4+5: Pharmacokinetics + Drug Metabolism Flashcards
What is pharmacokinetics?
The way of a drug through the body + what the body does to it
What is the significance of pharmacokinetics?
It determines the does of the drug that is available to the tissue
Which steps does a drug in the body undergo from Administration to removal?
A bsorbtion
D istribution
M etabolism
E xcretion
What are the different routes a drug can be administered?
…
Explain systemic and local administration
Systemic: entrire organism
Local: specific tissue of organism
What is enternal and parenternal administration of drugs?
Enternal: via GI tract
Parenternal: without GI tract
How do drugs move around in the body?
- Bulk flow transfer
- bloodstream, lymph
- Diffustion transfer
- molecule by moelcule over a short distance
Why do drugs have to pass aqueous and lipid compartments?
Aqueous: to move around e.g. in bloodstream, lymph , extracellulra, intracellular fluid
Lipid: To reach their target (to cross membranes)
Through which mechanisms do drugs cross cell membranes?
What kind of molecules can cross via the following routes? Which one is the least important?
Diffusion: Fat soluble molecules (or very small)
Diffusion through aqueous pores: small watersolube molecules —> barly any drug –> least important
Active transport: the rest
Which chemical feature do most drugs have in common? Why?
They are either weak acids or bases
–> can be ionised and unionised, depending on the environment (often therefore polar and non-polar)
How does the Handerson Hasselbach equation look like to determine, how the ration between Ionised and unionised forms of bases/acids look like when pka and pH are known?
Which factors influence drug distribution?
- Regional blood flow
- Extracellular binding (plasma protein)
- Capillary permeability
- Localisation in tissues
- Solibility (e.g. general anestetics are very fat soluble –> large proportion will be in fat even though only very little blood flow to it)
How does regional blood flow influence distribution of drugs?
Highly metabolically active tissues have more blood flow + denser capillary networks (can change e.g. with exercise in skeletal muscle)
How does extrcellular binding of drugs influence their distribution (passage of membranes)
Extracellular binding to plasma proteins
- determines availability e.g. if 95% is bound –> only 5% are able to cross membranes
How does capillary permeability influence drug distribution?
- Fat soluble: can cross all membranes, into all tissues (even blood-brain barrier)
- Water soluble: often rely on transport emchanisms /pores –> will me distributed more unevenly (and more in capillaries with large gaps)
How does localisation in tissues influence drug distribution?
Fat: 15% body weight, but 2% blood supply
Very fat soluble drugs – 75% partitioned in fat at equilibrium
–> disproportional high amounts of drugs in fat tissue (e.g. general anestetics)
What is the aim of metabolism of a drug?
Why is that so?
To make the drug more water soluble for easier excretion
- no diffusion back into bloodstream once in kidney nephron
- more drug in bloodstream (less in tissue) hence more excretion
Why are most drugs rather fat soluble?
To get into tissues (be able to cross cell membranes)
What are the two phases in drug metabolism? What are their respective aims
- Phase 1: introduce(add/unmask) a reactive group to the drug (to increase polarity)
- Phae 2: add a water soluble conjugate to the reactive group
What happens during phase one of drug metabolism?
Which reactions take place to let this happen?
Adding/unmasking a reactive group to the drug (increasing polarity)
- most reactions are oxidations (ofter start with hydroxylation)
- But also: redeuction, hydrolisis
Which is the most common enzyme to oxidise drugs in phase 1 of drug metabolism?
What are its characteristics
Cytochrome P450
- 57 enzymes (each do different drugs)
- has low specifity
Which characteristics can the metabolite have that is formed after Phase one of the drug metabolism?
What is a prodrug?
A drug that is activated by Phase 1 of drug metabolism (not active at administration)
What happens during phase 2 of drug metabolism?
What are common reactions?
Add a water soluble conjugate to the reactive group
there will be a conjugate and a conjugative agent
Recations involve
- Glucoronidation (most common)
- Sulfation
- Glutathionine conjugation
Less common:
- Acetylation
- Methylation
- Aminoacid conjugation
What is the most common reaction in phase 2 of drug metabolism?
What are its characteristics?
Glucoronidation
low affinity/high capacity – more likely to occur at high drug dosages
What is an example of a phase 2 drug high affinity low capacity metabolism?
Sulfation –> More likely to occur at low drug dosages
In which drug metabolism phase does glutathiodine conjugation take place? What does it require? What might be the problem with it?
Drug needs to be electrophilic to be conjugated or biotransformed to an electrophilic conjugate
–> But electropiles are extremely reactive
When overdosing –> no glutathiodine available –> electrophile might cause tissue damage
Why is drug metabolism important? (What are the overall aims - not on a chemical level)
- The biological half-life of the chemical is decreased.
- The duration of exposure is reduced.
- Accumulation of the compound in the body is avoided.
- Potency/duration of the biological activity of the chemical can be altered.
- The pharmacology/ toxicology of the drug can be governed by its metabolism.
Through which main organ systems are drugs excreted?
Mainly via the
- kidney
- liver
How are drugs excreted in the kidney?
Which factor influence each step?
-
Glumerular filtration
- size dependant
-
Active secretion
- dependant on available transporters + transport mechanisms
-
Passive reabsorbtion
- urine pH (–> determines ionisation) + drug characteristics, state of metabolism (fat soluble drugs just diffuse back into systemic circulation)
How does drug excretion via the liver work?
- Diffusion from sinusoids into hepativ tissue (via discontinuous capillaries/ diffusion through cells)
- Active transport (or fat soluble –> diffusion) into bile
- Excretion via bile
–> Mint the Enterohepatic cycling! (reabsorbtion)
How does the Enterohepatic cycling influence drug excretion?
Recycling of drugs can significantly increase half life and concentration of drugs!
Other than the kidney and liver: Through which routes can drugs also be excreted?
- lungs
- skin
- gastrointestinal secretions
- saliva
- sweat
- milk
- genital secretions
Define Bioavailability
Proportion of the administered drug that is available within the body to exert its pharmacological effect
(dependant on absorbtion + distribution???)
Define Apparent volume distribution
The volume in which a drug appears to be distributed
- an indicator of the pattern of distribution
Define Biological half life
Time taken for the concentration of drug (in blood/plasma) to fall to half its original value
(linked to metabolism/excretion)
Define Clearance (pharmacokinetics)
Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time
(Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes)
