Metabolism Flashcards
What is the definition of metabolism?
- conversion of drug to a more polar, water soluble, ionized substance usually with reduced pharmacological activity and toxicity
What are the sites of metabolism?
- bloodstream
- kidneys
- brain
- muscle tissue
- wall of GI tract (e.g. bacteria)
- lungs
The liver is the main organ of ________
biotransformation
What are the three chemical processes of phase 1 hepatic metabolism?
oxidation. reduction and hydrolysis
What are the three chemical process of phase 2 metabolism?
glucuronidation, acetylation and sulfation
What metabolic processes do barbiturates undergo in the body?
- glucuronidation
- oxidation
What metabolic processes do benzodiazepines undergo in the body?
- N-dealkylation
- hydroxylation
- glucuronidation
What are the metabolic processes that morphine undergoes in the body?
- glucuronidation
- morphine 6-glucuronide
- morphine 3-glucuronide
10% of codeine is demethylated to _____
morphine
The majority of anti-psychotic agents undergo the process of _____, but some also undergo glucuronidation
oxidation
What is the metabolic process that ethanol typically undergoes?
oxidation
What is the most prevalent phase 1 metabolism process?
oxidation
What are the chemical requirements to carry out an oxidation reaction?
requirement of NADPH, molecular oxygen and heme protein
Where in the cell are many of the phase 1 oxidation processes carried out?
in the smooth endoplasmic reticulum
Key element in the oxidative process is the hemeprotein cyctochrome _______
cytochrome P450 enzyme system
What families of the CYP enzyme is drug metabolism carried out by?
- carried out my families 1, 2 and 3
How many major P450 isoenzymes is the metabolism of drugs dominated by?
6
What are the drug substrates for enzyme CYP1A2?
phenacetin and theophylline
What are the drug substrates for enzyme CYP2C8/9/10?
hexobarbital, phenytoin
What are the drug substrates for the enzyme CYP2C18/19?
diazepam, mephenytoin
What are the drug substrates for the enzyme 2D6?
imipramine, propranol
What are the drug substrates for the enzyme CYP2E1?
acetaminophen
What are the drug substrates for the enzyme CYP3A4?
erythromycin and cyclosporin
Smoking _____ the enzyme CYP1A2, resulting in the activation of benzopyrene, a carcinogen in the cigarette smoke
induces
In what enzyme is there quite a bit of genetic polymorphism?
CYP2C9, CYP2C19
5% of caucasians and 20% of asians are poor metabolizers
There is an inhibition of S-Warfarin metabolism by _____
amiodarone
What other enzyme exhibits polymorphism between groups of individuals?
CYP2D6 (ultra rapid metabolizers of CYP2D6 need ultra high doses)
70% of the CYP3A4 isoform are present in the ___. What is the consequence of this?
gut
- this decreases bioavailability of the drug
The high incidence of drugs metabolized by CYP3A4 means that most of metabolism of drugs occurs in the ___
gut
Chronic alcoholism induces _____ and glutathione depletion leading to an accumulation of NAPQ1, a lethal byproduct of acetaminophen - leads to sever liver injury and possibly liver failure
CYP2E1
Alcoholism causes ____ of the liver, causing it to quit
oxidation
What are the two major reduction reactions?
nitro-reduction
azo-reduction
Where are reduction reactions most likely carried out?
- mostly carried out in the intestinal microflora - they carry out these reactions much more efficiently than in the livers of mammals
Reduction reactions are common for ____ administered drugs
orally
sulfasalazine, chloramphenicol
What are hydrolysis reactions mostly carried out by?
usually performed through respective esterase in the liver. They are also carried out by esterases in plasma and other tissues
Esterases hydrolyse esters to ____ and ________
alcohols
carboxylic acids
Phase 2 reactions involve what?
chemical conjugation or synthesis
What do phase 2 reactions generally result in?
- generally increase the water solubility and result in pharmacological deactivation
What must a compound be in order for phase 2 reactions to occur?
- a compound must be chemically active (usually occurs after phase 1 reactions)
What occurs in conjugation reactions?
a compound of a metabolite is combined with an endogenous molecule
What are the different factors that are known to affect drug metabolism?
- species (different animals have different enzyme titres)
- genetics
- age
- disease state
- drug/drug interactions
- food
Describe the paradox of modern drug development?
- clinical trials provide evidence of efficacy and safety at usual doses in populations (usually seen to be efficacious and safe in the LARGE group of HEALTHY people)
- physicians treat individual patients who can vary widely in their response to drug therapy (can have no response, can be efficacious, or can have an adverse drug reaction)
What was the first recognized genetic polymorphism?
N-acetyltransferase (NAT-2)
Is isoniazid active or not?
NO
The rate and extent of metabolism will affect the efficacy of the drug in treating ______
tuberculosis (fast and slow acetylators)
What groupings of people are rapid acetylators
inuit, japanese, american indian
Total body water and extracellular fluid in newborns is _____ than in adults
more than
What happens to the body composition of elderly individuals?
- the lean body mass of the person decreases, while the body fat increases
Newborns have ____ titres of hepatic microsomal enzymes. What does this do to glucuronidation reactions?
low
It decreases the extent of glucuronidation reactions
What is the definition of pharmacogenomics?
- avoiding adverse drug reactions from genetics and trying to maximize efficacy
What should be done with someone that is at a high risk of ADR’s?
- should treat them with an alternative medication
What should be done with someone who is at a medium risk of ADR’s?
- you should treat them with an alternative drug or dose
What should be done with someone who is at a low risk of ADR’s?
- you keep the drug
When you decrease the protein in the diet, what do you do to the drug metabolizing capacity?
you decrease the drug metabolizing capacity
When you decrease the lipids and you decrease the EFA, what do you do to the metabolism of ethylmorphine and hexobarbitone?
- you decrease it
High glucose intake does what to barbiturate metabolism?
- it inhibits barbiturate metabolism
Why does food increase the bioavailability of medications?
Because they increase the splanchnic blood flow
Charcoal broiled meats and smoked fish are potent inducers of what enzyme?
cytochrome p450 enzyme system
Grapefruit juice inhibits intestinal ____ enzymes and increase bioavailability of cyclosporine
p450
What enzyme family does grapefruit juice inhibit?
CYP3A
What drugs are metabolized by the family of CYP3A?
antihistamines, benzodiazepines, immunosuppressants
What did the ingestion of grapefruit juice result in in those patients taking large doses of nifedipine and terazosin? (used for blood pressure control)
marked hypotension
What enzyme does St. John’s Wart have an effect on and what is the result of this?
it induced CYP3A
- produces subtherapeutic doses of HIV drugs
What drug interactions are associated with ginseng?
- potential interactions with anti-depressants (headache and mania)
- warfarin (increased bleeding time), steroids (stronger effects)
What is the drug interactions associated with ginkgo and garlic?
- it increases the bleeding time with warfarin (increased risk of hemorrhages)
- —- simple advice! do not mix herbs and drugs!
What is the michaelis-menton equation?
Vmax C/(Km + C)
C= [drug] Vmax = maximum rate Km = michaelis constant =0.5 Vmax
