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Flashcards in Pharmacology - Sheet1 Deck (146):
1

pharmacokinetcs

What the body does to the drug

2

pharmacodynamics

What the drug does to the body.

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Important disadvantage oral administration

First pass effect, variable response

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First Pass effect

Drug must first pass through portal vein to liver before reaching other organs. Metabolized and changed. Affects oral and to some extenct rectal. NOT sublingual

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IM aqueous advantage

fast onset of action

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IM non aqueous advantage

slow sustained response

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What determines absorption in transdermal

lipid solubility

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pH rule of thumb regarding absorption

weak acids stomach, weak bases intestine

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bioavailability formula

AUC oral/AUC injected x 100

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distribution

process of leaving blood and entering other areas. 3 main areas

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3 Compartments and relative size for distribution

Plasma - 4L, ECF - 14L, Total Body Water - 42L

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Factors affecting distribution

blood flow, capillary permeability, degree of hydrophobicity, binding to plasma proteins

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Important factor when drugs are displaced from plasma binding

Must assess their Volume of distribution. If small at higher risk of toxicity

14

Volume of distribution equatino

bioavailability of dose/concentration of plasma at initial time.
hypothetical volume of fluid into which a drug is disseminated and prior to elimination.

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Phase 1 Drug Metabolism

oxidation involving cytochrome p450

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Phase 2 Drug metabolism

coupling endogenous substrate to a drug or phase 1 metabolite

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Cytochrome p450

made of many families of heme containing isozymes

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CYP families most involved in metabolizine enzymes

CYP 1,2,3 and CYP3A4

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What can increase CYP3A4

Rifampin (TB), St John's Wort. Effect is increased metabolism of the drugs

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What can decrease CYP3A4

grapefruit juice

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Which CYP polymorphisms are important

CYP2D6, CYP2C19

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3 processes renal excretion

glomerular filtration, active tubular secretion, passive tubular transport

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clearance equation

rate of elimination/concentration

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Type of clearance kinetics for most drugs

first order so increasing amount leads to an equal increasing excretion

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Relation of steady state to rate of elimination

Both require 4-5 half lives to reach steady state, indpeendent of dose or rate of dosing

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Graded dose response

increase dose - increase response

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quantal

all or none resopnse

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Intrinsic activity vs potency

Potency has to do with how much you must give to get 100% response. intrinsic activity has to do with highest % response you can achieve

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Agonist K3 value

1, antagonist is 0

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Muscarininc chlinergic agonist

ACH, muscarine, pilocarpine

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Muscarininc cholinergic antagonist

Atrpoine, Scopolamine

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Nicotinic chlinergic agonist

ACH, nicotine

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Nictinic cholinergic antagonist

Curare, succinylcholine

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Alpha- adrenergic agonists

norepinephrine, epinephrine

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Alpha 1 adrenergic antagonists

Prazosin, phentolamine

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Beta 1 adrenergic agonists

Epinephrine

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Beta 1 adrenergic antagonists

propranolol, metoprolol

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4 Types of antagonism

competitive, noncompetitive, chemical, physiologic

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Physiologic antagonism

One drug does exact opposite of another and works on entirely separate mechanism

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Therapeutic index

Take the 50 cumulative percent of negative outcom/positive outcome

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Safety Index Formula

Lethal Dose 01%/Effective Dose 99%

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Mineralcorticoids, location and function

Zona glomerulosa adrenal cortex - salt and water regulation

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Glucocorticoids location

Zona fasiculata

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Androgen/estrogen location

Zona reticularis

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Which two chaperone proteins does GR interact with LBD

Hsp90 and Hsp56

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Which end is AF2

C terminal

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AF2 function

ligand dependent transactivation domain. Only recruit co-regulators after steroid binds GR

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Which end is AF1

N terminal

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AF1 Function

ligand independent transactivation domain

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role of Heat shock proteins in Glucocorticoid receptor

