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Pharmacology > pharmacokinetics > Flashcards

pharmacokinetics Flashcards

1
Q

routes of administration

A

§ Intravenous - rapid response
§ Intramuscular
§ Subcutaneous
§ Oral - slowest response

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2
Q

Cmax

A

maximum concentration

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3
Q

Tmax

A

time taken to reach maximum concentration

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4
Q

MEC

A

minimum effective concentration

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5
Q

MTC

A

minimum toxic concentration, above which drug toxicity occurs

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6
Q

ability to cross lipid membranes depends on

A

size, solubility, polarity/charge, transporters

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7
Q

size affecting ability to cross lipid membranes

A

® Oral absorption decreases with increasing molecular weight

◊ Drugs that are too big may be poorly absorbed from the GI tract

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8
Q

lipinki’s rule

A

drug should be <500 g/mol

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9
Q

□ Solubility

affecting drugs ability to cross lipid membranes

A

® Orally absorbed drugs need a mix of 2 physiochemical properties
◊ Hydrophilicity (water loving)
◊ Lipophilicity (fat loving)

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10
Q

2 means of estimating lipid solubility

A

logP and polar surface area (PSA)

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11
Q

logP

A

} Layer of organic fluid (octanol) over water, add drug, mix, allow layers to equilibrate
} Measure ratio of drug concentrations both phases (partition coefficient) [P]
– Log of partition coefficient [LogP] predicts ability of drugs to cross membranes

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12
Q

◊ Polar surface area (PSA)

A

computer based PSA prediction based on amount of surface of the molecule that has a polar surface

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13
Q

◊ Egan’s egg

A

} Most drugs in clinical use lie in an egg shape in a graph of PSA against logP

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14
Q

□ Polarity/charge

A

◊ Drugs only diffuse across lipid membranes if they are in a neutral (uncharged) state

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15
Q

□ Transporter

A

® Drug transporters can influence drug accumulation and efflux

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16
Q

® P-glycoprotein

A

◊ P-Gp is a clinically-significant membrane transporter

◊ Member of ATP-binding cassette-type membrane transporters

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17
Q

p glycoprotein is encoded by

A

ABCB1 gene

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18
Q

what does p glycoprotein do

A

◊ Can return absorbed drug to gut lumen

} P-gp is an efflux pump (ATP dependant) that counteracts the oral absorption of lipophilic drugs

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19
Q

drug bioavailability is reported as

A

F ie. Fraction of administered dose that is absorbed

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20
Q

prodrugs

A

® Hydrophilic groups in molecule can be masked by adding metabolism-sensitive, lipophilic substituents
® After entering cell, group is cleaved, releasing the drug

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21
Q

transported affecting drug distribution

A

§ Key roles ABC transporters and SLC transporters

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22
Q

plasma concentrations of blood

A

§ Lipid soluble drugs distribute into fat and can achieve low plasma concentrations
§ Highly protein bound drugs distribute poorly into tissues and yeild higher plasma concentrations

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23
Q

Vdist

A

dose/plasma concentration(Co)

24
Q

Co

A

® C naught value is estimated plasma concentration at time = 0

25
Q

acidic drugs mainly stored by

A

albumin

26
Q

basic drugs mainly stored by

A

binds an a1 glycoprotein

27
Q

major drug transformations in the human body

A

oxidation, sulfonation, glucuronidation, glutathione conjugation, acetylation, etc

28
Q

2 phases of metabolism

A

oxidative reactions

conjugative reactions

29
Q

oxidative reactions are

A

functionalisation reactions

○ Introduce or expose a new functional group

30
Q

Conjugative reactions involve

A

formation of a new chemical bond between drug and an endogenous molecule (donated by a cofactor)
○ Ie. Formation of a conjugate

31
Q

oxidative reactions examples

A

○ Oxygenation, hydroxylation, N-Dealkylation

32
Q

conjugative reactions examples

A

○ Sulfonation, acetylation, gluceronidation, methylation, glutathione conjugation

33
Q

DMEs

A

drug metabolising enzymes

cytochrome P450

34
Q

CYP

A

§ Iron-containing proteins (contain Fe in haem group)

§ High versatile oxidising systems (many substrates)

35
Q

cofactors for CYP

A

§ Require NADPH (cofactor) & oxygen (O2) to metabolise drug substrate (SH)

36
Q

4 CYP families in humans

A 
□ CYP1
				□ CYP2
				□ CYP3
				□ CYP4
				□ 1-3 most important in human drug metabolism
				□ 4 metabolises fatty acids
37
Q

metabolism or renal clearance more important?

A

Metabolism is more important than renal clearance or bile

38
Q

2 CYP related properties of drugs that influencee clinical use of pharmaceuticals

A

CYP inducers and

CYP inhibitors

39
Q

induction of CYP450

A

◊ CYP expression can be increased by drugs and chemicals

40
Q

induction occurs via

A

◊ Usually occurs via drug receptors
} Xenosensors
} Bifunctional transcription factors
– After release from cytosol, act as tfs at CYP gene promoters
– Increased transcription o f CYP gene
– Increased CYP enzyme

41
Q
  1. CYP inhibitors (inhibition)
A
  • Common DDI mechanism (drug-drug interactions)
42
Q

2 main types of CYP inhibition

A

competitive and mechanism based

43
Q

◊ Competitive inhibition

A

} Occurs if 2 drugs compete for the same CYP isoform

} One drug inhibits the metabolism of the other

44
Q

Mechanism based inhibitors

A

} Drug forms a chemically reactive metabolite

} Attacks active site of CYP

45
Q

Grapefruit juice

A

◊ Contains furanocoumarin compounds which competitively inhibit gut CYP3A4 (not liver)
◊ Impair drug transport/excretion
◊ Affects drug with low oral availability

46
Q

2 examples of conjugative reactions

A

glucuronidation

sulfonation

47
Q

○ Glucuronidation

A

§ Very common reactions

§ Adds glucuronic acid (sugar) to a drug

48
Q

sulfonation

A

§ Forms sulfonate on a OH or NH2 group of drug

□ Enzyme is sulfotransferase

49
Q

type of drugs kidneys excrete

A

Excretes relatively small, water-soluble drugs and their metabolites into urine

50
Q

○ Three processess control levels of drugs and their metabolites in urine

A

glomerular filtration
passive diffusion
active transport

51
Q
  1. Glomerular filtration
A
  • Free (unbound) drugs in blood are filtered through pored in glomerulus (pass into ultrafiltrate)
52
Q
  1. Passive diffusion
A
  • Some drugs can passively diffuse back into blood (occurs for lipophillic and nonionised drugs)
53
Q
  1. Active transport
A
  • Energy-dependant transporters move drugs from blood into urine (at the proximal tubules)
54
Q

renal clearance =

A

active transport + glomerular filtration - passive diffusion

55
Q

bile formation

A

○ Bile forms in hepatocytes and is secreted into the canaliculi

		- Drains into bile duct then into duodenum (also stored in gall bladder) 
		- Biliary transporters eliminated large, polar molecules (inclduing drug conjugates) into the faeces

Pharmacology (14 decks)

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