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PHAR2210 > Drug Excretion > Flashcards

Drug Excretion Flashcards

1
Q

Drug metabolism

A

chemical transformation of a drug
into one or more products within the body

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2
Q

Drug excretion refers

A

solely to the physical processes that lead to the irreversible removal of a drug and its metabolites from the body

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3
Q

Drug metabolism and drug excretion =

A

Drug elimination

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4
Q

Drug elimination is

A

The removal of drug from the body through metabolic and/or excretory processes

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5
Q

A.D.M.E

A

Absorption
Distribution
Metabolism
Excretion

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6
Q

Drug elimination made up of

A

Drug metabolism (75%) mediated by CYP450
and
Drug excretion

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7
Q

Routes of Drug excretion

A

urine (kidneys)
faeces (bile)
breast milk - minor route and can pass from mother to baby
expired air (lungs)
hair
skin/sweat

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8
Q

Do hydrophilic drugs require hepatic metabolism

A

No

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9
Q

Factors that influence renal excretion (7)

A
  1. Molecular weight and size
  2. Drug concentration
  3. Urine pH
  4. Plasma protein binding
  5. Rena; blood flow
  6. Impaired renal Function
  7. Transporters
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10
Q

What types of drugs reduce renal function

A

non-steroidal and anti-immflamible drugs

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11
Q

3 types of renal excretion

A

Glomerular Filtration
Passive reabsorption
Active tubular Secretion

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12
Q

Glomerular Filtration

A

20% of renal plasma flow is filtered thru glomerular capillaries (GFR=120mL/min and declines due to aging or disease)
- Only small and free drugs can pass thru glomerular capillaries into the filtrate
-altered plasma protein binding can influence filtration

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13
Q

What is can influence glomerular filtration

A

-altered plasma protein binding can influence filtration

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14
Q

GFR

A

Glomerular filtration rate

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15
Q

Fu fraction of drugs ___ in plamsa

A

Unbound

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16
Q

Fu Equation

A

Cl(gf) = fu * GFR

renal clearance by glomerular filtration

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17
Q

Estimated GFR (eGFR) - measure blood____ level

A

creatinine

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18
Q

Impaired renal function →

A

blood creatinine level ↑

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19
Q

[2]Passive reabsorption

A
  • most filtrate returns to circulation through peritubular capillaries (1% becomes urine)
  • Water reabsorption → drug concentration ↑ in the filtrate
    • passive diffusion - small, lipophilic and unionised drugs
  • transporter-mediated (e.g., PEPT2 and peptide-like drugs)
  • urine pH affects drug ionisation and reabsorption
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20
Q

Peritubular capillaries

A

Peritubular capillaries are tiny blood vessels in your kidneys. They filter waste from your blood so the waste can leave your body through urine (pee). Peritubular capillaries also reabsorb nutrients your body needs to work properly, such as minerals.

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21
Q

Urine pH affects drug ionisation and___

A

reabsorption

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22
Q

Salicylate overdose facts

A
  • Aspirin or methyl salicylic acid (e.g., infant teething gels)
  • i.v. sodium bicarbonate (an alkalinising agent) injected intravenously.
  • ↑ urine pH
  • ↑ salicylic acid ionisation
  • ↓ reabsorption of salicylate
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23
Q

Salicylate overdose explain

A

Sodium bicarbonate (administered intravenously) increases the pH of the blood. By raising the blood pH, sodium bicarbonate facilitates the ionisation of salicylic acid, converting it into a less toxic form, salicylate ions.

By increasing urine pH, sodium bicarbonate facilitates the conversion of salicylic acid into its ionized form, which is more readily excreted in urine.

24
Q

Only what type of molecules can cross cell membranes (Ion ro Union)

A

Unionised

25
Q

Active tubular secretion

A

Peritubular capillaries→ the tubular lumen
- occurs predominantly in proximal tubules
- mediated by transporters

26
Q

Basolateral membrane and its transporters

A

the cell membrane which is oriented away from the lumen of the tubule

Solute carrier (SLC) transporters
liver-specific OATP1B1/1B3 - uptake of drugs and metabolites into hepatocytes

27
Q

Apical membrane and its transporters

A

cell membrane which is oriented towards the lumen

ATP-binding cassette (ABC) transporters
efflux transporters - eliminate large and polar
molecules into bile

28
Q

Lumen

A

The lumen is the space within the body’s tracts, tubes, cavities, and cells

29
Q

solute carrier (SLC) transporters

A
  • SLC22A6 - OAT1 (organic anion transporter 1)
  • SLC22A8 - OAT3 (organic anion transporter 3)
30
Q