Keeps the receptor ligand friends. 2Hsp90 and 1 HSP 56 subunit

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2 Examples of how glucocorticoids affect gene expression

Increase expression of lipocortin, downregulating PLA2 decreasing synthesis of PGs and lueoktrienes
inhibits production of IL-6 and IL-8

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2 glucocorticoid drugs that are very specific for glucocorticoid effects

Dexamethasone and Betamethasone

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Effect of prolonged steroids on hypothalmic pituitary axis

suppress the axis and supress endogenous cortisol production

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Addisonian Crisis

acute adrenal insufficiency bc sudden withdrawal of therapeutic glucocorticoids

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Which effector T cells can mediate steroid resistant rejection

Th17 producing IL 17,21,22

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Th1 produces

IFN gamma, IL-2, TNFalpha - T cell Drive

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Th2 produces

IL4,5,13 - B cell drive

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T regulatory

IL10 - TGF beta

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What downregulates Th2

INF-gamma

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What downregulates Th1

IL-10

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Basiliximab limitation

can be used to prevent induction but not to treat rejection because it is useless once the T cell has already received signal 3

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Equine anti-thymphocyte globulin use

anplastic anemia

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rabbit anti-thymocyte globulin

transplant

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Important liitation of polyclonal antibodies

risk of antibody response, toxicity, immunosuppresion

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Belatacet mechansim

Binds to CD80/86 better than CD28 and stops costimulation

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Belatacept major risk

increased risk of post-transplant lyphoproliferative disorder.
only use when have some other viral infection?

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High dose steroid effect

apoptosis of activated T and B cells

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Calcineurin examples

tacrolimus and Cyclosporine binding to FK binding protein-12 and cyclophilin

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Calcineurin mechanis

prevents calccineurin phosphatase. Inhibits IL-2 mediated response and transcription of IL-2, GM-CSF, TNFalpha and INF gamma

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Calcineurin metabolized by

CYP3A4 means you have to monitor levels differently. If on it need to give higher levels.

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Increased risk hyperglycemia/neurotoxicity (calcineurin)

tacrolimus

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increased risk hypertension, hyperlipidemia, hyperuricemia

cyclosporine

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Hirsutis/gingival hyperplasia

cyclosporine

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mTOR inhibitors

Sirolimus and everolimus

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mTOR inhibotor mechanism

inhibits protien kinase

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mTOR effect

decrease cytokine dependent cellular proliferation, at G1 to S, induce T cell cycle arrest. Inhibit activation and proliferation

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mTOR metabolized by

CYP3A, longer half-life than calcineurin so don't need to monitor as much

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mTOR major toxicity

wound healing impairment

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Azathioprine mechanism

blocks denotovo and salvage of purines. prevents DNA relplication

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Mycophenolic acid products

block de novo purine synthesis, prevent DNA replication

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Methotrexate

Folic acid antagonist. Arrest cells at S phase

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Common drug interaction with azathioprine

Allopurinol inhibits xanthine oxidase which normally metabolizes azathioprine. So when both need to keep azathioprine levels lower

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Monoclonal antibodies, IL2 receptor agonist

binds to alpha subunit of IL-2 receptor.

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Basiliximab common use

used as an induction agent in organ transplant

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basiliximab mechanism

anti CD-25 antbody that acts on activated T cells.

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basilixmab cannot be used for

treating rejection

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Induction therapies

basiliximab or rabbit antiglobulin

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Maintinence therapies

calcineurin or mTOR w azathioprine or MPA w prednisone

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3 types of Eicosanoids

Prostanoids, Leukotrienes, HETES and EETS

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Eicosanoids derived from

arachidonic acid in cell membrane

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Isoeicosanoids

products that do not depend on enzymes and are driven by free radicals

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Phospholipase A2 function

catalyzes release of Arachidonic acid from embrane

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COX function

AA to intermediary PGG2/PGH2

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PGG2 platelet synthesize

TxA2

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GI Endothelial cells PGG2 synthesize

