Pharmacokinetics - metabolism and elimination

Most drugs would have a prolonged duration of action if termination of their action depended solely on ___

renal excretion

Many drugs do not possess qualities favorable for ___

excretion via the kidneys

Biotransformation is the process by which xenobiotics are transformed to more ___ metabolites

polar (inactive)

Which drugs are inactivated by biotransformation?

Thiopental and phenobarbitol

Which drugs gain activity after biotransformation?

Clopidogrel (2-oxo-clopidogrel)

Active drugs can also lead to active metabolites in biotransformation? which drug is an example of this?

Diazepam (desmethyldiazepam)

Where does most biotransformation occur?

Liver

Some ___ do not need to undergo biotransformation to be eliminated?

lipophilic

What are the phase one reactions?

oxidation, reduction and hydrolysis

Phase I reactions usually convert a parent drug to a more polar metabolite by ___

introducing a functional group

If phase I metabolites are sufficiently polar they may be ___

excreted

In phase II reactions an endogenous substrate combines with a phase I product forming a ___

highly polar conjugate

What are the three important conjugation reactions?

Glucoronidation, acetylation, glutathione

Which drug undergoes glucoronidation?

Chloramphenicol

Which drugs undergo acetylation?

hydralazine, isoniazid, procainamide

Which drug undergoes glutathione conjugation?

acetaminophen

Mixed function oxidases (monooxygenases) are enzymes in smooth microsomes (from ER) involved in which reactions?

Phase I biotransformation

In the oxidation reduction process two microsomal enzymes play a key role:

- NADPH- cytochrome P450 oxidoreductase

- Cytochrome P450

Most liver CYP450 oxidases exhibit ___ substrate specificity

broad

The activated oxygen of CYP450 is a powerful ___ agent

oxidizing

P450 mediated reactions account for ___ of oxidative biotransformations

95%

3 multiple choice options

What are examples of non-P450 oxidases?

- alcohol dehydrogenase (ethanol metabolism)

- MAO (anti-depressants)

Enzyme inducers increase the activity of ___ in the liver

CYP450 enzymes

Anticonvulsants like phenytoin, barbiturates, and carbamazepine are enzyme ___

inducers

1 multiple choice option

Aromatic hydrocarbons are enzyme ___

inducers

1 multiple choice option

Rifampin (abx) is an enzyme ___

inducer

1 multiple choice option

Glucocorticoids are enzyme ___

inducers

1 multiple choice option

Griseofulvin (antifungal) is an enzyme ___

inducer

1 multiple choice option

Chronic alcohol use is an enzyme ___

inducer

1 multiple choice option

When enzyme inducers are activated drug intensity and duration is ___

decreased

Which drug counteracts oral contraceptives and can cause unintended pregnancy

phenytoin

Enzyme inducers promote ___ if the substrate drug induces its own metabolism

tolerance

Which drug is an enzyme inducer that causes its own metabolism?

Carbamazpine

Enzyme inducers cause some endogenous substances to be metabolized faster. What is an example?

Bilirubin

Cimetidine and omeprazole (anti ulcer drugs) are enzyme ___

inhibitors

1 multiple choice option

Grapefruit juice is an enzyme ___

inhibitor

1 multiple choice option

Chloramphenicol, macrolides, and ritonavir (abx) are enzyme ___

inhibitors

1 multiple choice option

ketoconazole (anti fungal) is an enzyme ___

inhibitor

1 multiple choice option

Acute alcohol intake is an enzyme ___

inhibitor

1 multiple choice option

What is a consequence of taking enzyme inhibitors?

Increased dose related toxicity

Isoniazid (INH) is an ___ drug

antitubercular

Hydralazine is an ___

antihypertensive

Procainamide is an ___

antiarrythmic

Hydralazine, isoniazid, and procainamide are examples of drugs that can be ___

acetylated at higher or lower rates (dosage dependent)

Risks of slow acetylators receiving too high of dosage?

drug induced lupus and peripheral neuropathy

Newborns and elderly need smaller doses than middle aged adults because ___

- enzyme activity decreases with age

- newborns enzymes are not fully developed

___ is converted into reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI)

acetaminophen

NAPQI is usually conjugated by ___ to be inactvated

glutathione (GSH)

In acetaminophen overdose ___ is depleted and leads to liver cell death

glutathione

Tx for acetaminophen overdose?

N-acetylcysteine

When a drug is given by IV what is the bioavailability?

100%

Lidocaine has a low bioavailability due to destruction by gastric enzymes and the liver so it is not effective ___

orally

3 multiple choice options

How is bioavailability calculated?

F= AUCoral / AUCiv

Renal blood flow is about ___% of systemic flow

25

Enhancing blood flow, increasing glomerular filtration rate, and decreasing plasma protein binding will ___

speed up drug excretion

3 multiple choice options

Urinary drug concentration increases in the ___

proximal tubule

3 multiple choice options

Drug concentration increases in the proximal tubules because of passive diffusion of ___ into renal tubules

uncharged drug molecules

Drug concentration increases in the proximal tubules because of ___ diffusion of charged and uncharged molecules

facilitated

Drug concentration increases in the proximal tubules because of active secretion of ___ molecules

anionic and cationic (penicillin)

Urinary drug concentration falls in the renal tubule because of ___ in the proximal and distal tubules

reabsorption

Reabsorption of drugs in the renal tubule is limited by ___

pH trapping

Urinary drug concentration falls in the renal tubule because of an ___ of urine output

increased rate

1 multiple choice option

Drugs can be secreted from the liver into the bile by members of the ___ family of transporter

ATP binding cassette

During elimination of bile through the intestine it may be reabsorbed leading to ___

enterohepatic circulation

In first order kinetics the rate of elimination is ___ to the plasma concentration of the blood

directly proportional

In zero order kinetics the rate of elimination is ___ of the plasma concentration

independent

Drugs that will not be saturated easily will follow ___ kinetics

first order

1 multiple choice option

In zero order elimination, a ___ amount of the drug is being eliminated per unit of time

constant

Few drugs follow zero order kinetics, name a few?

- Ethanol

- aspirin and phenytoin in high doses

In first order elimination a constant ___ of the drug is being eliminated per unit of time

fraction

Half life is constant for drugs following ___

first order kinetics

How many doses are required to reach a steady state of concentration?

4-5 typically

When a drug is repeatedly given at a constant interval the plasma levels of the drug will reach a ___

plateau

To maintain a constant plasma concentration over an extended period of time a ___ is required

maintenance dose

To achieve target plasma levels rapidly a ___ is required

loading dose

Loading dosages are useful for drugs with ___

long half lives