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Flashcards in Pharmacodynamics Deck (61):
1

pharmacodynamics

what the drug does to the body

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two concepts of pharmacodynamics

receptor activation & dose response

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four ways a drug can bring about an effect

1. drug/receptor complex=effect
2. drug/receptor complex=effector molecule=effect
3. drug/receptor complex=activation of coupling molecule=effector molecule=effect
4. drug/receptor complex=inhibition of endogenous activator metabolism=increased activator=increase effect

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receptor

a protein that binds a signaling molecule and in doing so generates a signal of its own

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constitutively active receptor

receptors that remain in active conformation even in absence of agonist binding

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agonist

a molecule that binds to and activates a receptor to bring about an effect

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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

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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

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inverse agonist

drug has higher affinity for inactivated receptor and stabilizes large fraction of Ri-D pool. constitutive activity of receptor is lost

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antagonist

molecule that prevents activation of receptor by an agonist by binding to the active site. maintain same level as constitutive activity

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potency

concentration of drug required to achieve a certain effect (EC50: half of the maximum effect)

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efficacy

magnitude of the drugs action at the limit of its concentration (Emax, plateau)

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action of allosteric activator

amplifies agonist by binding to separate site on receptor. increases efficacy

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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

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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

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dose response relationship

receptors largely determine the quantitative relationship between dose or concentration of drug and pharmacologic effect

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5 types of transmembrane signaling mechanisms

steroid receptors, cytokine receptors, receptor tyrosine kinase, ion channel, GCPRs

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steroid receptors

a lipid soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor

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cytokine receptors

signal binds to the EC domain of the receptor, activating the enzymatic activity of the cytoplasmic domain of the receptor (JAK STAT)

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receptor tyrosine kinase

signal binds to the EC domain of the receptor bound to a tyrosine kinase, which it then activates via phosphorylation

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ion channel

signal binds and directly regulates the channel's opening. electrical potential of membrane is altered

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GCPRs

the signal binds to a cell surface receptor linked to an effector enzyme by a G protein

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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

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effector elements associated with GPCRs

adenylyl cyclase, ion channel, etc

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intracellular second messengers associated with GPCRs

cAMP, Ca2+

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Gs

associated with adenylyl cyclase. s=stimulation, increases levels of cAMP

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Gi

associated with adenylyl cyclase. i=inhibition, decreases levels of cAMP

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Gq

associated with phospholipid C (PLC-beta). stimulatory. increases intracellular calcium levels

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epinephrine receptor

beta adrenergic receptors increase cAMP via Gs

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acetylcholine receptor

muscarinic or nicotinic receptors decrease cAMP via Gi

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Gq associated with histamine in bronchiolar smooth muscle

associated with H1 receptor. increased Ca levels via PLC leads to vessel constriction

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Gs associated with epinephrine in bronchiolar smooth muscle

associated with B2 receptor. increases cAMP levels via adenylyl leading to vessel dilation

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TxA2 action in platelets

goes through Gq pathway in which increased Ca levels lead to platelet aggregation

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prostaglandin 2 (PGI2) action in platelets

goes through Gs pathway in which increased cAMP leads to disaggregation (relaxation)

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histamine via Gq

in bronchiolar smooth muscle cells. leads to contraction (anaphylaxis)

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histamine via Gs

in vascular smooth muscle cells. leads to relaxation/vasodilation

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GPCR downregulation

heterodimerization leading to endocytosis and then recycling or destruction

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GPCR desensitization

response to drugs/agonist diminishes over time.

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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.

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is desensitization reversible/irreversible?

reversible following exposure to more agonist

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G protein structure

heterotrimeric (alpha, beta, gamma). dissociates upon ligand binding

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therapeutic leverage

can target drug action by synthesizing molecule to pick out a specific subtype of receptor

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graded dose response

with increasing dose, there is an increase in response

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quantal dose response

all or none dose response

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narrow therapeutic index

the difference between lethal dose and effective dose is small

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K3

measurement of a drugs intrinsic activity

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K3=1

drug is an agonist

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K3=0

drug is an antagonist

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1>K3>0

drug is a partial agonist

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threshold dose

the dose at which we start seeing a response to the drug

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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

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left shifted dose curve

indicative of higher potency

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competitive antagonist

involves receptors, completely reversible with increased agonist concentration

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noncompetitive antagonist

involved receptors, agonist fails to reverse it

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chemical antagonist

one drug binds to another drug, inactivating it or blocking its absorption

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physiologic antagonist

one drug does exactly the opposite of another drug and works on a different receptor

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ED50

the median dose required to have effects on 50% of people

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LD50

the median dose required to cause death in 50% of people

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therapeutic index formula (TI)

LD50/ED50

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what TI makes for a safe drug?

>10/15

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safety index

LD01/ED99