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F PHARM Flashcards

1
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

What is an ADR?

*LOB: Compare and contrast the characteristics of Types A and Type B ADRs

A

Adverse Drug Reaction

at the wrong dose/administration route all medicine have the potential to become toxic

**Undesirable effect of drug beyond its anticipated therapeutic effects **

WHO – ‘Noxious and unintentional drug effect’

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2
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

What is a type A ADR?

*LOB: Compare and contrast the characteristics of Types A and Type B ADRs

A
  • Pharmacological and most common
  • Consequence of drug action – predictable from knowledge of drug pharmacodynamics and pharmacokinetics
  • Often dose-dependent
  • Not usually life-threatening
  • Can be resolved by lowering dose or withdrawing treatment
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3
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

Examples of a type A ADR?

*LOB: Compare and contrast the characteristics of Types A and Type B ADRs

A

NSAIDS: GI bleeds, peptic ulcer, renal impairment, bronchospasm
- Due to COX inhibition, reduction of PGs

Diuretics: hypotension, dehydration, electrolyte changes
- Due to vasodilatation effects, excess fluid/electrolyte excretion

Opioids: vomiting, confusion, constipation, urinary retention, respiratory depression (overdose)
- Due to stimulation of opiate receptors

Insulin/Oral hypoglycaemic drugs: hypoglycaemia
- Due to poor control of blood glucose, excess glucose uptake, storage

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4
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

What is a type B ADR?

*LOB: Compare and contrast the characteristics of Types A and Type B ADRs

A
  • idiosyncratic or bizarre and Rare
  • Unrelated to known pharmacology of drug so difficult to predict
  • Not dose related
  • Often involves immune system and/or genetic abnormality
  • Can be fatal
  • Need to withdraw drug – do not use again
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5
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

Examples of Type B ADRs

*LOB: Compare and contrast the characteristics of Types A and Type B ADRs

A

**Hypersensitivity reactions
**
Can lead to anaphylaxis shock – life-threatening

Amoxicillin (broad-spectrum penicillin), Anti-convulsants

**Steven Johnson Syndrome **
Very severe, Very rare, Very difficult to predict
Linked to genetics, infections,
poor liver metabolism of drug metabolites

Flu like symptoms/high fever

Blistering of skin, mucous membranes
Skin falls off

<10% body affected – mortality of 5%
organ damage, blindness

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6
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

How do drugs induce hypersensitivity reactions?

*LOB: Compare and contrast the characteristics of Types A and Type B ADRs

A

Immunogenic penicilloyl hapten
Trigger immune response
Mast cells – release histamine
Anaphylaxis

Essentially an antidrug antibody

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7
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

How do ADRs occur due to chronic drug administration?

*LOB: Compare and contrast the characteristics of Types A and Type B ADRs

A

Some drugs must be taken long term, indefinitely

Corticosteroids for arthritis, Lupus, IBS
Long term ADRs
Balance required between benefits and risk

The overall dose increases its toxicity

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8
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

How can ADR be reduced?

*LOB: Compare and contrast the characteristics of Types A and Type B ADRs

A

Pharmacovigilance

Minor Type A reactions may be tolerable
e.g., Indigestion with NSAIDs

Continue to treat, and then treat the ADR with another drug
e.g., constipation with opiates, use laxatives

‘Accept’ more severe ADRs – risk vs potential therapeutic effect
e.g., alopecia with cytotoxic drugs (chemotherapy)

Be aware of vulnerable groups and drugs likely to cause interactions, know your pharmacology, particularly mechanisms of action of drugs, signalling pathways involved!!!

Good drug history essential, e.g., previous drug reactions

Keep up to date with drug info (e.g., BNF)

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9
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

What is Pharmacovigilance

*LOB: Outline different methods of reporting ADRs

A

Monitoring the safety of drugs

Enable clinician/patient to balance risk and reward
benefit should always exceed risk

Can lead to:
Drug withdrawal from market
Contraindication
Warnings given
Dose changes

Withdrawn drugs

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10
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

How are ADR reported?

*LOB: Outline different methods of reporting ADRs

A

Yellow card

Black triangle

Green form

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11
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

Pros and Cons of UK ADR reporting systems?

