Test 1 Flashcards

1
Q

Receptor types (ie I, II, III)

A

I - plasma membrane
II - cytoplasm
III - nucleus

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2
Q

How many half lives does it take to get to a drug’s steady state concentration?

A

4-6

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3
Q

Restrictive vs Non-restrictive hepatic clearance

A

Restrictive - The clearance of a drug by hepatocytes is related only to binding and metabolism. The liver is saturated and it doesn’t matter how much drug is presented. ex Warfarin and phenytoin

Non-restrictive - The clearance of a drug by the liver is related to the amount of drug that is delivered. The liver has the capacity to get rid of as much drug as is brought to it, so more blood flow = more clearance. ex Lidocaine and propranolol

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4
Q

Cyp2D6

A

20-25% of all drugs, but inactive in 2-10% of the population.

Tricyclic antidepressants, antiarrhythmics, beta-blockers, and neuroleptics

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5
Q

Cyp2C9

A

15% of all drugs. 40% of population is heterozygous, 1% are deficient entirely.

Warfarin

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6
Q

Cyp2C19

A

5% of all drugs. Common inactive allele.

Clopidogrel (Plavix) (can’t digest if patient is Cyp2C19*2

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7
Q

Cyp3A4

A

50% of all drugs. No inactivating polymorphisms.

Grapefruit juice, though, will coat the enzyme and decrease its activity.

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8
Q

N-acetyltransferase (NAT)

A

Phase II metabolism. Some people have a “slow acetylator phenotype,” so their NAT’s take longer to metabolize drug products.

Isoniazid, hydralazine, sulfonamides.

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9
Q

Vitamin K epoxide reductase (VKORC1)

A

Target of warfarin. Polymorphisms in this gene account for about 25% of warfarin’s variability, and together with Cyp2C9 polymorphisms it accounts for about 60% of warfarin’s variability.

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10
Q

hERG

A

Potassium channel (Ikr) that many compounds interact with, leading to elongated QT intervals. All new drugs are tested for interactions with this channel.

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11
Q

Acetaminophen metabolism

A

Normally, Phase II reactions convert it and that leads to its elimination. Also metabolized slightly via a phase I reaction by CYP2E1 into NAPQI. This slight amount is then reacted with GSH in a phase II reaction and then excreted. If GSH is overwhelmed, either via overdose or alcohol consumption (alcohol increases CYP2E1 amount because it is trying to metabolize the alcohol), then NAPQI binds to proteins and leads to cell death.

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12
Q

Red Man Syndrome

A

Drugs act directly on mast cells (not IgE receptors) leading to degranulation.

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13
Q

Steven-Johnsons syndrome

A

Blistering and separation of the epidermis from the dermis.

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14
Q

Potency

A

Concentration of drug needed to elicit 50% of the maximal response.

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15
Q

Maximal Efficacy

A

The maximal response produced by the drug.

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16
Q

Therapeutic index

A

The distance between the median effective dose and the median lethal dose on a Quantal-dose response curve.

17
Q

Therapeutic window

A

The distance between the minimum effective therapeutic dose and the minimum lethal dose. More useful in determining the safety of a drug.

18
Q

Ligand regulated transmembrane enzymes

A

Protein tyrosine kinases, when activated they phosphorylate tyrosines or serines.

Ex insulin, ANF, EGF

19
Q

Cytokine receptors

A

Similar to ligand regulated transmembrane receptors, but the phosphorylated subunit (STAT, phosphorylated by JAK) is not intrinsic to the membrane and detaches upon phosphorylation. They then travel to the nucleus to initiate transcription.

20
Q

Ligand-gated channel receptors

A

Fast. Pentamer with 4 subunits. Ach bind alpha subunits inducing a conformational change and opening of a channel.

Ex is nicotinic cholinergic receptor.

21
Q

G-protein linked receptors

A

7 pass transmembrane protein. N-terminus is extracellular, C-terminus is intracellular and has serines available for phosphorylation that results in regulation. 3rd intracellular loop interacts with G proteins inside the cell.

Ex. dopamine, norepinephrine, 5-HT (serotonin), and Acetylcholine.

G-proteins activate adenyl cyclase to make cAMP–>PKA–>response amplification

PIP2–>IP3 and DAG.
IP3 –> Ca2+ release–>CAM kinases–>amplification of reponse
DAG –> PKC–>amplification of response

22
Q

G proteins activate what second messengers?

A

adenyl cyclase to make cAMP–>PKA–>response amplification

23
Q

PIP2 activates what?

A

PIP2–>IP3 and DAG.
IP3 –> Ca2+ release–>CAM kinases–>amplification of reponse
DAG –> PKC–>amplification of response

24
Q

Tachyphylaxis

A

Rapid development of a diminished drug response

25
Q

SLC transporters

A

Solute carrier superfamily. Influx/uptake transporters (except for MATE transporters).

26
Q

ABC transporters

A

ATP-binding cassette superfamily. ATP dependant efflux transporters.

27
Q

OAT transporters

A

Organic anion transporters. Link facilitated efflux to alpha-ketoglutarate, which is maintained via Na/K ATPase.

Found in liver (OAT2) and proximal tubules (OAT1-3 from blood, OAT4 from tubule).

Methotrexate, NSAIDs, cidofovir
(NSAIDs inhibit OAT1 increasing methotrexate toxicity)
(cidofovir has high renal toxicity, so administer with probenecid (OAT1 inhibitor) to prevent renal toxicity)

28
Q

OATP transporters

A

Organic anion transporter polypeptides. Influx of substrates in exchange for HCO3-.

Found in gut (OATP 1A2/2B1), liver (OATP1B1/1B3/2B1 from blood and OATP1A2 from bile), and kidney proximal tubules (OATP4C1 from blood and OATP1A2 from tubule).

OATP1B1 interacts with statins and is inhibited by cyclosporins.

29
Q

OCT transporters

A

Organic cation transporter. Uptake/influx of small cations, mediates passive facilitated diffusion.

Found in gut (OCT3/N1/N2), kidney (OCT2/3 from blood, OCTN1 from tubular lumen), liver (OCT1/3).

Cisplatin, metformin, and procainamide (antiarrhythmic with narrow therapeutic window). Inhibited by cimetidine.

30
Q

MATE transporters

A

Multidrug and toxin extrusion. Efflux of small cations via H+ antiport.

31
Q

Metformin and OCT/MATE transporters

A

A decrease in metformin clearance leads to higher insulin, which decreases blood glucose, which leads to ketone metabolism and lactic acidosis.

32
Q

Cimetidine and OCT/MATE transporters

A

Cimetidine inhibits OCT channels, leading to decreased clearance of procainamide (an antiarrhythmic –>toxicity).

It is also used to prevent cisplatin from entering the renal tubules.

33
Q

Pgp/MDR1 transporters

A

P-glycoprotein/multi-drug resistant protein-1. On apical/lumenal faces of the gut, kidney, and liver.

Eliminate digoxin and loperamide, inhibited by cyclosporin, induced by rifampin and St. John’s wort.

34
Q

BCRP transporters

A

Breast cancer resistance protein. Found on gut enterocytes, liver, blood brain barrier, and mammary epithelium.

Efflux of statins, concentrates riboflavin (B12) in breast milk.

35
Q

MRP transporters

A

Multidrug-resistant proteins. Expressed in many tissues.

Endogenous - glutathione, glucuronide, and sulfate conjugates
Exogenous - methotrexate and anthracyclins

36
Q

Issues with loperamide and cyclosporin

A

Cyclosporine inhibits P-gp/MDR-1, so administered with loperamide –> loperamide crosses the blood brain barrier and induces respiratory depression.