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S1 Pharmacology > Principles Of Metabolism And Excretion > Flashcards

Principles Of Metabolism And Excretion Flashcards

1
Q

Role of the Liver in Pharmacokinetics

A
  • Liver is prime site of drug metabolism
    • Ultimate elimination organ
    • Responsible for pre-systematic
    elimination (First-Pass Effect)
    • Most drugs are metabolised in the liver
    • Metabolism primarily involves cytochrome P450 enzymes (CYP450), located in hepatocytes
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2
Q

What is drug metabolism?

A
  • Enzymatic modification of a molecule’s chemical structure
  • often targeting xenobiotics but may also involve endogenous molecules.
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3
Q

What is the primary purpose of metabolism ?

A
  • to make fat soluble chemicals water soluble
    • Pathways for excretion generally require water solubility (e.g., urine, bile, faeces)
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4
Q

What are two key concepts in drug removal by the liver?

A
  • Hepatic Clearance (CLH) and Hepatic Extraction Ratio (EH)
  • Drug metabolising enzymes present in almost all tissues but most abundant in liver
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5
Q

Why are lipid-soluble drugs poorly excreted in urine?

A
  • Lipid-soluble drugs are poorly excreted in urine because they are stored in adipose tissue or circulate until they are converted to water-soluble metabolites.
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6
Q

Where are water soluble drugs excreted ?

A
  • more readily excreted in the urine.
    • May be metabolised, but not generally by CYP enzymes
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7
Q

How do drugs administered intravenously (IV), transdermally (TD), or subcutaneously (SC) enter the body?

A
  • Drugs administered IV, TD, or SC enter systemic circulation directly, reaching target organs before undergoing hepatic modification.
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8
Q

How are oral drugs absorbed and delivered to the liver?

A
  • Oral drugs are absorbed in the GI tract and delivered to the liver via the portal vein.
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9
Q

What is the first-pass effect?

A
  • liver metabolizing drugs before they reach systemic circulation, reducing their bioavailability.
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10
Q

What is the bioavailability implication of drugs with extensive first-pass metabolism?

A
  • require a larger oral dose than an equivalent IV formulation to achieve the same effect
  • as more drug is metabolized in the liver before reaching systemic circulation.
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11
Q

What is the bioavailability implication of drugs with low first-pass metabolism?

A
  • Drugs with low first-pass effect (theophylline, phenytoin, diazepam) require similar or only slightly higher oral doses compared to when given i.v.
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12
Q

Can drugs with no first-pass effect still have low bioavailability?

A
  • Yes, drugs with no first-pass effect can still have low bioavailability due to factors like poor absorption, limited solubility, or rapid elimination.
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13
Q

Which routes allow drugs to avoid the first-pass effect?

A
  • Sublingual and rectal routes allow drugs to bypass the liver’s first-pass metabolism
  • leading to more drug reaching systemic circulation.
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14
Q

What happens to most metabolic products of drugs?

A
  • Most metabolic products of drugs are less pharmacologically active than the parent compound.
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15
Q

Important exceptions:

A
  • Where the metabolite is more active, such as pro-drugs (e.g. terfenadine)
    • Where the metabolite is toxic (e.g. paracetamol)
    • Where the metabolite is carcinogenic
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16
Q

Why is there a close relationship between drug metabolism and normal biochemical processes in the body?

A
  • often involves enzymes and pathways designed for endogenous compounds like steroid hormones, cholesterol, and bile acids
  • which can also metabolize drugs that resemble natural substrates.
17
Q

What do Phase I reactions do to a drug?

A
  • convert the parent compound into a more polar (hydrophilic) metabolite
  • by adding or unmasking functional groups like -OH, -SH, -NH2, -COOH, making it easier for excretion.
18
Q

What is the outcome of Phase II reactions in drug metabolism?
.

A
  • involve conjugation with endogenous substrates (e.g. glucuronide, sulfate, acetate, amino acids)
  • to increase the drug’s aqueous solubility, often making the metabolite inactive
19
Q

What is the role of Phase III in drug metabolism?

A
  • Phase III involves transmembrane transport, where efflux of metabolites, and sometimes the unchanged parent drug, occurs to remove substances from the cells.
20
Q

What is the role of Phase III in drug metabolism?

A
  • Phase III involves transmembrane transport, where efflux of metabolites, and sometimes the unchanged parent drug, occurs to remove substances from the cells.
21
Q

What happens during oxidation reactions in drug metabolism?

A
  • oxygen is incorporated into the drug, often leading to the loss of part of the drug and making it more polar for easier excretion.
22
Q

What enzyme system is primarily responsible for oxidation reactions in drug metabolism?

A
  • The Cytochrome P450 enzyme
23
Q

Phase II Reactions

A

• Glucuronidation by UDP-Glucuronosyltransferase:(-OH, -COOH, -NH2, SH)

24
Q

What is elimination ?

A
  • Is any process involved in the excretionof drugs from the body/ removal of drugs from the body
25
Q

What is elimination ?

A
  • Is any process involved in the excretionof drugs from the body/ removal of drugs from the body
26
Q

What are some minor elimination routes for drugs?

A
  • exhalation (for anesthetic gases),
  • sweat,
  • saliva
  • breast milk
27
Q

Major elimination routes

A
  • Kidney
    • Liver
28
Q

How does excretion occur through lungs kidney and liver ?

A
  • Kidney = Excretion via urine
  • Liver = Excretion via bile (faeces)
  • Lung = Excretion via air
29
Q

What is the role of filtration in renal drug elimination?

A
  • Filtration in the kidneys allows only free (unbound) drugs to pass through the Bowman’s capsule
  • meaning albumin-bound drugs cannot be filtered
  • If albumin can be measured in the urine -> indicator for kidney disease
30
Q

How does reabsorption affect drug elimination in the kidneys?

A
  • Usually substances like glucose and amino acids are reabsorbed
    • No hydrophilic drugs get reabsorbed whereas lipophilic drugs do
    • Metabolism makes a drug more water-soluble to prevent reabsorption
    • A change in pH and charge prevent reabsorption (= ion trapping)
31
Q

4 stages of renal drug elimination

A
  • filtration
  • reabsorption
  • secretion
  • excretion
32
Q

What is CLrenal ?

A
  • Renal clearance is the volume of plasma per unit time that gets filtered of a drug
    • Unit: volume over time (mL/min) or (L/h)
  • CLrenal does not provide information about the amount of drug cleared
  • but the rate of elimination (ROE) indicates how much drug is eliminated
33
Q

What is the equation for ROE ?

A
  • ROE (mg/min) = CLrenal × C, where C is the plasma concentration of the drug
34
Q

Two terms that are very closely associated with CLrenal are….

A
  • Glomerular Filtration Rate (GFR)
    • Creatinine Clearance (CLcreatinine)
35
Q

How does lower GFR affect ROE ?

A
  • GFR is an indicator of kidney function, and a lower GFR means less drug is eliminated (↓ ROE)
36
Q

What is biliary excretion ?

A
  • Excretion through the faeces
37
Q

What is Biliary secretion ?

A
  • active secretion of endogenous and exogenous
    drugs/substances from the hepatocytes in to the bile and duodenum
38
Q

Pharmacokinetic Half-life

A
  • Half-life is individual and constant for each drug
  • Follows first order elimination rate
  • Half-life time determines the dose and the dosing interval
  • > 95% of the drug is excreted always after 5 half-life times (t1/2)
39
Q

Phase I reactions

A
  • Oxidation

S1 Pharmacology (33 decks)

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