Pharmacokinetics 2 Flashcards
Describe the two phases of metabolism in the liver
Phase 1:
• Generally oxidation, reduction or hydrolysis
- Introduce/reveal a reactive chemical group
• Products are often more reactive
Phase 2:
• Synthetic, conjugative reactions
• Makes it more hydrophilic (transport more dependent on carrier transport which is more selective, so more likely to get rid of it), inactive compounds generated
What are the functions of cytochrome P450 enzymes?
- Biosynthesis of steroids, fatty acids and bile acids
* Metabolism of endogenous and exogenous substrates
What are cytochrome P450 enzymes?
Mixed function monooxygenases
• Throughout the body, extensively in the liver
• Phase 1 metabolism enzymes
• They can be induced or inhibited
Where does metabolism mainly occur?
The liver
Which drugs are eliminated more readily?
Hydrophilic over lipophilic (except in the lungs)
What are the possible sources of excretion?
- Breath
- Urine
- Saliva
- Perspiration
- Feces
- Milk
- Bile
- Hair
What is the most important organ involved in the elimination of drugs and their metabolites?
The kidneys
What are the factors that can affect pharmacokinetic parameters?
- Age
- Sex
- Pregnancy
- Body weight
- Genetic variability
- Diet
- Disease
- Other medications
- Ethnicity
Describe the onset, duration and metabolism of vecuronium
Onset: medium
Duration: medium
Metabolism: Liver- eliminated via the urine and bile
Describe the onset, duration and metabolism of atracurium
Onset: medium
Duration: medium
Metabolism: Spontaneous degradation in the plasma
Describe the onset, duration and metabolism of mivacurium
Onset: Fast
Duration: Short
metabolism: Plasma cholinesterase
Describe enterohepatic recirculation of drugs
• Hydrophobic drug molecule enters the liver
(• Hydrophilic metabolite)
• Conjugate form of the drug
• Passes out in the bile
• Travels to the intestine
• De-conjugation and re-uptake
• Re-enters the liver and in conjugate form
• Repeats
- Increases the duration of action
- Dependent on gut biota
- Become less effective if on antibiotics
Describe the metabolism of paracetamol
• Majority is conjugated with glucoronide
• Then most of the rest is conjugated with sulphate
• The rest is converted to a toxic metabolite by cytochrome P450 then:
If there are normal glutathione levels:
• Conjugated with glutathione then excreted
If the glutathione levels are reduced:
• Combined with hepatic proteins
• Leads to toxicity of the liver
Which drug can decrease the effect of warfarin and why?
Phenobarbital by increasing the expression of CYP450s which is what warfarin is metabolised by
What is the effect of grapefruit juice on CYP450s?
They inhibit CYP450s (mainly in the gut)
Describe the interaction between grapefruit and simvastatins
- Simvastatins are metabolised by CYP3A4 in the gut wall and the liver
- Increases the plasma concentration
In the lungs, what characteristic of drug is more likely to be exhaled?
- Lipophilic
* Volatile
What is minimum effective concentration?
The minimum plasma concentration that needs to be achieved before evidence of a the therapeutic effect could be observed.
For some drugs the longer you keep above this concentration the better
How is minimum effective concentration measured?
• Dose escalation trials and relating the plasma concentration to observed effect
What is minimum toxic concentration?
The minimum plasma concentration required to observe unwanted or toxic effects of the drug. Avoiding being above this level is favourable
What is the therapeutic window?
The gap between the minimum effective concentration and the minimum concentration that has unwanted side effects (toxicity)
What is meant by a closed therapeutic window?
When the therapeutic window is closed, you can’t separate toxicity from clinical use
How do you calculate the therapeutic window?
- Drug plasma concentration graph
* Draw a horizontal line alone the minimum effective concentration and another along the minimum toxic concentration
What is the onset of action?
How long it takes your drug plasma concentration to reach the ‘minimum effective concentration’ following administration
