Metabolism & Excretion Flashcards
What is catabolism?
Breaking down of organic matter
What is anabolism?
Uses energy to build up or construct components of cells such as proteins and nucleic acids.
What is metabolism a combination of?
Catabolism and anabolism
What is catabolism in drug metabolism?
Break down of drugs
What is anabolism in drug metabolism?
Addition
Modification with the addition of water solubilizing groups
What do lipid-soluble drugs require?
Metabolism
Lipid soluble drugs require more metabolism to become polar, ionizable and easily excretable which involve both phase I and phase II mechanisms.
What is drug metabolism?
Alteration
Any chemical alteration of a drug by the living system
What is the purpose of drug metabolism?
Enhance
To enhance water solubility (hydrophilicity) and hence excretability
Where is the main site of drug metabolism?
Main site - liver (before the drug has become available for use, is called the first pass effect)
involves cytochrome p450
Where are the other sites of drug metabolism?
- Gastrointestinal wall
- Kidneys
- Blood.
What are the factors affecting drug metabolism
Physiochemical properties, complex structure
-The structure of a drug influences its physicochemical properties.
- The more complex the structure, the more potential sites for metabolism.
- Blocking/altering sites of metabolism can improve the availability of the drug.
Hydrophobic compounds are…
Hydrophobic compounds are metabolised during two metabolic phases.
What is Phase I?
Phase I -oxidative transformations
- Production of new polar groups is introduced or exposed by oxidation, reduction, hydrolysis.
What is Phase II?
Phase II – conjugation
- Original drug or its metabolite – made more polar by conjugation reactions.
- Adding something hydrophilic
What type of metabolism is Phase II?
Anabolic
In phase I metabolism, what are oxidations catalysed by?
Oxidations are catalysed by the enzyme cytochrome p450 (CYP).
Oxidation is…
Oxidation is the loss of electrons or an increase in oxidation state by a molecule , atom, or ion
Reduction is…
Reduction is the gain of electrons or a decrease in oxidation state by a molecule, atom, or ion.
What molecules are used for redox reactions?
- NAD+
- FAD
What are heme-containing proteins?
When their active site contains a porphyrin ring co-ordinated to iron at the active site.
What is a CYP inhibitor?
Where a drug binds to a particular CYP and inhibits it, thereby preventing it from metabolising other substrates - important when multiple drugs are dosed together.
What is a CYP induction?
- Where a drug leads to the expression of greater levels of a particular CYP, again this can have effects on the pharmacokinetics of co-administered compounds.
- Metabolises things quickly
What are esters vulnerable to?
Hydrolysis
If an ester is broken down via hydrolysis what would the product be?
Acid + alcohol
If an amide is brokwn down via hydrolysis what would the product be?
Amine
What are the three things that typically get added in Phase II?
- Gluronide formation (sugar)
- Sulphate
- Glutathione derivatives
Why is sugar added in Phase II metabolism?
It’s very polar and water soluble which will make the molecule more hydrophilic so it stays in solution better.
Why is sulphate added in Phase II metabolism?
- Its a very hydrophilic component and as its an anion will add a charge.
- It also has lots of hydrogen bond acceptor capacity.
Why is Glutathione derivatives added in Phase II metabolism?
- It’s almost peptide-like with glycerine, cysteine and glutamine acid.
- The acid groups on either side make it very soluble
- It can bind things through the sulfur atom which is a good nucleophile.
When does Glucuronidation happen?
To drugs with:
- Carboxylic acid
- Alcohol
- Phenol
- Amine
When does sulphation happen?
To drugs with:
- Alcohol
- Phenol
- Amine
When does Glutathione conjugation happen?
To drugs with:
- Halogenated-compounds
- Epoxides
What is a pro-drug?
- Inactive compounds are converted to active compounds in the body.
- This usually happens through metabolic processes but can occur by simple chemical reactions.
What is the purpose of prodrugs?