*LOB: Outline different methods of reporting ADRs

A
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12
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

Considerations for pharmacokinetics and ADR

*LOB: Outline considerations surrounding drug pharmacokinetics (cytochrome p450 inducers and inhibitors), drug interactions and ADRs

A

Changes in drug absorption, distribution, metabolism, excretion (ADME) lead to profound effects on drug action

Changing onset time, duration of action, plasma concentration -

Drugs can be Cytochrome P450 inhibitors or inducers

IE) Grapefruit juice - inhibit P450 (prevents breakdown of drugs) so higher circulation, higher dose.

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13
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

Why do you not give a beta-blocker to an asthmatic treated with salbutamol?

*LOB: Outline considerations surrounding drug pharmacokinetics (cytochrome p450 inducers and inhibitors), drug interactions and ADRs

A

Beta-2 receptors make up most of the pulmonary lung tissue
Beta blockers are competitive antagonists

Salbutamol is the first selective short-acting β2-agonist

Beta-blockers can precipitate bronchospasm and should therefore usually be avoided in patients with a history of asthma.

Beta blockers can inhibit the bronchodilatory effects of salbutamol

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14
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

Why should you not drink alcohol with diazepam?

*LOB: Outline considerations surrounding drug pharmacokinetics (cytochrome p450 inducers and inhibitors), drug interactions and ADRs

A

Both diazepam and ethanol can inhibit the central nervous system via the GABAa Receptor (GABAAR).

GABA is inhibitory. Increasing inhibition can result in sedation and hypnosis, relieve anxiety and muscle spasms, and reduce seizures

ALSO: chronic alcohol exposure results in CYP3A4 activation and diazepam is primarily metabolized via CYP2C19 and CYP3A4

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15
Q

Drug Safety and Drug Side Effects by Prof. Anthony Albert

Why caution taking warfarin with grapefruit juice?

*LOB: Outline considerations surrounding drug pharmacokinetics (cytochrome p450 inducers and inhibitors), drug interactions and ADRs

A

Grapefruit juice can** block the action of intestinal CYP450 and CYP3A4**, so instead of being metabolized, more of the drug enters the blood and stays in the body longer.

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16
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

What is drug absorption

Describe how key factors of speed of onset, convenience/compliance, bioavailability, and potential side effects govern drug route and absorption

A

The process by which unchanged drug gets from
site of delivery to the circulation

Medicines need to be absorbed
unless given directly into the circulation

Different routes of administration
present different barriers to absorption

Different routes of administration
result in different bioavailability and onset

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17
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

What is Bioavailability

Describe how key factors of speed of onset, convenience/compliance, bioavailability, and potential side effects govern drug route and absorption

A

: proportion of administered drug reaching the systemic circulation – 100% for drugs given i.v.

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18
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

What must be considered in delivering a drug?

Describe how key factors of speed of onset, convenience/compliance, bioavailability, and potential side effects govern drug route and absorption

A

Speed of onset

Convenience - oral or i.v.?

Bioavailability

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19
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

What are the routes of admission?

Describe how key factors of speed of onset, convenience/compliance, bioavailability, and potential side effects govern drug route and absorption

A

IV
IM
Subcut
Inhalation
Oral
Rectal
Vaginal

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20
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

What are the routes of admission?

Describe how key factors of speed of onset, convenience/compliance, bioavailability, and potential side effects govern drug route and absorption

A

IV
IM
Subcut
Inhalation
Oral
Rectal
Vaginal

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21
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

Define Transcellullar and Paracellular

Describe how key factors of speed of onset, convenience/compliance, bioavailability, and potential side effects govern drug route and absorption

A

Absorption requires drugs to cross biological barriers
(layers of cells with semi-permeable, lipophilic membranes)

Most absorption occurs through cells, some occurs between cells

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22
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

Absorption can occur by:

transport

Describe how key factors of speed of onset, convenience/compliance, bioavailability, and potential side effects govern drug route and absorption

A

Active transport through cells (very few medicines)
Facilitated diffusion through cells (few medicines)
Passive diffusion (most medicines)

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23
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

What is Fick’s Law

Describe how key factors of speed of onset, convenience/compliance, bioavailability, and potential side effects govern drug route and absorption

A
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24
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

\_\_\_\_\_\_ and \_\_\_\_\_\_ are key determinants of drug permeability

*Describe how acidic and basic drugs use ion trapping for drug absorption and retaining drugs in interstial and intracellular spaces

A

Lipid solubility and Ionization

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25
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

Why are Unionised drugs (AH or B) are absorbed more easily across membranes?

