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Mechanism of Drug Action > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

What is the equation for total plasma concentration of drugs (C)?

A

C = Cfree + Cbound

Cfree = Free drugs in plasma

Cbound = Drugs bound to plasma proteins

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2
Q

What is the most abundant drug binding plasma protein?

A

Albumin

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3
Q

What factors determine total amount of drugs in the body?

A
  1. Absorption
  2. Distribution
  3. Elimination
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4
Q

What are the different routes of drug administration?

A
  1. Intravenous (infusion/injection)
  2. Intramuscular/subcutaneous injection
  3. Transdermal absorption
  4. Inhalation
  5. Sublingual/buccal absorption
  6. Rectal absorption
  7. Oral administration
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5
Q

What are the numbers of barriers that need to be crossed by drug in order to reach blood for each route of administration?

A
  1. Intravenous (infusion/injection) - 0
  2. Intramuscular/subcutaneous injection - 1 (endothelium)
  3. Transdermal absorption - 2 (skin epithelium, endothelium)
  4. Inhalation - 2 (lung epithelium, endothelium)
  5. Sublingual/buccal administration - 2 (mucosal epithelium, endothelium)
  6. Rectal administration - 2 (mucosal epithelium, endothelium)
  7. Oral administration - 2 (gut epithelium, endothelium)
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6
Q

What are the advantages of intravenous injections/infusions?

A
  1. Quick absorption and minimum delay for effect
  2. Control: Can be immediately stopped and started when required.
  3. Accuracy: Rate of administration directly relates to plasma concentration (due to 100% bioavailability)
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7
Q

What are the disadvantages of IV administration?

A
  1. Irreversible
  2. Great skill for administration
  3. Infusion requires special equipment
  4. Inconvenient
  5. Risk of infection
  6. High initial concentration straight after injection
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8
Q

What factors affect rate of absorption from intramuscular/subcutaneous injection?

A
  1. Concentration of drug at site of injection:
    - Amount of drug injected
    - Water solubility of drug (if drug precipitates, concentration remains constant as long as precipitate remains)
    - Rate of absorption
  2. Blood flow:
    - Type of tissue (muscle > skin)
    - Physiological state (temperature, exercise…)
  3. Lipid solubility of drug
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9
Q

What are the advantages of IM/SC injection?

A
  1. Absorption is slow and prolonged
  2. Large amounts can be administered with less fear of overdose
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10
Q

What are the disadvantages of IM/SC injection?

A
  1. Inconsistent, unpredictable rate of injection
  2. Painful
  3. Risk of infection
  4. Absoprtion can be very slow (if drug precipitates)
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11
Q

What factors determine rate of transdermal absorption?

A
  1. Lipid solubility of drug
  2. Blood flow to skin
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12
Q

What are the advantages of transdermal absorption?

A
  1. Slow and prolonged absorption
  2. Avoids first pass metabolism in liver
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13
Q

What are the disadvantages of transdermal absorption?

A
  1. Very slow
  2. Highly variable rate of absorption
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14
Q

What factors determine rate of inhalation absorption?

A
  1. Lipid solubility of drug
  2. Concentration of drug
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15
Q

What are the advantages of sublingual/buccal absorption?

A
  1. Rapid onset
  2. Avoids first pass metabolism
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16
Q

What are the disadvantages of sublingual/buccal absorption?

A
  1. Bad taste
  2. Small surface area of absorption
  3. Washing away by saliva
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17
Q

What are the advantages of rectal absorption (suppositories)?

A
  1. Avoids first pass metabolism
  2. Can be used in patients who are persistently vomiting
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18
Q

What are the disadvantages of rectal absoprtion?

A
  1. Slow
  2. Variable rate of absorption
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19
Q

What are the factors influencing rate of absorption by oral administration?

A
  1. Availability of drug
    - Rate of dissolution

> Dosage form (tablet or sugar syrup)

> Particle size

  • Food in gut
  • Pathological state (e.g. diarrhoea, vomiting)
    2. Permeability of drug
  • Ionisation

> Gut pH

> Drug pKa

  • Lipid solubility of drug
  • Size of water-soluble drug particles
    3. Surface area of gut epithelium (small intestines have the greatest SA)
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20
Q

How does the pH of environment and pKa of drug affect rate of absorption?

A
  • Drugs that are weaks acids absorb well in acidic environments (stomach, pH = 1)
  • Drugs that are weak bases absorb well in neutral environments and basic environments
  • Small intestines absorb all types of drugs well due to high SA
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21
Q

What is an important class of drugs absorbed from the stomach?

A

Tetracyclines

22
Q

How can the stomach secrete drugs?

A

Weak base drugs diffuse into gastic fluid from blood and become protonated and trapped.

23
Q

What is bioavailability?

A

The fraction of dose given that is absorbed and reaches systemic circulation

24
Q

What factors influence oral bioavailability?

A
  1. Inability to cross gut epithelium
  2. Active transport out of gut epithelial cells
  3. Metabolism of drug in gut epithelium
  4. First pass metabolism
25
Q

What factors affect volume of distribution (Vd)?

