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pharmacology > principles of pharmacokinetics > Flashcards

principles of pharmacokinetics Flashcards

1
Q

What is pharmacodynamics?

A

The biochemical, physiological, and molecular effects of a drug on the body.

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2
Q

What is pharmacokinetics?

A

The fate of a chemical substance administered to a living organism.

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3
Q

Why is pharmacokinetics important in clinical practice?

A

It helps determine:

  • How quickly a drug reaches its site of action and response time.
  • Likelihood of drug interactions.
  • Need for dose adjustments in disease states (e.g., organ impairment, sepsis).
    Required monitoring.
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4
Q

pharmacokinetics 4 processes

A
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5
Q

What is drug absorption?

A

Transfer of a drug molecule from the site of administration to systemic circulation.

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6
Q

How do barriers to absorption vary?

A

Barriers vary depending on the route of administration.

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7
Q

Which administration routes deliver 100% of the dose to systemic circulation?

A

IV (intravenous) and IA (intra-arterial).

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8
Q

What must happen for drugs given by other routes to reach systemic circulation?

A

They must cross at least one membrane.

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9
Q

Name some common drug administration routes.

A
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10
Q

What are the main mechanisms for drug permeation across cell membranes?

A
  1. Passive diffusion through hydrophobic membranes.
  2. Passive diffusion through aqueous pores.
  3. Carrier-mediated transport.
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11
Q

What type of drugs use passive diffusion through hydrophobic membranes?

A

Lipid-soluble molecules.

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12
Q

What type of drugs use passive diffusion through aqueous pores?

A

Very small water-soluble drugs (e.g., lithium).
most drug molecules are too big for this route.

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13
Q

How does carrier-mediated transport work?

A

Proteins transport specific substances like sugars, amino acids, neurotransmitters, trace metals, and some drugs.

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14
Q

What does “hydrophilic” mean?

A

Water soluble = poor lipid solubility.

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15
Q

What does “hydrophobic” mean?

A

Lipid soluble = poor water solubility.

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16
Q

Can lipid-soluble molecules diffuse through cell membranes?

A

Yes, they can diffuse along the concentration gradient.

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17
Q

Can water-soluble molecules diffuse through cell membranes?

A

No, they must be transported via alternative mechanisms.

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18
Q

Why do ionised drugs have poor absorption?

A

Ionised drugs have poor lipid solubility, making them poorly absorbed.

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19
Q

What are most drugs classified as in terms of ionisation?

A

Most drugs are weak acids or weak bases with ionisable groups.

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20
Q

What determines the proportion of drug ionisation?

A

The pH of the aqueous environment.

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21
Q

Which form of a drug can pass through cell membranes?

A

Unionised drugs can diffuse through cell membranes.

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22
Q

Why is oral drug administration popular?

A

It is convenient and cost-effective.

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23
Q

What is the major site of drug absorption in the body?

A

The small intestine.

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24
Q

What are two main factors affecting oral drug absorption?

A
  1. Barriers to the drug being absorbed into systemic circulation.
  2. The stomach, which absorbs some drugs but poses barriers to others reaching the small intestine.
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25
Q

Why does the stomach pose a challenge for some drugs?

A

It can hinder drug delivery to the small intestine where absorption is more efficient.

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26
Q

What are some patient factors affecting oral drug absorption?

A
  • Food (a full stomach slows absorption).
  • Gastric motility (can be altered by drugs or disease).
  • Previous surgery (e.g., gastrectomy).
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27
Q

How can gastric enzymes affect drugs?

A

They can digest certain drugs, especially peptides and proteins (e.g., insulin, biologics like ‘mab’ drugs).

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28
Q

How does stomach pH affect drug absorption?

A

Low pH can degrade certain drugs (e.g., benzylpenicillin).

A drug’s pKa affects the balance of ionised vs unionised forms, influencing absorption.

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29
Q

What is pKa in relation to drug molecules?

A

The pH at which 50% of drug molecules are ionised and 50% are unionised.

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30
Q

Where are weak acids like aspirin best absorbed?

A

In the stomach (low pH).

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31
Q

Where are weak bases best absorbed?

A

In the intestine (higher pH).

