Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
80 Cards in this Set
- Front
- Back
Biotransformation
|
Conversion of a pharmacologically active, lipophilic drug into one or more hydrophilic and OFTEN (but not always) inactive metabolite(s)
|
|
Biotransformation facilitates?
|
more rapid excretion of the drug via urine or bile
|
|
Why is biotransformation not always synonymous with inactivation or with detoxification?
|
1. Many drugs have pharmacologically active metabolites
2. Some drugs are formulated as inactive prodrugs; drug metabolite is pharmacologically active 3. Some drug metabolites have toxic properties |
|
Name 3 sites of biotransformation : relative activity
|
1. Liver - 100%
2. Lung - 10-20% 3. Kidney 8% |
|
Types of biotransformation
|
1. Phase I
2. Phase II 3. Combination reactions (phase I to phase II) |
|
Phase I reactions are also called?
|
degradation reactions
|
|
What reactions are included in Phase I- degradation reactions?
|
Oxidation, reduction, hydrolysis
|
|
Phase II reactions are also called?
|
Conjugation reactions (make it more water soluble)
|
|
Combination reactions are?
|
very common
|
|
In oxidation, what enzymes are responsible?
|
cytochrome P-450
|
|
Where are the cytochrome P-450 enzymes located?
|
in the membranes of the smooth ER
|
|
What are other names for the cytochrome P-450 enzyme?
|
microsomal enzymes or mixed function oxidases
|
|
What does an oxidized drug look like?
|
O2 + drug ---> drug-O + H20
|
|
What contain several P450 isoenzymes?
|
hepatocytes
|
|
CYP3A4 isozyme
|
is responsible for the biotransformation of 50% to 60% of clinically prescribed drugs, including opioids (fentanyl, alfentanil, sufentanil), benzodiazepenes (midazolam, diazepam), amide local anesthetics (lidocaine, ropivacaine), and calcium channel blockers
|
|
2E1 isozyme
|
is responsible for biotransformation of halogenated anesthetics
|
|
CYP2D6 isozyme
|
is responsible for biotransformation of codeine, oxycodone (Percocet), and hydrocodone (Vicodin) to their pharmacologically active metabolites - morphine, oxymorphone, and hydromorphone
|
|
P450 enzymes are subject to?
|
induction
|
|
Induction means?
|
Substances increase P450 enzyme activity
|
|
What substances increase P450 activity and are referred to as inducers?
|
barbituates, tobacco smoke, chronic alcohol ingestion, carbamazepine, St. John's wort
|
|
induction leads to?
|
enhanced biotransformation of the inducer as well as drugs metabolized by the particular P450 isozyme
|
|
Inhibition of P-450 activity, what drugs?
|
cimetidine, ketoconazole, SSRIs, erythomycin
|
|
What environment factors inhibit P450 activity?
|
grapefruit juice
|
|
Inhibition of P450 activity may?
|
enhance plasma levels of drugs metabolized by the affected enzyme
|
|
Name 3 examples of P450-dependent oxidations
|
1. Hydroxylation
2. Dealkylation 3. Deamination |
|
Reduction occurs where?
|
in the smooth ER
|
|
In reduction, is cytochrome P450 involved?
|
unclear
|
|
When may reduction become important?
|
when tissue PO2 is low
|
|
Hydrolysis occurs how?
|
nonmicrosomal enzymes (not inducible)
|
|
What type of enzymes carry out hydrolysis?
|
1. esterases: succinylcholine, procaine, esmolol, aspirin
2. amidases: lidocaine, procainamide |
|
Conjugation reactions, name 4
|
1. Glucuronidation
2. Acetylation 3. Sulfation 4. Amino acids |
|
What is the most common conjugation reaction and why?
|
glucuronidation due to the availability of glucose
|
|
Glucuronidation involves what type of enzymes?
|
microsomal enzymes, therefore inducible
|
|
Glucuronidation is important for what drugs?*
|
morphine, diazepam, acetaminophen, and lorazepam
|
|
Of the conjugation reactions which reactions are carried out by nonmicrosomal enzymes?
|
acetylation, sulfation, amino acids
|
|
What would be an example of Phase I and Phase II biotransformation reactions?
|
Hydrolysis followed by glucuronidation
|
|
What factors may cause individual variations in drug metabolism?
|
1. Genetic polymorphisms
2. Dietary/environmental factors may affect P-450 activity 3. Age 4. Gender |
|
What are 4 examples of how genetic polymorphisms may cause variations in drug metabolism?
|
1. CYP450 enzymes exhibit many allelic variations
2. Abnormal pseudocholinesterase 3. Slow acetylators vs. fast acetylators 4. racial/ethnic differences |
|
What dietary/environmental factors may affect P450 activity?
|
1. Inducers: tobacco smoke, industrial pollutants
2. Inhibitors: grapefruit juice |
|
How does age affect drug metabolism?
|
slower metabolism in children and elderly individuals
|
|
How does gender affect drug metabolism?
