Pharmacodynamics Flashcards
pharmacodynamics
what the drug does to the body
two concepts of pharmacodynamics
receptor activation & dose response
four ways a drug can bring about an effect
- drug/receptor complex=effect
- drug/receptor complex=effector molecule=effect
- drug/receptor complex=activation of coupling molecule=effector molecule=effect
- drug/receptor complex=inhibition of endogenous activator metabolism=increased activator=increase effect
receptor
a protein that binds a signaling molecule and in doing so generates a signal of its own
constitutively active receptor
receptors that remain in active conformation even in absence of agonist binding
agonist
a molecule that binds to and activates a receptor to bring about an effect
full agonist
drug/agonist that saturates receptor pool, binds to active form, and stabilizes it so that large percent is in Ra-D form. brings about higher maximum response
partial agonist
drug with low intrinsic activity. binds to Ra and stabilizes it so that a low % stays in Ra-D pool regardless of dose
inverse agonist
drug has higher affinity for inactivated receptor and stabilizes large fraction of Ri-D pool. constitutive activity of receptor is lost
antagonist
molecule that prevents activation of receptor by an agonist by binding to the active site. maintain same level as constitutive activity
potency
concentration of drug required to achieve a certain effect (EC50: half of the maximum effect)
efficacy
magnitude of the drugs action at the limit of its concentration (Emax, plateau)
action of allosteric activator
amplifies agonist by binding to separate site on receptor. increases efficacy
allosteric inhibitor
binds to separate site of receptor and cause conformational change that prevents agonist from binding or lowers its affinity once bound. changes the maximal response of the drug
competitive inhibition
fights for binding site with agonist. causes reduction in response but ultimately drug still reaches maximal effect. can be overcome by increasing concentration of agonist
dose response relationship
receptors largely determine the quantitative relationship between dose or concentration of drug and pharmacologic effect
5 types of transmembrane signaling mechanisms
steroid receptors, cytokine receptors, receptor tyrosine kinase, ion channel, GCPRs
steroid receptors
a lipid soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor
cytokine receptors
signal binds to the EC domain of the receptor, activating the enzymatic activity of the cytoplasmic domain of the receptor (JAK STAT)
receptor tyrosine kinase
signal binds to the EC domain of the receptor bound to a tyrosine kinase, which it then activates via phosphorylation
ion channel
signal binds and directly regulates the channel’s opening. electrical potential of membrane is altered
GCPRs
the signal binds to a cell surface receptor linked to an effector enzyme by a G protein
mechanism of action of GCPR
extracellular ligand binds to cell surface receptor, receptor triggered activation of a G protein located on cytoplasmic face of plasma membrane, activated G protein changes activity of effector element, which changes the concentration of intracellular second messenger
effector elements associated with GPCRs
adenylyl cyclase, ion channel, etc
intracellular second messengers associated with GPCRs
cAMP, Ca2+
Gs
associated with adenylyl cyclase. s=stimulation, increases levels of cAMP
Gi
associated with adenylyl cyclase. i=inhibition, decreases levels of cAMP
Gq
associated with phospholipid C (PLC-beta). stimulatory. increases intracellular calcium levels
epinephrine receptor
beta adrenergic receptors increase cAMP via Gs
acetylcholine receptor
muscarinic or nicotinic receptors decrease cAMP via Gi
Gq associated with histamine in bronchiolar smooth muscle
associated with H1 receptor. increased Ca levels via PLC leads to vessel constriction
Gs associated with epinephrine in bronchiolar smooth muscle
associated with B2 receptor. increases cAMP levels via adenylyl leading to vessel dilation
TxA2 action in platelets
goes through Gq pathway in which increased Ca levels lead to platelet aggregation
prostaglandin 2 (PGI2) action in platelets
goes through Gs pathway in which increased cAMP leads to disaggregation (relaxation)
histamine via Gq
in bronchiolar smooth muscle cells. leads to contraction (anaphylaxis)
histamine via Gs
in vascular smooth muscle cells. leads to relaxation/vasodilation
GPCR downregulation
heterodimerization leading to endocytosis and then recycling or destruction
GPCR desensitization
response to drugs/agonist diminishes over time.
how does desensitization occur?
phosphorylation of the serene residues in the GPCR carboxyl tail recruits beta arrestin, which decreases receptor ability to interact with G protein subunit.
is desensitization reversible/irreversible?
reversible following exposure to more agonist
G protein structure
heterotrimeric (alpha, beta, gamma). dissociates upon ligand binding
therapeutic leverage
can target drug action by synthesizing molecule to pick out a specific subtype of receptor
graded dose response
with increasing dose, there is an increase in response
quantal dose response
all or none dose response
narrow therapeutic index
the difference between lethal dose and effective dose is small
K3
measurement of a drugs intrinsic activity
K3=1
drug is an agonist
K3=0
drug is an antagonist
1>K3>0
drug is a partial agonist
threshold dose
the dose at which we start seeing a response to the drug
Emax
the maximal effect of a drug. where it plateaus. if you add any more drug, no further effect will be seen, but toxicity will occur
left shifted dose curve
indicative of higher potency
competitive antagonist
involves receptors, completely reversible with increased agonist concentration
noncompetitive antagonist
involved receptors, agonist fails to reverse it
chemical antagonist
one drug binds to another drug, inactivating it or blocking its absorption
physiologic antagonist
one drug does exactly the opposite of another drug and works on a different receptor
ED50
the median dose required to have effects on 50% of people
LD50
the median dose required to cause death in 50% of people
therapeutic index formula (TI)
LD50/ED50
what TI makes for a safe drug?
> 10/15
safety index
LD01/ED99
