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Pharmacology > PK: Drug Excretion > Flashcards

PK: Drug Excretion Flashcards

1
Q

2 ways drugs are eliminated

A

Metabolism

Excretion

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2
Q

Absorption vs elimination phase during the time post-ingestion

A
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3
Q

6 routes for drug excretion // elimination

A
  1. Renal
  2. Biliary/gastrointestinal
  3. Pulmonary
  4. Skin
  5. Mammary - drug delivery to baby
  6. Salivary - drug monitoring
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4
Q

Name 3 renal processes that account for renal drug excretion

A

Glomerular filtration

Active tubular secretion

Passive reabsorption across tubular epithelium

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5
Q

What passes through glomerular filtration

A

Molecules less than 20 kDa filtered i.e. enter filtrate

Protein bound drugs or not filtered (plasma albumin 68 kDa)

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6
Q

What is tubular secretion

What compounds does it apply to

MOA

A

Active carrier mediated elimination

secretory mechanisms for both acidic and basic compounds

can transport against electrochemical gradient and when the drug protein is bound

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7
Q

Describe reabsorption

What drugs does it apply to

A

Passive diffusion back across the tubular epithelium

Lipid soluble drugs with a high tubular permeability are excreted slowly

  • polar water soluble drugs remain in the urine
  • pH partitioning is relevant
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8
Q

Generally, what is renal excretion most important for

A

Low MW polar substances

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9
Q

GLOMERULAR FILTRATION

What drugs does it allow to cross

What is it affected by

What is GFR

A
  • Free drug in plasma (unbound) if use across capillary membrane into filtrate in Bowman’s capsule
  • Large drugs > 20,000 Da retarded
  • Not affected by pH or lipid solubility
  • GFR = 120ml/min (movement into Bowman’s capsule
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10
Q

ACTIVE TUBULAR SECRETION

What % of plasma is unfiltered in glomerulus

How are drugs transported to lumen

Give an example

A
  • 80% plasma is unfiltered in glomerulus
  • 2 carrier systems transport drugs to lumen
  • 1 carries acid drugs, other carries bases
  • Carried against electrochemical gradient
  • e.g. penicillin
  • Not dependent on PP binding
  • Carrier removes free drug and alters equilbrium
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11
Q

Give an example of competition with regard to active tubular secretion

A

Probenecid inhibits tubular secretion

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12
Q

What is reabsorbed in distal tubule

What is this reabsorption limited by

A
  • Water is greatly reabsorbed
  • 99% of filtered drug is reabsorbed passively
  • Lipophilic drugs cross passively - easily
  • Polar (metabolised) drugs stay in lumen and are excreted
  • Reabsorption is limited by pH trapping
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13
Q

Define renal clearance

A

Volume of plasma, containing amount of substance that is eliminated by the kidney per unit time

Cp = plasma conc

Cu = urinary conc

Vu = rate of urine flow

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14
Q

Variation in renal clearance for different drugs

A

< 1ml/min to theoretical max of 700 ml/min

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15
Q

How is the theoretical max of renal clearance measured

A

PAH clearance (nearly 100%)

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16
Q

How to know if a substance will be secreted or reabsorbed

A

Baseline renal clearance = f*GFR

If actual renal drug clearance is GREATER than f*GFR, the drug must be secreted

If actual renal clearance is LESS than f*GFR, it must be reabsorbed

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17
Q

What significantly limits the time course of action of the drug at its targets

A

Drug clearance

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18
Q

If hepatic blood flow is 800 ml/min and 10% of the drug is metabolised by hepatic enzymes with each passage through the liver, what will be the rate of clearance of the drug from the blood

A

80 ml/min of blood cleared of the drug

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19
Q

Define total body clearance

A

Sum of all the different clearance processes occurring for a given drug

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20
Q

What would a short half-life result from

A

Rapid metabolism

Rapid excretion

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21
Q

What would a long half-life result from

A

Extensive plasma protein binding

Slow metabolism

Poor excretion

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22
Q

IV vs oral administration

A
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23
Q

IV administration on a semilog plot

A
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24
Q

2 parameters Plasma t1/2 is determined by

A

Activity of metabolising enzymes or excretion mechanisms - clearance

Distribution of drug between blood into tissues - high Vd (drug mainly located in tissue) results in prolonged t1/2

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25
Q

As a general rule, what happens after 4 half lives

A

4 half lives after stopping drug, plasma conc will have fallen by 94%

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26
Q

First order vs zero order kinetics of elimination

A

1ST ORDER - constant proportion of drug is eliminated per unit time (majority of drugs)