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32
Q

What form of a drug crosses the gut wall more easily?

A

The unionised form.

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33
Q

What are some patient factors affecting oral drug absorption?

A

Intestinal motility (altered by drugs or disease).
Previous surgery (e.g., short bowel, ileostomy).
Malabsorption (e.g., cystic fibrosis, coeliac disease).

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34
Q

What are some drug factors affecting oral absorption?

A
  1. Lipid solubility: lipid-soluble drugs are readily absorbed.
  2. Molecule size: very large molecules cannot be absorbed.
  3. Medicine formulation:
    * Tablet/capsule coating delays release.
    * Modified release formulations slow absorption.
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35
Q

What additional factors affect oral drug absorption?

A

Drugs as substrates for p-glycoprotein.
Drugs subject to first-pass metabolism.

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36
Q

What are P-glycoproteins (P-gp)?

A

Drug transporter proteins widely distributed in the body.

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37
Q

What is the function of P-glycoproteins in drug absorption?

A
  1. Excrete toxic substances (including drugs) out of cells.
  2. Reduce absorption of exogenous substances in the GI tract.
  3. Mediate the efflux of drugs/toxins from intestinal mucosa into the intestinal lumen.
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38
Q

Are all drugs substrates for P-glycoproteins?

A

No, not all drugs are substrates.

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39
Q

Name some examples of P-gp substrates.

A

Rivaroxaban, digoxin, tacrolimus.

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40
Q

What is first-pass metabolism?

A

Drug metabolism that occurs in the liver or intestinal wall before the drug reaches systemic circulation.

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41
Q

What factors limit the proportion of a drug reaching systemic circulation?

A

Biologic activity near the absorption site.
Degradation by enzymes in the intestinal wall.
Metabolism via liver enzymes after absorption into the hepatic portal vein.

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42
Q

How can first-pass metabolism be avoided?

A

By using routes that bypass splanchnic circulation, such as rectal or sublingual administration.

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43
Q

Does the degree of first-pass metabolism vary between individuals?

A

Yes, it can vary significantly.

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44
Q

What is bioavailability?

A

The proportion of an administered dose that reaches systemic circulation.

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45
Q

What factors affect bioavailability?

A
46
Q

Is bioavailability affected by the rate of absorption?

A

No, it is not affected by absorption rate.

47
Q

Why are dose adjustments needed when switching formulations?

A

Different formulations have varying bioavailability (e.g., digoxin: tablet = 63%, oral solution = 70%, IV injection = 100%).

48
Q

What are the pros and cons of the rectal (PR) route of administration?

A

Pros: Local administration, avoids first-pass metabolism, useful for nausea/vomiting.
Cons: Variable absorption, patient preference.
Example: Diazepam suppositories for epileptic seizures.

49
Q

What are the pros and cons of the inhaled (Inh) route of administration?

A

Pros: Well-perfused large surface area, local administration.
Cons: Effectiveness depends on inhaler technique.
Examples: Gaseous anaesthetics, salbutamol inhalers for asthma.

50
Q

What are the pros and cons of the subcutaneous (S/C) route of administration?

A

Pros: Faster onset than oral, rate of absorption can be controlled by formulation.
Cons: Not as rapid as intravenous.
Examples: Long-acting insulins for T1 and T2DM.

51
Q

What are the pros and cons of the transdermal (TD) route of administration?

A

Pros: Continuous drug release, avoids first-pass metabolism.
Cons: Suitable only for lipid-soluble drugs, slow onset of action.
Example: Fentanyl patches for chronic pain.

52
Q

What are less common routes of administration?

A

Intramuscular, buccal, vaginal, topical, nasal, ocular, intrathecal, intraperitoneal, intra-arterial, intraosseous.

53
Q

What are the four compartments in the body where drugs can distribute?

A

Plasma
Interstitial fluid
Intracellular fluid
Fat

54
Q

How do drugs move between compartments?

A

Drugs travel from the plasma to interstitial fluid, intracellular fluid, and fat, and can move back depending on their properties.

55
Q

What drug factor affects distribution between compartments?

A

Molecule size.

56
Q

How does molecule size affect drug distribution?