*Describe how acidic and basic drugs use ion trapping for drug absorption and retaining drugs in interstial and intracellular spaces

A

non-ionised drugs generally have higher lipid solubility, which makes them more permeable across lipid-rich cell membranes.

The cell membrane is primarily composed of lipids, and non-ionised drugs can diffuse through the lipid bilayer more easily than ionized drugs.

non-ionized drugs can more easily penetrate cell membranes.

Lipid solubility is influenced by the polarity of a substance

The degree of polarity in a drug molecule can impact its interaction with the lipid bilayer. Generally, less polar (more lipid-soluble) drugs have an advantage in terms of absorption.

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26
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

REMINDER: What are Acids and Bases?

*Describe how acidic and basic drugs use ion trapping for drug absorption and retaining drugs in interstial and intracellular spaces

A
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27
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

Henderson-Hasselbalch equations predict extent of ionisation

*Describe how acidic and basic drugs use ion trapping for drug absorption and retaining drugs in interstial and intracellular spaces

A

pKa = pH when drug is 50% ionised

Acidic drugs: more unionised the more acidic the environment

Basic drugs: more unionised the more basic the environment

The rate of disociation will be the same as the proportion of protons when 50% of the drug is ionised?

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28
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

Example - Absorption of aspirin at the gastric mucosa

*Describe how acidic and basic drugs use ion trapping for drug absorption and retaining drugs in interstial and intracellular spaces

A

Aspirin is weak acid (acetylsalicyclic acid)

In the stomach where pH=1it is unionised
(Acidic drugs: more unionised the more acidic the environment )
This lets it pass through the cell membrane.
When it passes to the circulation, pH =7.2
So it is ionised.

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29
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

Why are basic drugs poor for oral administration?

*Describe how acidic and basic drugs use ion trapping for drug absorption and retaining drugs in interstial and intracellular spaces

A

Basic drugs are absorbed less efficiently in the stomach because they accept protons from the stomach acid and become polar, they cant enter.

30
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

How does ion trapping work?

*Describe how acidic and basic drugs use ion trapping for drug absorption and retaining drugs in interstial and intracellular spaces

A
  • Acidic drugs in stomach stay unionised
  • This means they can be absorbed
  • But when absorbed, the pH is less acid (neutral) so they become polar. (pKa=pH so 50% ionised)
  • Because they are polar they cant cross the phospholipid bilayer
  • And stay in circulation.
31
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

How does ion trapping apply to excrection?

*Describe how acidic and basic drugs use ion trapping for drug absorption and retaining drugs in interstial and intracellular spaces

A

Similar principles of ion trapping apply to the renal excretion of drugs
**urine is alkaline **

Basic drugs stay unionised in basic fluids

Acidic drugs are trapped in their ionised form and cannot be reabsorbed

Remember glomerular filtration is only about ion size not polarity.

32
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

Can basic drugs be given orally?

*Describe how acidic and basic drugs use ion trapping for drug absorption and retaining drugs in interstial and intracellular spaces

A

Yes – unless very basic or permanently ionised

Absorbed poorly in stomach
Absorbed better from the intestine (pH 6.6-7.5)
High surface area in the intestine

33
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

What are The Lipinski Rules

*Outline the Lipinski rules, and how they govern druglikeness

A

An orally-active drug likely has no more than one violation of the following:

Molecular weight < 500 Da
No more than 5 H-bond donors
No more than 10 H-bond acceptors
Log P < 5 (partition coefficient)

This does not predict pharmacodynamics, only ADME

While optimizing ADME properties, there might be a trade-off with desirable. For example, optimizing one aspect, like receptor binding, may lead to minimizing other desirable properties.

34
Q

FPHARM: Pharmacokinetics 1: Drug Absorption by Prof Antony Albert

What is druglikeness?

*LOB: Outline the Lipinski rules, and how they govern druglikeness

A

The concept of “druglikeness” is introduced, which refers to the likelihood that a compound will be a successful drug.