To improve ADME properties:
- Improve membrane permeability by reducing polarity
- Improve prolong drug activity by releasing the active compound slowly
What is the problem with carboxylic acids on drug molecules?
It is charged and very polar and will keep something nicely water soluble but It isn’t orally available. It also wouldn’t get much into the blood stream as its too polar.
Esterases…
Esterases break down esters
What does aldehyde dehydrogenase do?
An enzyme which is going to oxidise the carbon and put a carbonyl on
What is elimination?
The irreversible transfer of a drug from the systemic circulation
What are the major routes of elimination?
- Metabolism
- Renal excretion
- Biliary excretion
- Lungs
- Sweat
What is renal excretion?
Elimination through kidneys and urine
Where are most things excreted?
Into the urine as all the blood gets filtered through the kidneys
What is tubular reabsorption?
- The removal of water (~99%) and solutes from the filtrate
- The water and solutes return to the blood via the peritubular capillaries
What is tubular secretion?
Transport of excess solutes and wastes from the peritubular fluid into the tubular fluid
How is blood filtered?
- Blood flows through little pockets called Bowman’s capsules where there’s loads of thin capillaries and everything that’s in the blood that goes through these gets filtered and the water and excessive things dissolved in the blood get pushed into tubules
- Excess water and excess things dissolved in the water will pass through the tubules
As the water and excessive things pass through these tubules they can leave it passively so water can be reabsorbed back out of the tubules and so can the solutes.
All unbound drugs in plasma…
- All unbound drugs in plasma is filtered through the glomerulus.
- This is only significant for very polar molecules
What compounds go through renal excretion?
Only polar compounds which is why metabolism adds polar groups to the compounds
What happens to neutral and unionised solutes?
Neutral and unionised solutes can come out of the tubules before they get to the bladder so they have a second chance of escaping if they are non-polar enough
What happens to polar and small solutes?
They get collected in the urine
If a molecule has undergone hydrolysis, what effect can this have?
Metabolism can sometimes make things smaller if they had undergone hydrolysis which promotes excretion into urine.
What is polymorphism?
- One compound can crystallise in a variety of ways.
- Each version will have different solubility.
How can you fix poor solubility?
- Change the compound design
- Create a salt
- Change formation
- Make a prodrug
In terms of changing the compound design, what can you add to make an acid more acidic?
Add an electron-withdrawing group
In terms of changing the compound design, what can you add to make an acid less acidic?
Add an electron-donating group
In terms of changing the compound design, what can you add to make a base less basic?
Add an electron-withdrawing group
In terms of changing the compound design, what can you add to make a base more basic?
Add an electron donating group
What is an example of an electron-withdrawing group?
Aromatic ring
When can you create a salt to help with solubility?
If you have an ionisable part so an amine or carboxylic normally you could give it as a neutral compound or as a salt.
What are the two ways you can change the formation to increase solubility?
- Use cyclodextrin - a circle of sugars and hydrophilic but the middle bit can accommodate hydrophobic molecules
- A different way is to use Liposomes, take lipids and make a tiny capsule of them, inside the capsule you can put the drug which will change its solubility properties.
- Sometimes this happens inside the core of the liposome and sometimes you have the drug encapsulated in the lipid bilayer itself.
What are fillers?
Bulking agents which make a small quantity easer to handle (e.g. starch, calcium salts, sugars such as lactose)
What are lubricants/antiadherants?
Reduce friction during manufacturing (e.g. magnesium stearate)
What are binders?
Polymers used to turn powders into granules and pills (e.g. gelatin, polyethylene glycol, polysaccharides)
What are preservatives?
Usually anti-oxidants (e.g. vitamin C, citric acid) or antifungal/bacterials (parabens)
What are flavourings?
Sweeteners (usually artificial) or others to mask unpleasant taste
What are coatings?
Also protect from unpleasant taste, usually hydroxypropyl methylcellulose. Capsules are coated in gelatin. All dissolve in the stomach.
What are vehicles?
In liquids and gels, the rest of the liquid: water, mineral oil, DMSO