A

Small molecules = increased distribution.
Large molecules = reduced distribution.

57
Q

How does lipid solubility affect drug distribution?

A

Hydrophilic drugs: Reduced distribution.
Lipophilic drugs: Increased distribution.

58
Q

How does protein binding affect drug distribution?

A

Increased protein binding: Decreased distribution.
Decreased protein binding: Increased distribution.

59
Q

What is the volume of distribution (Vd)?

A

Theoretical volume in which a drug is distributed in the body (apparent volume of distribution).

60
Q

What does a high volume of distribution (Vd) indicate?

A

The drug is well distributed in the body.

61
Q

What does a low volume of distribution (Vd) indicate?

A

The drug is poorly distributed and mainly stays in the plasma.

62
Q

What does Vd represent in terms of plasma?

A

The volume of plasma needed to contain the total administered dose.

63
Q

What is the blood-brain barrier (BBB)?

A

A membrane that separates foreign substances in the blood from the CNS, formed by a layer of endothelial cells with tight junctions.

64
Q

What does the BBB do?

A
  1. Maintains a stable environment and protects the brain.
  2. Challenges drug delivery to CNS conditions.
  3. Removes water-soluble molecules using efflux pumps.
65
Q

What are ways for drugs to reach the CNS?

A
  1. High lipid solubility: E.g., lipophilic psychiatric drugs with a large Vd.
  2. Intrathecal administration: E.g., baclofen for MS or chemotherapy.
  3. Inflammation: Makes the BBB leaky.
66
Q

When can the BBB be advantageous?

A

In preventing drug entry, e.g., naloxegol for opioid-induced constipation.

67
Q

What should you consider when dosing drugs with a small Vd in obese patients?

A

Use ideal body weight for drugs like aciclovir, which are not distributed to fat.

68
Q

How do disease states affect drug distribution?

A

Sepsis: Leaky blood vessels increase distribution and BBB penetration.
Liver impairment: Hypoalbuminaemia reduces protein binding.

69
Q

How does age affect drug distribution?

A

Smaller Vd for water-soluble drugs in elderly patients.
Leads to higher plasma concentrations—caution is required.

70
Q

What is a potential side effect of drugs crossing the BBB?

A

CNS side effects are more likely.

71
Q

Why is aciclovir dosing adjusted in obese patients?

A

Aciclovir has a small Vd (0.7L/kg), is not distributed to fat, and is dosed based on ideal body weight.

72
Q

What is drug elimination?

A

The process by which a drug becomes unavailable to exert its effect on the body.

73
Q

What are the two components of drug elimination?

A

Metabolism: Modification of chemical structure to form a new chemical entity (metabolite).
Excretion: Removal of unchanged drug (hydrophilic, polar molecules).

74
Q

What happens in Phase 1 of drug metabolism?

A

Oxidation, reduction, or hydrolysis introduces a reactive group to the chemical structure.

75
Q

What happens in Phase 2 of drug metabolism?

A

Conjugation of a functional group produces a hydrophilic, inert molecule.

76
Q

Which enzymes are responsible for most Phase 1 metabolism?

A

Cytochrome P450 (CYP450) enzymes.

77
Q

Where are CYP450 enzymes primarily located?

A

Mostly in the liver, with extrahepatic locations like the small intestine and lungs.

78
Q

How do lipophilic, unbound drugs interact with hepatocytes?

A

They readily cross the hepatocyte membrane.

79
Q

What does Phase 1 metabolism produce?

A

Reactive metabolites by creating or unmasking reactive functional groups.

80
Q

What factors affect CYP450 enzyme function?

A

Genetic variation.
Reduced function in severe liver disease.
Interactions with drugs or food, which can reduce or increase enzyme activity.

81
Q

How many CYP450 enzymes are there?

A

57 CYP450 enzymes.

82
Q

Which CYP450 enzymes are most significant for drug metabolism?

A

CYP3A4, CYP2C9, CYP2C19, CYP1A2, CYP2D6.

83
Q

What are some drugs metabolised by CYP1A2?

A

Caffeine, paracetamol, theophylline, warfarin.

84
Q

What are some drugs metabolised by CYP2C9?