0 ORDER - constant amount of drug is eliminated per unit time e.g. ethanol

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27
Q

Importance of t1/2

A

Helps to determine the time required to reach steady state with chronic dosing

Determines duration of action after a single dose (usually logarithmic)

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28
Q

How many half lives does it take to reach steady state

A

3-5 half lives

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29
Q

What is the importance of dosing frequency

A

Avoids large fluctuations in plasma conc during the dosing interval

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30
Q

How can the elimination half life help

A

WILL NOT help us understand the dose per day to administer but will help us decide how frequently to give the drug

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31
Q

Dosing frequency effects on drug plasma levels

A
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32
Q

Determination of steady state from plasma half life

A

4 half lives after starting drug plasma conc, steady state is reached

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33
Q

Why does it take 4-5 half lives to reach steady state

A
  • When a patient is taking a drug on a regular basis, there is an ongoing process of drug absorption and, concurrently, an ongoing process of drug removal with the drug’s metabolism and clearance
  • Eventually there comes a point when the amount of drug going in is the same amount of drug getting taken out => steady state
  • The average serum level in the 2nd dosing interval is (most likely) higher than that of the 1st dosing interval and this trend will continue
  • Around 4 x t1/2 - 5 t1/2 from the 1st dose has disappeared from the serum, there is no substantial difference in the average serum conc from dose N to the next dose => steady state
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34
Q

Infusion characteristics

A
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35
Q

How to ensure a drug will act almost immediately

A

Infusion and bolus dosing

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36
Q

What values are equal to each other @ steady state

A

Infusion rate = elimination rate

Clearance x plasma conc = elimination rate

Clearance x plasma conc = infusion rate

Clearance = infusion rate/plasma conc

ml/min = mg/min//mg/ml

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37
Q

Define therapeutic dosing

A

Seeks to maintain the peak plasma drug conc below the toxic conc and the trough drug conc above the minimally effective concentration (MEC)

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38
Q

Why is clearance important

A

Determines the maintenance dose rate to achieve Css (Conc of drug at steady state plateau)

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39
Q

At steady state, what is elimination rate equal to

A

Maintenance dose rate (DR)

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40
Q

At steady state, what is maintenance dose rate equal to

A

Elimination rate

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41
Q

Formula for maintenance dose rate (DR)

A

DR (mg/hr) = CL (L/hour) * Css (mg/L)

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42
Q

How is clearance measured

Formula for clearance

A

Many drugs are cleared by a combination of drug metabolism and renal excretion

Rate of excretion in urine and the blood conc at the same time

CL = U*V/P (U = urine drug conc, V = urine flow and P = plasma conc)

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43
Q

What is metformin used to treat

A

Type 2 diabetes

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44
Q

How does frequency affect drug conc

A
45
Q

Infliximab treats

A

Inflammatory bowel disease

46
Q

Lithium treats

A

Psychiatric disorders

47
Q

Aminoglycosides (vancomycin, gentamycin) are used to treat

A

Antibiotics to fight infection

48
Q

Describe the structure of the antibiotic gentamicin

How does this affect the way it is administered

A

Highly polar cation - poorly absorbed in the GI tract

Needs to be administered IV, because given orally the drug would not work

49
Q

Maintenance dose only VS loading and maintenance dose

A
50
Q

How are most drugs eliminated

A

By a first-order process

51
Q

Definition of steady state

A

Equilibrium point where amount of drug administered exatly replaces the amount excreted

52
Q

Define clearance

A

Represents the theoretical volume of blood which is totally cleared of drug per unit time

53
Q

Define t1/2

A

Time necessary for the concentration of drug in the plasma to decrease by half

54
Q

Why would a loading dose of drug be given

A

To achieve therapeutic drug concentration rapidly

55
Q

How can the inter-individual variability in responses to a drug be classified

A
56
Q

Internal factors as sources of variability

A

Age

Race & ethnicity

Sex

Prengnancy

Disease

Genetic polymorphisms of drug metabolism

57
Q

External factors as sources of variability

A

Drug-drug interactions

Diet

Environment influences on drug metabolism

58
Q

Effect of age on drug elimination

A

Drug elimination is less efficient newborn babies (and older adults)

  • relative lack of conjugating activity in the newborm

drugs commonly produce greater and more prolonged affects at the extremes of life

59
Q

Metabolism of chloramphenicol (eye infections)

Effect on baby

A

Metabolised to a toxic metabolite, which is normally conjugated and removed

In newborns to conjugation enzymes are not developed leading to toxic accumulation of the metabolite leading to pallor and cyanosis (grey baby syndrome)