|
males may metabolize some drugs more rapidly than females
|
|
What disease can impair drug biotransformation?
|
1. Liver disease: cirrhosis, hepatitis, cancer
2. Heart disease: reduced blood flow to the liver |
|
What are the 2 most common routes of excretion?
|
1. Renal
2. Biliary |
|
Renal excretion is dependent on four processes, what are they?
|
1. Glomerular filtration
2. Tubular secretion 3. Tubular reabsorption 4. pH and drug/drug metabolite trapping in tubule |
|
What occurs in GF?
|
non-protein bound (free) drug is filtered and elimination is dependent on GFR
|
|
Tubular secretion
|
1. Weak acids and bases
2. Active transport across tubular epithelium 3. Can enhance elimination of highly protein-bound drugs |
|
Tubular reabsorption is the?
|
return of filtered and/or secreted drug to circulation
|
|
In tubular reabsorption, what drugs are extensively reabsorbed?
|
lipid-soluble drugs
|
|
Since lipid-soluble drugs are extensively reabsorbed this stresses the importance of?
|
drug biotransformation to hydrophilic metabolites, which may then be excreted in the urine
|
|
In pH and drug/drug metabolite trapping in tubule, what are excreted more rapidly in alkaline urine? acidic urine?
|
weak acids, weak bases
|
|
Weak acids are excreted more rapidly in alkaline urine, why?
|
The equilibrium shifts to favor the ionized form which is the form that is not reabsorbed, therefore speeding up the excretion
|
|
A weak base is excreted more rapidly in acidic urine because?
|
the equilibrium shifts to favor the ionized form which is the form that is not reabsorbed
|
|
Biliary excretion
|
Unchanged drug or drug metabolites (eg, glucuronides) are secreted in the bile ---> small intestine
|
|
In biliary excretion, what circulation may occur?
|
enterohepatic circulation (ileum--> portal vein --> liver) may occur
|
|
Most drugs exert their pharmacological effects by interacting with?
|
receptors
|
|
Most receptors are?
|
proteins, either on cell membranes or within cells
|
|
Drugs can act as receptor?
|
agonists or antagonists
|
|
Agonist
|
is a compound that interacts with a receptor and produces a physiological (endogenous agonist) or pharmacological (exogenous agonist) effect
|
|
Dissociation constant (Kd)
|
The receptor has a certain binding affinity for the agonist, ie, the concentration of free agonist at which binding is half-maximal
|
|
The lower the value of Kd, the?
|
higher the binding affinity
|
|
Full agonist
|
exerts a maximal pharmacological effect without necessarily occupying all available receptors
|
|
Partial agonist
|
exerts less response than does a full agonist, and not necessarily because of reduced binding affinity
|
|
Neutral antagonists
|
these drugs interact with receptors, exert no agonist effect, and block or reverse the effects of agonists
|
|
Competitive antagonist
|
antagonism can be overcome by increasing concentrations of agonist; reversible binding of antagonist to receptor
|
|
Noncompetitive antagonist
|
antagonism cannot be completely overcome by increasing the concentration of agonist; irreversible binding of antagonist to receptor
|
|
Receptors exist in equilibrium between?
|
inactivated and activated states; there occurs spontaneous conversion from the inactivated to activated state
|
|
Agonist bind to and stabilize?
|
the active state of the receptor, therefore shifting the receptor equilibrium to favor the active site
|
|
If a drug is a full agonist what occurs?
|
they fully stabilize the active receptor state and produce a maximal effect
|
|
If a drug is a partial agonist what occurs?
|
they only partially stabilize the active receptor state and produce a submaximal effect, even at high doses
|
|
If a drug is a neutral antagonist what occurs?
|
it binds equally to the inactivated and activated receptor states and does not alter the baseline equilibrium
|
|
Structure-activity relationships
|
the ability of a drug to combine with a specific receptor is dependent on the molecular size, three-dimensional shape, and electrical charge of the drug
|
|
Optical isomers (enatiomers) may ?
|
not have the same binding affinity (Kd)
|
|
What usually exist for agonists and antagonists?
|
multiple receptors
|
|
What receptors exist?
|
1. Alpha and beta
2. nicotinic and muscarinic cholinergic 3. receptors for opioids, histamine, dopamine, and serotonin |
|
What three bonds exist for drug-receptors?
|
1. Covalent bond
2. Ionic bond 3. Hydrogen bond |
|
Covalent bond
|
stong bond, frequently irreversible; binding of phenoxybenzamine to alpha-1 adrenergic receptors is an example (uncommon)
|
|
Ionic bond
|
electrostatic interactions; important for drugs that are ionized at plasma pH
|
|
Hydrogen bond
|
-OH, -NH2 interact with electronegative groups (weakest form of interaction)
|
|
The fraction of activated receptors is very low in the absence of a(n)?
|
agonist
|
|
Most receptors are in what state at rest?
|
inactivated state
|