Molecular weight < 500 Da (Daltons)

No more than 5 hydrogen bond donors

No more than 10 hydrogen bond acceptors

Log P < 5 (partition coefficient

35
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is the aim of good therapeutics?

*Outline and compare zero- and first-order drug kinetics

A

The aim of good therapeutics is to deliver medicines to their site of action at effective concentrations

In multiple-dose therapy, the aim is to keep
these levels as stable as possible

36
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is the aim of good therapeutics?

*Outline and compare zero- and first-order drug kinetics

A

The aim of good therapeutics is to deliver medicines to their site of action at effective concentrations

In multiple-dose therapy, the aim is to keep
these levels as stable as possible

37
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

Most drugs obey first-order kinetics. What is first-order kinetics?

*Outline and compare zero- and first-order drug kinetics

A

A constant fraction of drug is removed -> constant clearance

Time to remove the drug is independent of dose
(if you increase [dose] the same fraction of drug is removed)

constant half-life

38
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

A few drugs obey zero-order kinetics. What is zero-order kinetics?

*Outline and compare zero- and first-order drug kinetics

A

A constant amount of drug is removed (not fraction)

The bigger the dose the longer the time to remove it

39
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What are examples of zero- and first-order drugs?

*Outline and compare zero- and first-order drug kinetics

A

zero
Ethanol, Phenytoin, Salicylates, Cisplatin, Fluoxetin, Omeprazol.

first
others

40
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is saturation?

*Outline and compare zero- and first-order drug kinetics

A

Saturable processes involved in drug elimination

Remember enzymes, transporters in the liver and kidneys involved in metabolism and excretion work at a maximum/saturable level

Drugs may accumulate very quickly – dosing regimes

41
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is bioavailability?

*Outline what is biovailability, volume of distribution, half-life, and plasma clearance

A

Bioavailability refers to the fraction of an administered dose of a drug that reaches systemic circulation in an unchanged form.

It is typically expressed as a percentage and can vary depending on the route of administration (e.g., oral, intravenous, subcutaneous).

42
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is half life?

*Outline what is biovailability, volume of distribution, half-life, and plasma clearance

A

Half-life is the time it takes for the concentration of a drug in the bloodstream (or plasma) to decrease by half.
It is an important pharmacokinetic parameter that helps determine the dosing interval of a drug

Driven by clearance and volume of distribution

43
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is plasma clearance?

*Outline what is biovailability, volume of distribution, half-life, and plasma clearance

A

Describes activity of metabolising enzymes/excretion mechanisms

Volume of plasma cleared of drug per time (ml/min)

A constant for 1st order reactions (constant half-life, t1/2)

44
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is the average Vascular & Extravascular space?

*Outline what is biovailability, volume of distribution, half-life, and plasma clearance

A

Vascular space 4 L
Extravascular space 6 L

45
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is volume of distribution?

*Outline what is biovailability, volume of distribution, half-life, and plasma clearance

A

Total amount of drug / [Plasma] = Apparent volume of distribution (Vd)

e.g., 20 mg i.v. dose and 2 mg / L drug in plasma -> V = 10 L

Indicates the extent of distribution for a drug

Clinically important for adjusting dosage

Influenced by lipid/water solubility, binding to plasma proteins, where distributed (e.g., muscles etc.)

46
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What Pharmacokinetic Parameters modulate drug Distribution

*Outline and compare zero- and first-order drug kinetics

A

Volume of distribution (Vd)

Half-life (t1/2)

Clearance (CL)

Bioavailability (F)

47
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is bioavailability?

*Outline what is biovailability, volume of distribution, half-life, and plasma clearance

A

Fraction of drug in circulation compared to dose
Measures extent of absorption

Calculated by: Equal oral/iv doses, measure AUC oral / AUC iv
e.g., oral dose, F = 0.1 (10% bioavailability)

48
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

Most drugs obey first-order kinetics. What is first-order kinetics?