60
Q

Why is morphine not used in labour

A

Can pass through the placenta

Therapeutic level for mother is toxic for baby

61
Q

What happens to our body composition as we age

A

Fat contributes to a greater proportion of body mass

62
Q

What effect might increased fat (as part of our body mass) have on drugs

A

Half life of lipid soluble drugs might increase (e.g. benzodiazepines)

63
Q

How does our GFR change as we age

What affects free plasma levels of drugs

A

GFR declines by 50% by 75, and closely correlates with decline in creatinine clearance

Doses may need to be adjusted over time for long-term medicines

General decrease in metabolic capacity, lower levels of albumin can affect free plasma levels of drugs

64
Q

Variation in drug consumption between older and younger people

A

Older adults typically consume more drugs than younger adults (polypharmacy), increasing the potential for drug-drug interactions

65
Q

How does sex impact plasma drug conc

A

Content of water and lipid varies between genders that will have an impact on plasma drug conc

e.g. ethanol

66
Q

How does pregnancy affect the drug disposition of the mother

A

Maternal plasma albumin levels are reduced - influences protein binding

Cardiac output, GFR and renal elimination are increased - potential increase of renal elimination of drugs

CYP2D6 is induced in pregnancy, leading to increased metabolism of certain drugs

67
Q

How does pregnancy affect the foetus

A

Most drugs that are uncharged with MW < 600 will traverse the placental barrier

In the foetus, drug metabolising capacity is very limited, and the kidneys are not efficient at eliminating drugs

68
Q

Effect of renal dysfunction

A

Impaired renal function can cause toxicity, as the drugs that are metabolised and/or renally eliminated will accumulate

69
Q

Effect of nephrotic syndrome

A

Oedema of intestinal mucosa and reduced plasma albumin binding

70
Q

Liver dysfunction (cirrhosis) and drug metabolism

A
  • Oxidative metabolism is impaired, affecting metabolism of benzodiazepines using this pathway e.g. diazepam
  • Drugs metabolised by glucuronidation (e.g. loraxepam, morphine) are NOT affected
  • Conversion of prednisone (prodrug) → prednisolone is reduced
71
Q

Drugs affected by liver cirrhosis and their route of metabolism

A

Diazepam - N-demethylation

Barbituates - oxidation

Methadone - oxidation

72
Q

Drugs NOT affected by liver cirrhosis and their routes of metabolism

A

Lorazepam - glucuronidation

Morphine - glucuronidation

Paracetamol - glucuronidation

73
Q

What do pharmaceutical companies avoid doing

A

Avoid development of a drug that is metabolised by a highly polymorphic enzyme

74
Q

What is a possible risk succynylcholine (muscle relaxant)

A

impaired enzyme that prolongs action, resulting in resp paralysis

75
Q

What is Isoniazid used to treat

What is its nickname

A

Anti-TB drug

Slow acetylator

76
Q

What is clopidrogel used to treat

What is it metabolised by

A

Anti-platelet drug - ischaemic heart disease treatment

A pro-drug metabolised by P4502C19 - some patients are deficient in this enzyme

77
Q

What enzyme is involved in metabolising 20% of drugs

In what populations is it functionally inactive

A

CYP4502D6

Functionally inactive in 8% of caucasians, 1% of Asians

(also G6PD deficiency)

78
Q

Where are dietary heterocyclic amines found

How are they activated

What do they cause

In what species are they present

A
  • BBQ, fry, roast
  • Activated by CYP1A2
    Cause colon tumours
  • Constitutively present in humans and rats but not monkeys
79
Q

How is Isoniazid (anti-TB) metabolised

In what populations are slow acetylators present

What proportion of people have fast acetylators

How does this affect the blood levels of ioniazid

A

Isoniazid is metabolised by N-acetyltransferase

45% of whites and blacks in the US have slow acetylators

> 90% of Asians and Inuits have fast acetylators

Blood levels of ioniazid are 4-6 times higher in slow acetylators than fast acetylators

80
Q

Isoniazid metabolism

A
81
Q

Why is codeine of no benefit to some people

A

Must be 0-demethylated for activation, by CYP2D6

82
Q

What enzyme metabolises 25% of all drugs

In what proportion is the inactive polymorphism of this enzyme present

A

CYP2D6

5-10% in European caucasians

< 2% in Southern Asians

83
Q

What sort of gene is associated with G6PD

What does it result in

What does it leave the person susceptible to

A

X-linked gene

G6PD confers partial resistance to malaria

Susceptible to haemolysis in response to oxidative stress, by exposure to dietary factors (broad/fava beans) or drugs (primaquine, nitrofurantoin)

