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Introduction to Metabolism and Pharmacology > Pharmacokinetics - Metabolism and Excretion > Flashcards

Pharmacokinetics - Metabolism and Excretion Flashcards

1
Q

What is Excretion ?

A

The process by which a drug (unchanged) or its metabolite is removed from the body

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2
Q

Where does excretion primarily occur ?

A

In the kidneys (urine), but can take place in the biliary system (faeces), lungs (expired air), skin (sweat) , hair and breast milk

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3
Q

Excretion of drugs by the kidney is dependent on 3 main mechanisms:

A
  1. Glomerular filtration of unbound drug
  2. Active tubular secretion of drug transporters
  3. Tubular reabsorption by passive diffusion down the concentration gradient
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4
Q

The rate of drug elimination depends on ?

A

The balance between filtration, secretion and reabsorption

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5
Q

Excretion =

A

Filtration + Secretion - Reabsorption

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6
Q

Capillaries in the glomerulus allow drugs with a ?

A

Molecular weight (MW) <20kD to pass into the filtrate

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7
Q

Large molecules like heparin and drugs that bound to?

A

Protein (albumin ~68kDa) - like warfarin (98% bound) - cannot be filtered

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8
Q

What does the amount of filtered drug depend on ?

A

Renal blood flow, glomerular filtration rate and degree of drug binding to plasma proteins

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9
Q

What does the glomerular filtration rate vary on ?

A

It varies between individuals, the normal range is 110-130 ml/min

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10
Q

What happens to ~20% of the blood which enters the glomerulus is ? and what happens to the remaining ~80% ?

A

~20% of the blood which enters the glomerulus is filtered. The remaining 80% will pass on to the peritubular capillaries and possibly undergo tubular secretion in the proximal tubules

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11
Q

What is Tubular secretion ?

A

Transfers of molecules from peritubular capillaries to renal tubular lumen

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12
Q

Secretory mechanisms in the tubules are not ? but depend on ?

A

They are not drug specific. But depend on non-selective carrier systems (transporters):

  • Organic cation transporters (OCTs)
  • Organic anion transporters (OATs)
  • P-glycoprotein (an ABC transporter)
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13
Q

The carriers can be ?

A

Saturated, usually only occurs in drug interactions, where one drug competitively inhibits the secretion of another
E.g. probenecid competes with penicillin for OATs, reduces extraction ratio and prolongs action of penicillin

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14
Q

Explain Organic cation transporter (OCT) ?

A
  • Can only transport molecules DOWN an electrochemical gradient (passive transport)
  • Uniporters (only one substrate)
  • Substrates include histamine, morphine, pethidine
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15
Q

Explain Organic anion transporters ?

A
  • Can transport molecules against their gradient (active transport)
  • Use energy of Na+ gradient
  • Can therefore extract virtually all of a drug from the plasma
  • E.g. penicillin and p-aminohippuric acid (PAH) are almost completely extracted
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16
Q

OCT and OAT transporters ?

A

Transporters in the kidney

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17
Q

Explain Tubular reabsorption?

A

Only ~1% of the glomerular filtrate actually leaves the body, in the rest (~99%) is reabsorbed into the blood

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18
Q

Tubular reabsorption is the process by which ?

A

Solutes, drugs, metabolites and water are removed from the tubular fluid

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19
Q

These transport processes are mostly driven by ?

A

Passive diffusion in the distal tube

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20
Q

Lipid-soluble (hydrophobic) drugs are passively reabsorbed into ?

A

Plasma down the concentration gradient in the distal tube. They are extensively reabsorbed and poorly excreted

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21
Q

Polar/charged drugs are unable to ?

A

Be reabsorbed and are voided in urine

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22
Q

Hence metabolism of drugs to make them more ?

A

Polar increases renal excretion

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23
Q

Many drugs are either weak bases or acids and thus the pH of the filtrate can ?

A

Greatly influence the extent of tubular re-absorption for many drugs

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24
Q

When urine is alkaline, weak acid drugs will ?

A

Not be reabsorbed

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25
Q

Due to pH partitioning, acidic drugs are ?

A

Better excreted if urine is alkaline, and vice versa

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26
Q

These changes can be quite significant as urine pH ?

A

Can vary from 4.5 to 8.0 depending on the diet (e.g. meat can cause a more acidic urine) or drugs (which can increase or decrease urine pH)

27
Q

How can urine pH be increased or decreased ?

A

It can be increased by oral dose of sodium bicarbonate and decreased by dose of ammonium chloride

28
Q

What can this be useful to increase ?