PGE2

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Vascular endothelial cels PGG2 synthesize

prostacyclin PGI2

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Phospholipase A2 forms

cytosolic and inducible

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Cox 1 function

constitutive activity

99

Cox 2 function

inducible and not in all cells

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Platelet Cox form

Cox 1

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Enthothelial cell Cox form

Cox 2

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PGE2 ligand for

EP receptors (1-4)

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PGI2 ligand for

IP receptor

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TxA2 ligand for

TP receptor

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PGF2alpha ligand for

FP receptor

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TxA2 function

induce platelet aggregation, vasoconstriction, smooth muscle cell proliferation

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PGI2 (prostacyclin I2)

inhibits platelet aggregation and smooth muscle cell proliferation, vasodilator and pro-inflammatory

108

Prostaglandin E1 and 2 function

cytoprotection in Gut w inhibition of gastric secretions

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Which Cox for inhibition of gastric secretions

Cox 1

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Prostaglandin E function on vessels

vasodilation (COX 1 and 2)

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Prostaglandin E function on homeostasis

Regulate sodium and water with renin release (COX 1 and 2)

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Prostaglandin E function, gastroutero muscles

contraction of smooth muscles COX1 and 2

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Prostaglandin E inflammatory effects

Controls body temperature. Pro-inflammatory through COX 2

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Prostaglandin F2 function

vascular smooth muscle and uterine contraction. Vasoconstrictor COX 1 and 2

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Prostaglandin D2 effect vessels

cutaenous vasodilation. Inhibitino of aggregation

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Prostaglandin D2 effect unusual

promotes sleep and changes hair follicle activity

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Prostaglandin D2 immune effect

produced by mast cells->chemotaxis Th2 lymphocytes

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Prostanoids in pain

PGE2, PGE1 PGI2

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Prostanoids in heat

PGE2 and PGE1

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Prostanoids in redness

PGE2, PGE1, PGI2

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Prostanoids in swelling

PGI2, PGE2, PGD2

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Reduces release of AA from membrane

steroids

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reduce AA to PGG2/PGH2

attack COX, NSAIDS

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Reduce production of prostanoids

target isomerases, Ridogrel

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Ridogrel

Inhibits throboxane synthase

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PGF2alpha medical function

causes luteal regression and induces smooth muscle contraction

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carbaprost

PGF2 analogue for abortifacient and post partum bleeding

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PGE2 PGE1 medical use

INduce uterine contraction

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Misoprostol

PGE2 analogue used as abortifacient and gastric cytoprotection

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Dinoprostone

PGE2 analogue for inducing labor

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NSAID basics

weak acids that have sleectivity for both COX

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Gold standard NSAID

Aspirin

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Aspirin mechanism

inhibition of COX by competing for active site

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Aspirin effect

acetylates SER-530 and causes irreversible inhibition

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NSAID side effect

limit cytoprotection = gastropathy

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Gastropathy mechanism

reduce PGE1,2 = reducegastric mucus and pH. Reduce TxA2 = inhibit clot = erosion, bleeding, ulcer

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Which COX causes gastropathy

COX 1 inhibition

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Coxib problem

inhibited only COX2 but had cardiovascular risks

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Coxib problem mechanism

get an imbalance of the TxA2 and PGI2. Endothelial cells need COX 2 for antiplatelet effects.

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NSAID renal adverse effects

renal disease need the vasodilation from prostaglandin. Inhibition leads to renal toxicities

141

NSAID renal effect mechanis

PGE induced renin secretio causes elevated blood pressure bc sodium reabsorption

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Aspirin low dose

Inhibits platelet COX 1

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High dose Aspirin

analgesic

144

Highest dose aspirin

anti-inflammatory

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Reyes syndrome (aspirin)

hepatic toxicity, limits pediatric use

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Salicylate toxicity (Aspriin

headache, tinnitus, dizziness. Ringing in ears most important