ATP-binding cassette (ABC) transporters

A
  • ABCB1 - MDR1 (multidrug resistance protein 1) or P-gp (P-glycoprotein)
  • ABCC2 - MRP2 (multidrug resistance-associated protein 2)
  • ABCG2- BCRP (breast cancer resistance protein)
31
Q

MDR1

A
  • large lipophilic cationic compounds
  • neutral compounds
    multidrug resistance protein 1
32
Q

Transporter-mediated active secretion (basolateral membrane)

A

OAT1 and OAT3
* overlapping substrate specificity

33
Q

Transporter-mediated active secretion (OAT1/3-mediated drug excretion)

A

e.g., cephalexin (a drug of the cephalosporin class)
- mostly excreted unchanged via urine
- glomerular filtration and active tubular secretion
- drug-drug interaction: probenecid* (an OAT1/OAT3
inhibitor; pharmacokinetic enhancer) co-administration
- Cmax
- AUC

34
Q

Hepatobiliary excretion

A

hepatocytes produce and secrete bile
- stored in the gallbladder
- drained into bile duct then duodenum
drug excreted into bile
- glucuronides are concentrated in bile

35
Q

drug metabolising enzymes produce ___ ____

A

conjugated metabolites

36
Q

Basolateral membrane transporters:

A

e.g., liver-specific OATP1B1/1B3 - uptake of
drugs and metabolites into hepatocytes

37
Q

Apical membrane transporters:

A

efflux transporters - eliminate large and polar molecules into bile

38
Q

Enterohepatic recirculation

A

Lipophilic drugs (e.g., morphine) undergo absorption
↓
hepatic metabolism
↓
conjugates excreted into bile
↓
glucuronides in the GI tract
[hydrolysed by ß-glucuronidase
(expressed by GI bacteria)]
↓
generate unconjugated drug
↓
Back to Lipophilic drugs (e.g., morphine) undergo absorption

39
Q

Enterohepatic recirculation Morphine

A

hydrolysed by ß-glucuronidase
(expressed by GI bacteria)
↓
Morphine back to parent drug
↓
reabsorbed to systemic circulation
↓
Prolonged effects of morphine and long half-life

40
Q

Breast milk as a minor route of drug excretion

A

Most drugs enter breast milk via passive diffusion
- can be important for lipophilic and basic drugs (breast milk is slightly acidic)
[Slides]

41
Q

Individual variation in drug response definition

A

individual variation in drug response refers to differences in response between individuals to the same
dose of a drug

42
Q

Individual variation in drug response: intrinsic factors

A

genetics, age, sex, disease status or physiological conditions such as pregnancy

43
Q

Individual variation in drug response: extrinsic factors

A

concomitant medications, diet and exposure to chemicals and other environmental causes

44
Q

single nucleotide polymorphism (SNP)

A
  • e.g., drug metabolising enzymes
    • common and clinically important
    • CYP SNPs
      -CYP2D6 is most polymorphic
45
Q

Drug clearance definition

A

Drug clearance refers to the efficiency of drug elimination, defined as the ratio of the elimination rate (e.g., mg∙h-1) to the concentration of drug in plasma
(e.g., mg∙L-1)

46
Q

Drug clearance

A
  • the volume of plasma that would be completely cleared of drug per unit time (e.g., L∙h-1)
  • total body clearance = hepatic clearance + renal clearance + clearance by other routes OR
  • clearance by a specific organ;
    renal clearance = glomerular filtration + active secretion - reabsorption
47
Q

fe- the fraction of administered drug
excreted ____ in the urine

A

unchanged

48
Q

Drug clearence
dose adjustment due to impaired renal or
hepatic functions

A
  • renal impairment - eGFR
  • hepatic impairment - Child-Pugh score
49
Q

Hepatic clearance influence fe

A

low fe
lots of hepatic metabolism and metabolites are excretede

50
Q

renal clearance influence fe

A

high fe
little or no hepatic metabolism and the parent drug is eexcreted

51
Q

Determine total body clearance

A

Slides

52
Q

Drug bioavailability definition

A

Drug bioavailability (F) is the fraction of administered dose of the parent drug that reaches the systemic circulation

53
Q

If a drug is administered intravenously what is the bioavailability of the drug in a fraction or %

A

1 or 100%

54
Q

Drug bioavailability

A
  • intravenously administered drug bypasses absorption and first-pass metabolism - F = ?
  • drug administered by other routes - F is between 0 (or 0%) and 1 (or 100%)
55
Q

Drug bioavailability Equations on slides

A

Drug elimination last slide

56
Q

Probenecid

A
  • (an OAT1/OAT3
    inhibitor; pharmacokinetic enhancer) co-administration. Will increase:
  • Cmax
  • AUC

PHAR2210 (23 decks)

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