*Outline and compare zero- and first-order drug kinetics

A

A constant fraction of drug is removed -> constant clearance

Time to remove the drug is independent of dose
(if you increase [dose] the same fraction of drug is removed)

constant half-life

49
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

Low bioavailability is caused by

*Outline how steady-state plasma drug concentration may be achieved using different dosing regimens and loading doses depending on half-life of drug

A

Poor absorption
Chemical reactions at site of delivery
First-pass metabolism

50
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

Choice of route guided by

*Outline how steady-state plasma drug concentration may be achieved using different dosing regimens and loading doses depending on half-life of drug

A

Bioavailability
Chemical properties of drug
Convenience
Need to control specificity of action
Desired onset/duration/offset of action

51
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

Choice of route guided by

*Outline how steady-state plasma drug concentration may be achieved using different dosing regimens and loading doses depending on half-life of drug

A

Bioavailability
Chemical properties of drug
Convenience
Need to control specificity of action
Desired onset/duration/offset of action

52
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is Dosing Regimens

*Outline how steady-state plasma drug concentration may be achieved using different dosing regimens and loading doses depending on half-life of drug

A

Multiple dosing leads to a ‘steady state’
Dose before drug falls to zero

[Drug] variation depends on half-life and dose interval

53
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is a steady state?

*Outline how steady-state plasma drug concentration may be achieved using different dosing regimens and loading doses depending on half-life of drug

A

Idea of dosing regime is to balance:

Dosing rate = Rate of elimination

Dosing rate = Plasma Clearance (CL) x Drug

**Dosing rate x bioavailability (F) = CL x Target [Drug]
**

54
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

What is a loading dose?

*Outline how steady-state plasma drug concentration may be achieved using different dosing regimens and loading doses depending on half-life of drug

A

For drugs with long half-lives achievement of steady state
can be accelerated by a loading dose
followed by smaller maintenance dose

55
Q

F:PHARM Pharmacokinetics 2: Drug Distribution

How is a steady state achieved?

*Outline how steady-state plasma drug concentration may be achieved using different dosing regimens and loading doses depending on half-life of drug

A
  • Repeated doses of drug eventually produce a steady [Drug]
  • Time to plateau is 4-5 x drug half-life
  • When dose is changed a new plateau is reached in 4-5 half-lives
  • Steady state levels are not actually flat
  • Fluctuation size is inversely proportional to the number of daily doses
  • Fluctuations create the potential for sub-therapeutic treatment or toxicity
  • For drugs with long half-lives achievement of steady state can be accelerated by a loading dose
  • Important considerations when prescribing
56
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

What is metabolism?

*Describe the two phases of drug metabolism and outline the role of cytochrome P450 enzymes

A

Removal of lipid-soluble drug molecules
to prevent reabsorption by kidneys

Achieved by converting drugs into water-soluble molecules

Mostly in the liver, but also in plasma, lung and intestinal epithelium

57
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

What is Excretion?

*Describe the two phases of drug metabolism and outline the role of cytochrome P450 enzymes

A

Removal of drug/metabolites from the body

Mostly in urine, but also via bile/faeces, sweat, tears, saliva, exhaled air & milk

58
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

Why is Drug Metabolism & Excretion Important?

*Describe the two phases of drug metabolism and outline the role of cytochrome P450 enzymes

A
  • Metabolism / clearance determine the amount of drug
    available at site of action
  • Time taken for a drug to reach steady state levels
  • Metabolism produces new chemical entities that may have their own effects
59
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

What is Excretion?

*Describe the two phases of drug metabolism and outline the role of cytochrome P450 enzymes

A

Removal of drug/metabolites from the body

Mostly in urine, but also via bile/faeces, sweat, tears, saliva, exhaled air & milk

60
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

What happens to metabolised drugs?

*Describe the two phases of drug metabolism and outline the role of cytochrome P450 enzymes

A

Loss of (or reduced) biological activity
Increase polarity produces less receptor binding

Potential for toxic metabolites

Some drugs are “activated” by metabolism (prodrug)
e.g., enalapril (ACEi) into active form enalaprilat by esterases
Some drugs eliminated unchanged, e.g., digoxin

61
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

Metabolism Phase 1 introduces ___________

*Describe the two phases of drug metabolism and outline the role of cytochrome P450 enzymes

A

Phase 1 introduces chemically reactive groups

  • Oxidation in the liver
  • Addition of oxygen molecules to carbon, nitrogen, sulphur in drug structure
  • Carried out by cytochrome P450 enzymes
  • Bind drug + molecule oxygen
  • Other reactions : hydrolysis, hydration etc.
    *
62
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

Metabolism Phase 2 increases ___________

*Describe the two phases of drug metabolism and outline the role of cytochrome P450 enzymes

A

water solubility of drug for excretion
Conjugates the Phase 1 product with an endogenous substance through production of stable covalent bonds

63
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

Paracetamol skips Phase _________ ?

