicotinic Receptors
Nm: NMJ: end plate depolarization
Nn: Autonomic ganglia: depol. of post ganglionic neuron
105
M1 Receptor
Gq (peripheral and central nerves)
Depolarization of nerves
Activates PLC
106
M2 Receptor
Gi (heart nerves and smooth muscles)
Decrease electrical conductance
Inhibits AC
107
M3
Gq (glands, smooth muscle)
increased secretion and muscle contraction
Activates PLC
108
M4
Gi (CNS)
inhibit depolarization
Inhibit AC
109
M5
Gq (CNS)
Depolarization
Activated PLC
110
Alpha 1
Gs (vascular, smooth m.)
contraction and secretion from glands
Activated PLC
111
Alpha 2
Gi (Nerve Terminals)
Decrease NE release
Inhibit AC
112
Beta 1
Gs: activate AC
(cardiac m)- increased force and rate of contraction
Glands: increased secretion
113
Beta 2
Gs- activate AC
(vascular, smooth m): relaxation
(Skeletal mu): Glycogenolysis
(Liver): glycogenolysis
114
Beta 3
Gs- Activate AC
| Adipose tissue: lipolysis
115
Characteristics of monoclonal antibodies
Homogenous for antibody type, amino acid sequence. affinity and specificity
High specificity, monospecific
High affinity
Long half life
116
How are antibodies administered?
Parenterally
IV: 100% bioavailability
SQ or IM: 24-95% bioavailability (absorbed through lymph and diffusion into blood vessels)
117
Neonatal Fc Receptor (FcRn)
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
Metabolism & elimination of therapeutic Ig
- 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
Mechanism of Therapeutic Ig
| - targets?
Ig binds to specific site at variable Fab
| Targets soluble antigens or cell surface proteins ( act extracellularly)
120
Mechanism from antigen-Ig binding:
Antagonism/ Neutralization
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
Mechanism from antigen-Ig binding:
Cell signaling inhibition
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
Mechanism from antigen-Ig binding:
| delivery of toxins
toxins or radionuclids are conjugated to an Ig
| Ig binds to surface protein--> selectivity delivers toxins or radionuclid
123
Mechanism from antigen-Ig binding
Radiocontrast agent
Ig binds to cell surface protein--> targets delievery of imaging agent
Radiocontrast agent imaged