A
  1. Plasma protein binding: Decreases Vd below ECF
  2. Sequestration in tissue (e.g. fat): Increases Vd above ECF
26
Q

How can drugs be sequestered into tissue?

A
  1. Partition (e.g. fat)
  2. Adsorption (e.g. bone, muscle)
27
Q

What factors affect the distribution of drugs?

A
  1. Binding to plasma protein: Restricts drugs to plasma compartment
  2. Sequestration into tissues: Removes drug from plasma and prevents action
  3. Tissue perfusion: Better perfused tissues contain more drugs
  4. Barriers to movement: Restricts drugs to certain compartments in body
  5. Disease states
28
Q

What affects presence barriers of movement in distribution of drug?

A
  1. Physical barrier surrounding a tissue
  2. Lipid solubility of drug
  3. Presence of transporters for drug
29
Q

What are the ways in which drug action can be terminated?

A
  1. Redistribution
  2. Metabolism
  3. Elimination
30
Q

What are the common routes of excretion?

A
  1. Liver → Bile
  2. Kidneys → Urine
  3. Lungs → Lungs
31
Q

Why are drugs more commonly metabolised first before being excreted?

A

Most drugs are too lipophilic to be excreted directly from kidneys. Metabolism converts drug into more hydrophilic form.

32
Q

What are the 2 phases of drug metabolism?

A
  1. Phase 1 (Functionisation): Creation of reactive group in preparation for conjugation
  2. Phase 2 (Conjugation): Attachment of chemical group to drug to make it more polar
33
Q

What types of reactions occur during phase 1 metabolism?

A
  • Oxidation
  • Reduction
  • Hydrolysis
34
Q

What groups are attached to drug molecules in conjugation reactions?

A
  • Glucuronyl
  • Sulfate
  • Methyl
  • Acetyl
  • Glycine
  • Glutathione
35
Q

Which group of enzymes are responsible for metabolism of majority of drugs?

A

Cytochrome P450 enzymes (in liver)

36
Q

What are the common features of CYP enzymes?

A
  • Contains haem group
  • Has peak absorbance at 450nm when bound to carbon monoxide in reduced form
  • Found on smooth ER and so only act intracellularly on lipophilic drugs
37
Q

Which phase of drug metabolism is the rate-limiting phase and why?

A
  • Phase 2
  • Conjugating groups are not widely available in body
38
Q

What types of proteins mediate secretion of drugs from the liver?

A

P-glycoproteins

39
Q

What are the factors that create individual variation in drug metabolism?

A
  1. Age (reduced in neonates and elderly)
  2. Sex
  3. Pathology (mainly liver, e.g. hepatitis)
  4. Genetics
  5. Drug interactions
40
Q

What is induction of metabolism?

A
  • Repeated administration of drugs causes increased expression of CYP enzymes mediating their activation
  • Increases rate of metabolism and elimination to cause tolerance
41
Q

How can drugs inhibit CYP enzymes?

A

Complexing with heme group (e.g. imidazole-containing drugs (azole antifungals) or erythromycin)

42
Q

What criteria must drug satisfy for induction/inhibition to be significant?

A
  1. Concentration must be therapeutically critical
  2. Induction/inhibition must change clearance substantially
43
Q

What are the variables that affect rate of renal secretion?

A
  1. Rate of filtration
  2. Rate of reabsorption
  3. Rate of secretion
44
Q

What is the equation for rate of renal filtration for drugs that are freely filtered?

A

Rate of filtration = GFR x [Drug]Plasma

45
Q

What drugs are freely secreted from the kidneys?

A

Aminoglycoside antibiotics

46
Q

How can rate of renal tubular reabsorption be decreased?

A
  1. Making drug molecule more polar
  2. Changing urine pH to promote formation of ionised form of drug
47
Q

Why are most drugs not efficiently excreted from the kidneys?

A
  • Low rate of filtration due to plasma protein binding
  • High rate of reabsorption due to being lipophilic
48
Q

What is the equation for rate of excretion for drug that is freely filtered, not reabsorbed and not secreted?

A

Rate of excretion = GFR x [Drug]Plasma

49
Q

What is the equation for rate of excretion for drug that is may be reabsorbed, secreted and not freely filtered?

A

Rate of excretion = Urine flow rate x [Drug]Urine

50
Q

What are the types of drug elimination kinetics?

A
  • Zero-order: Rate of elimination is independent of [Drug]Plasma
  • First-order: Elimination is directly proportional to [Drug]Plasma
51
Q

When is zero-order elimination observed?

A

When drug elimination requires enzyme (metabolism) and enzyme is saturated.

52
Q

When is first-order elimination observed?

A
  1. When drug is eliminated via non-saturable route (e.g. kidneys)
  2. When drug is eliminated by enzyme, but enzyme is not saturated (Km of enzyme >> [Drug]Plasma)

Mechanism of Drug Action (28 decks)

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