A

Increase excretion in cases of overdose or poisoning with acidic or basic drugs

29
Q

Where are some drugs secreted from ?

A

Plasma to bile in liver (biliary system)

exceptions e.g. temoporfin (anticancer) - 99.9% excreted in faeces

30
Q

What are the mechanisms for drug excretion in bile ?

A

Mechanisms include OCTs, OATs and P-glycoprotein transport

31
Q

How does bile enter the duodenum ?

A

Via the hepatic duct

32
Q

Drugs can therefore be eliminated, how ?

A

In faeces (if they are not reabsorbed in gut)

33
Q

Glucuronide conjugates from?

A

Phase 2 metabolism are often secreted into bile

34
Q

Drugs entering the liver via ? may be what ?

A

Via the portal vein (from the intestine) or via the hepatic artery (from the general circulation) may be glucuronidated in the liver

35
Q

The glucuronide metabolite re-enters the intestine via?

A

The bile duct, destined to be excreted in faeces

36
Q

However, the glucuronic acid can be cleaved off by ?

A

β- glucuronidase produced by the bacteria in gastro-intestinal tract, re-forming the original drug can be reabsorbed

37
Q

This recycling traps ?

A

The drug in the body, and prolong drug action,

-E.g. steroid hormones, contraceptives, morphine, chloramphenicol

38
Q

Glomerular Filtration Rate (GFR) is used ?

A

To indicate renal function

39
Q

What is Glomerular Filtration rate ?

A

This is the volume of plasma filtered from the glomerular capillaries into the Bowman’s capsule per unit time

40
Q

Inulin is filtered but not ?

A

Secreted and reabsorbed

Inulin clearance = GFR

41
Q

Why is Inulin not used to measure GFR?

A

It is a plant polysaccharide and must be administered intravenously (IV) to achieve constant plasma levels

42
Q

What is Creatinine ?

A

An endogenous substance with inulin-like properties used instead

43
Q

What is the clinical application of Bioavailability (F) ?

A

Determines the amount of drug reaching the systemic circulation and therefore the amount at the site of action

44
Q

What is the clinical application of Volume of distribution (Vd)?

A

Determines the size of a loading dose

45
Q

What is the clinical application of Clearance (CL)?

A

Determines the maintenance dose

46
Q

What is the clinical application of Half-life (t½)?

A

Determines the amount of time needed to reach steady state plasma concentrations or eliminate the drug (4-5 t½)

47
Q

In order to have the desired therapeutic effect, a drug has to be ?

A

At a concentration within a certain therapeutic window/range

48
Q

What happens if the concentration are too high or too low ?

A

Too high concentration- toxic

Too low concentration- sub-therapeutic (not effective)

49
Q

What does single compartment model assume ?

A

The drug is in a single well-stirred compartment of volume Vd

50
Q

How is the dose Q administered ?

A

IV bolus injection

51
Q

Cp decreases exponentially over time, as the drug ?

A

Is metabolised and excreted

52
Q

Many drugs show this behaviour - ?

A

First-order kinetics

53
Q

Rate of elimination is directly proportional to ?

A

To the drug concentration

54
Q

Elimination half life defined as ?

A

The time taken for half of the drug to be eliminated

55
Q

Drugs with short half-lives reach steady state quickly but may require?

A

Frequent administration or continuous infusion to maintain a constant concentration in the body

56
Q

Drugs with a long half-life may require ?

A

A large ‘loading dose’ followed by smaller maintenance doses as they take longer to reach steady state

57
Q

If a drug is administered by intravenous (IV) infusion. Cp increases exponentially until it reaches a ? and at the end of drug administration ?

A

Steady state concentration, Css, where the rate of infusion is equal to the rate of elimination of the drug. At the end of drug administration, Cp decrease exponentially

58
Q

Drugs with long t½ may need a ? and what is this called ?

A

Larger initial dose in order to reach Css more quickly. This is called loading dose

59
Q

Loading dose given initially to ?

A

Reach Css

60
Q

A maintenance dose is then given to ?

A

Keep the plasma concentration at Css

61
Q

If a drug is give by means other than IV injection, what must be considered?

A

The absorption

62
Q

What does rate of absorption, Kabs , depend on ?

A

The drug and method of administration

63
Q

Faster Kabs causes ?

A

Causes faster increaser in Cp - drug reaches the effective concentration sooner

Introduction to Metabolism and Pharmacology (16 decks)

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