Block 1 Lecture 4 -- Pharmacodynamics II Flashcards
Pharmacophore:
the structural features of a drug that define how it interacts with a particular receptor
Pharmacophore (IUPAC):
an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response
What are the types of chemical bonding that can occur during association with a receptor?
1) covalent
2) ionic
3) hydrogen
4) van der walls
Energy of covalent bond:
100 kcal/mol
Energy of ionic bond:
5 kcal/mol
Energy of hydrogen bond
2 kcal/mol
Energy of Van der Waals forces:
0.5 kcal/mol
When might Van der Waals forces apply during drug-receptor interactions?
tertiary drug-receptor interactions
What is the therapeutic index?
relationship between desired effects to adverse reactions caused by the drug
Equation for TI
TD50/ED50
Receptor desensitization:
the refractory period of the receptor. DR complexes are formed but signal transduction is not possible or is reduced as a result of binding
What is homologous receptor desensitization?
agonist binding leads pathway activation that intrinsically turns off the same pathway
What is heterologous receptor desensitization?
desensitization caused by
depletion of intracellular signaling mechanisms
ex) multiple receptors using common signaling pathways
Natural Drug Tolerance:
high end of normal frequency distribution (Quantal DRC)
Acquired Drug Tolerance:
reduced sensitivity to a drug following long-term administration
What are types of acquired drug tolerance?
PK
PD
Tachyphylaxis:
the rapid, progressive lessening of a response following acute administration of a drug
What are the 4 receptor families?
LGIC
GPCR
ligand-gated TM enzymes
intracellular receptors
What are the ionotrophic receptors?
LGICs
What are the metabotrophic receptors?
GPCRs
Ligand-gated TM enzymes
intracellular receptors
What are types of LGICs?
1) nAChR (a4, a7)
2) ionotrophic glutamate (NMDAr, AMPAr)
3) GABAa
4) Glycine
5) 5-HT3
How do the nAChR’s vary?
a4 likes Na more than Ca
a7 likes Ca more than Na
What are the ionotrophic glutamate receptors and how do they vary?
NMDAr likes Ca more than Na
AMPAr likes Na more than Ca
What is the ion for the glycine LGIC?
Cl
Describe the ion affinity for the 5HT3 receptor.
Na more than Ca
Describe the characteristics of LGICs
1) protein subunits form ion channel
2) ligand binds a subunit
3) many allosteric modulators
4) rapid on, rapid off
What is the largest receptor superfamily?
GPCR
How are GPCRs placed into classes?
sequence homology/functional similarity
What are the general details about GPCR classes?
6 classes
Class A/1 (Rhodopsin-like) has many human drug targets
– adrenergic, muscarinic, histamine, dopamine
Class B-F are mostly orphans
What are some GPCR receptors?
1) adrenergic
2) muscarinic
3) metabotrophic glutamate
4) serotonin (- 5-HT3)
6) GABAb, cannabinoid, neuropeptides
Describe GPCR structure.
amino extracellular
carboxyl cytoplasmic
7 transmembrane-spanning regions
Gi mechanism
1) decreases cAMP
2) increases K+ efflux
3) inactivates Ca++ channels
Gs mechanism
1) increases cAMP
2) activates Ca++ channels
Gq mechanism
1) increases PLC activity
2) increases DAG, IP3
3) increases protein-po4
4) increases cytoplasmic Ca++
What are classes of ligand-regulated TM enzymes?
1) Receptor TK
2) Receptor associated TK
3) Guanylate Cyclase
4) Ser/Thr Kinases
What are types of Receptor TKs?
1) insulin receptor
2) neurotrophic factor receptors – VEGF, NGF, FGF
What are types of Receptor Associated TKs?
Cytokine receptors (IL-6, IL-10)
NGF
nerve growth factor
FGF
fibroblast growth factor
VEGF
vascular endothelial growth factor
What are ligands for intracellular receptors?
corticosteroids, mineralocorticoids, sex, thyroid hormone, vit d, PPAR
How long is required for an alteration in protein synthesis (via intracellular receptors)
hours
What factors govern drug properties?
1) physical nature of drug
2) size of drug
3) shape of drug/stereoisomerism
4) type of chemical bonding during DR formation
What drug sizes are used clinically and most useful?
clinically: 7-60,000 mw
useful: 100-1000 mw
In equilibrium k1 notates:
rate of association between drug and receptor
In equilibrium k-1 notates:
rate of dissociation of DR
What is measured in an equilibrium radioligand binding assay?
affinity and saturation
How is affinity determined in an equilibrium radioligand binding assay?
Affinity = (k1/k-1)
= DR association rate
What is the equilibrium dissocation constant?
Kd – the [radioligand] when 50% is bound as DR and 50% is free
= k1 / k-1
How are affinity and Kd related?
inversely proportional
What is Bmax?
maximal number of receptors in the tissue studied
Why does the law of mass action not predict drug efficacy in all patients?
PK and PD variability
What are sources of PK variability?
gender, race, weight
…
compliance
Anything that effects ADME
What are sources of PD variability?
gender, race drug intx, environment, concomitant dz *placebo effect *polymorphisms *tolerance, tachyphylaxis
What is acute behavioral tolerance?
tachyphylaxis
What is pharmacodynamic tolerance?
when repeated drug administration causes a homeostatic change in cellular responsiveness of a target tissue
What changes to the DRC do you expect from PD tolerance?
right-shift
possible decrease in max efficacy
What are mechanisms of receptor down-regulation?
increased internalization
increased catabolism
reduced synthesis
What is PK tolerance?
aka metabolic or drug disposition tolerance
– when repeated drug administration causes induction of catabolic enzyme systems
What changes to the DRC do you expect from PK tolerance?
right-shift
no change in max efficacy
When might cross tolerance occur?
When 2 drugs share similar MoA or catabolic enzymes
When does sensitization usually occur?
w/ stimulant drugs due to changes in DA neurons of brain
– amphetamine, cocaine
What changes to the DRC do you expect from sensitization?
left-shift