*Describe the two phases of drug metabolism and outline the role of cytochrome P450 enzymes

A

Phase 1
Paracetamol metabolism – direct Phase 2 reactions

64
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

The kidney’s role is to …

*Describe the role of the kidney in drug excretion: glomerular filtration, tubular reabsorption and tubular secretion mechanisms

A
  • excretes polar (charged) drugs more readily than non-polar (uncharged) drugs
  • Non-polar (uncharged drugs) can be reabsorbed by kidney back into plasma

drug elimination changes with age, renal disease

65
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

How does the glomerulus filter drugs?

*Describe the role of the kidney in drug excretion: glomerular filtration, tubular reabsorption and tubular secretion mechanisms

A

Drug may/may not bind to albumin
Glomerular capillaries allow drugs of MW < 20kDa to be filtered freely, but not when bound on albumin (albumin MW ~ 68kDa)

Anti-coagulant drug warfarin 98% bound to albumin : 2% into filtrate
Thi

66
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

How are drugs passive tubular reabsorbed

*Describe the role of the kidney in drug excretion: glomerular filtration, tubular reabsorption and tubular secretion mechanisms

A

Reabsorption of H2O increases [Drug] in tubular filtrate

This increases drug concentration gradient for reabsorption back into blood plasma from filtrate

Urinary pH is an important determinant of passive reabsorption of drugs

Uncharged or unionised drugs are (lipophilic) so Cross lipid membrane

Alkaline Urine: Weak acids wont reabsorb and are excreted

67
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

How are drugs excreted from the Tubular?

*Describe the role of the kidney in drug excretion: glomerular filtration, tubular reabsorption and tubular secretion mechanisms

A

This occurs mainly in the proximal convoluted tubule

Cation transporter e.g., Morphine
(weak base, proton acceptor at physiological pH)

Anion transporter e.g., Penicillin
(weak acid, proton donor at physiological pH)

Transporter are non-specific
Bind any cationic/anionic drug

(as they are

Competition can occur between drugs at these transporters

68
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

Factors Affecting Drug Metabolism & Excretion

*Describe the role of the kidney in drug excretion: glomerular filtration, tubular reabsorption and tubular secretion mechanisms

A

Age
Cyto P450 activity reduced in neonates/elderly
GFR reduced greatly in neonates/elderly
Increased % fat content in elderly (change vd)

Genetics
45% in Europe & USA; 80-90% Asians fast acetylators
1/3000 slow metabolism by pseudocholinesterase

Drug metabolising enzymes
Induced by other drugs or lifestyle factors
Inhibited by other drugs or lifestyle factors

Disease
Liver disease impairs drug metabolism - drug toxicity
Renal disease may alter pharmacokinetics

69
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

When do you Monitor drug concentration

*Describe the role of the kidney in drug excretion: glomerular filtration, tubular reabsorption and tubular secretion mechanisms

A

For drugs that have a narrow therapeutic index

To individualise therapy

To confirm adherence of therapy

To diagnose toxicity

To determine the presence of other drugs before starting therapy

As part of post-marketing surveillance
to detect drug-drug interactions

70
Q

F:PHARM Pharmacokinetics 3: Drug Metabolism and Elimination

Describe the role of drug metabolism in paracetamol overdose

*Describe the role of drug metabolism in paracetamol overdose

A

the majority of paracetamol is metabolized to N-acetyl-p-benzoquinone imine (NAPQI)

NAPQI decreases the liver’s glutathione and directly damages cells in the liver

Under normal conditions, NAPQI is detoxified by conjugation with glutathione to form cysteine and mercapturic acid conjugates.

But in high concentrations or in liver damage NAPQI cannot be conjugated for excretion.

71
Q

How does ionisation, polarity and pH mean absorption changes?

A

The ionization state of a molecule also affects its polarity. Ionized forms are typically more polar than their non-ionized counterparts.
Weak acids and weak bases, depending on the environmental pH, can exist in ionized or non-ionized forms. Non-ionized forms are often more lipid-soluble and, therefore, more readily absorbed.

Med 2 Life Control (4 decks)

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