A

Ibuprofen, warfarin.

85
Q

What are some drugs metabolised by CYP2C19?

A

Omeprazole, phenytoin.

86
Q

What are some drugs metabolised by CYP2D6?

A

Codeine, warfarin.

87
Q

What are some drugs metabolised by CYP3A4?

A

Simvastatin, warfarin, DOACs (e.g., apixaban, rivaroxaban), carbamazepine, diltiazem.

88
Q

What is Phase II metabolism?

A

Conjugation of an endogenous functional group (e.g., glycine, sulfate, glucuronic acid) to produce a non-reactive, polar (hydrophilic) molecule.

89
Q

What is the purpose of Phase II metabolism?

A

To create hydrophilic metabolites that can be renally excreted.

90
Q

Can you give an example of Phase II metabolism?

A

Aspirin is metabolised into salicylic acid (Phase I), which is then conjugated to glucuronide in Phase II for excretion.

91
Q

What is a pro-drug?

A

A pharmacologically inactive drug that is converted into an active compound in vivo by enzymatic or chemical transformation.

92
Q

What are the benefits of pro-drugs?

A

Improved pharmacokinetic profile.
Delivery of active drug to the intended site of action.
Minimisation of side effects.

93
Q

Give an example of a pro-drug and its activation.

A

Cyclophosphamide:

  • Activated by CYP hepatic enzymes.
  • Used as a cytotoxic and immunosuppressant drug with limited GI toxicity.
94
Q

How is codeine activated in the body?

A

Codeine is a pro-drug activated to morphine by the CYP2D6 enzyme.

95
Q

What are the effects of CYP2D6 activity levels on codeine metabolism?

A
96
Q

What factors should be considered in severe liver impairment for drug metabolism?

A
97
Q

What role do CYP450 enzymes play in drug interactions?

A

CYP450 enzyme induction/inhibition can affect drug metabolism, leading to interactions.

98
Q

What is the consequence of metabolic pathway saturation?

A

Saturation can lead to drug or metabolite accumulation, causing toxicity.

99
Q

In what forms can drugs and metabolites be excreted?

A

Liquids: Urine, bile, sweat, tears, breast milk (small, polar molecules).
Solids: Faeces via biliary excretion (large molecules).
Gases: Volatiles via expired air.

100
Q

What is the most significant route of drug excretion?

A

Through urine via the kidneys.

101
Q

What is the first process in renal drug excretion?

A

Glomerular filtration:

20% of plasma is filtered.
Only free/unbound drug molecules are filtered.
Very large molecules are excluded.

102
Q

What does glomerular filtration exclude?

A

Very large molecules.

103
Q

What is the second process in renal drug excretion?

A
104
Q

Which transport systems are involved in active tubular secretion?

A
  • Organic anion transporter (OAT) and organic cation transporter (OCT).
105
Q

What is the third process in renal drug excretion?

A

Passive reabsorption:

  • Drugs diffuse down the concentration gradient from the tubule into peritubular capillaries.
  • Hydrophobic drugs diffuse easily.
  • Highly polar drugs are excreted.
106
Q

How do hydrophobic and polar drugs behave in passive reabsorption?

A

Hydrophobic drugs: Diffuse easily.
Polar drugs: Excreted.

107
Q

What role do kidneys play in drug elimination?

A

Kidneys excrete drugs and drug metabolites (both active and inactive).

108
Q

What happens when kidney function is reduced?

A

Accumulation and toxicity of renally cleared drugs can occur.

109
Q

What is gentamicin, and how is it eliminated?

A
  • An aminoglycoside antibiotic for gram-negative bacteria.
  • 90% excreted unchanged in urine.
110
Q

Why is serum monitoring important for gentamicin?

A
  • To prevent nephrotoxicity and ototoxicity.
  • Gentamicin is often avoided in severe renal impairment.
111
Q
A

E) Highly lipid soluble

Explanation:
Lorazepam, like other benzodiazepines, is highly lipid soluble. This property allows it to readily cross the blood-brain barrier and exert its effects on the central nervous system, making it effective for managing symptoms like alcohol withdrawal.

pharmacology (7 decks)

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