84
Q

What does Abacavir treat

What side effect did some patients experience

Side affect is associated with…

What measure has now been introduced

A
  • A reverse transcriptase inhibitor effective in treating HIV infection
  • Some patients noted getting a severe rash
  • Susceptibility to this effect found to be closely related to a particular HLA variant
  • Testing for HLAB*5701 now standard of care for all patients before receiving Abacavir
85
Q

Give an example of hormones (proteins) used as drugs

A

Recombinant hormones

Therapeutic monoclonal antibodies (adalimumab, infliximab)

86
Q

What are thiopurine drugs (e.g. azathioprine) used for

A

Immunodilators in autoimmune diseases

e.g. inflammatory bowel disease, vasculitis

87
Q

Give an example of a thiopurine drug

A

Azathioprine

88
Q

What is azathioprine a prodrug of

What can azathioprine cause

What is the standard of care as a result

A

Mercaptopurine

Can cause bone marrow suppression if patients have low thiopurine-S-methyltransferase

TPMT testing is now the standard of care before starting treatment with a thiopurine

89
Q

Differences between conventional drugs and biopharmaceuticals

A
90
Q

What does trastuzumab do

A

A humanised monoclonal antibody that antagonises epidermal growth factor (EGF) by binding to one of its receptors

(Human EGF receptor-2: HER2)

91
Q

What are all breast cancers now tested for

What patients receive Trastuzumab

A

All breast cancer patients are now tested for overexpression of HER2

HER2 +ve patients receive Trastuzumab

HER2 -ve patients do not, because they would not benefit

92
Q

What was theralizumab (TGN1412) supposed to be a potential treatment for

A

B cell lymphoma

93
Q

Effect of atropine on the body

A

Inhibits gastric emptying, Ca2+ supplements and levothyroxine

94
Q

Name the inducers of microsomal enzymes

What are the consequences

A

Drugs e.g. barbituates, carbamazepine, ethanol

Environmental pollutants

Industrial chemicals

Food

A drug can increase its own metabolism, or that of a co-administered drug OR can result in the production of toxic levels of reactive drug metabolites

95
Q

What drugs inhibit tubular secretion

A

Probenecid and penicillin

96
Q

What effect do diuretics have

A

Increase reabsorption of lithium

97
Q

Difference in control and epileptic subjects when exposed to anticonvulsant medications

A
98
Q

What does enzyme inhibition result in

Give an example of an inhibitor of microsomal enzymes

A

Decreased metabolism of drugs that can allow the drug levels to reach toxic conc and prolong the presence of the active drug in the body

e.g. Ketoconazole (anti-fungal agent)

99
Q

What is alendronate used to treat

A

Parkinsons

100
Q

What is the systematic bioavailability of alendronate sodium

How does it change with the ingestion of food

Recommendation for its administration

A

0.75%

Absorption is further reduced by 40% when the drug is taken 1-2 hours before ingestion of food and by as much as 90% when taken up to 2 hours after food ingestion

Alendronate must be taken after overnight fast, at least 30 mins before food

101
Q

How does grapefruit juice affect drug metabolism

A

Psoralen derivatives and flavonoids inhibit P4503A4, decreasing first-pass metabolism of coadministered drugs e.g. statins

102
Q

How does cranberry juice affect drug metabolism

A

Inhibits CYP3A and CYP2C9

103
Q

How does St Johns Wort affect drug metabolism

A

Can induce P450 expression and thus increase metabolism of co-administered drugs

104
Q

How does cigarette smoke affect drug metabolism

A

Polycylic hydrocarbons can induce P450 enzymes

105
Q

Gentamicin -

ABSORPTION

A

Gentamicin is highly polar cation - poorly absorbed in GIT => needs IV

106
Q

Gentamicin - DISTRIBUTION

A

Protein binding < 30% => high Vd

High conc in renal cortex - risk of nephrotoxicity

Water soluble - dose based on lean body weight

107
Q

Gentamicin - EXCRETION

A

Hydrophilic - readily excretable

Urine - > 70% as unchanged drug

Half life depends on renal function, hence measuring renal function is very important

108
Q

Ideal pharmacokinetics of a drug in development

A
  • Once daily, small dose required
  • well absorbed
  • small First pass effect
  • high absolute oral bioavailability
  • small/moderate protein binding
  • known correlation between plasma levels and effects
  • metabolites are not active or toxic
  • balanced clearance between liver and kidney

Pharmacology (23 decks)

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