Pharmacology Chapter 5

Most drug metabolizing enzymes are in what CYP families ?

1,2,3

What enzyme is very common to metabolize many drugs; its presence in the GIT is responsible for poor oral availability of many drugs

CYP3A4

____ putative functional gene and ___ pseudogenes in the mouse

102, 88

---

_____putative functional gene and ____ pseudogenes in humans

57, 88

CYP families

CYP plus arabic numeral ex. CYP1

>40% homology of amino acid sequence

CYP Subfamily

Additional arabic numeral when more than 1 subfamily has

been identified

40-55% homology of amino acid sequence

ex. CYP1A2

Gene

italics indicate gene

ex. CYP1A2

What is a major catalyst of drug and endogenous compound oxidations in liver kidney, GIT, skin, lungs

CYP monooxygenase enzyme family

What do oxidative reactions require ?

• CYP heme protein

• the reductase

• NADPH

• phosphatidylcholine

• molecular oxygen

Where are CYPs located

smooth endoplasmic reticulum

what serves as the electron source for the oxidative reaction cycle

the reductase

Microsomal drug oxidations require

P450, P450 reductase, NADPH, molecular oxygen

Step 1 P450 cycle

oxidized (Fe+3) P450 combines with a drug substrate to form a binary

complex

Step 2 CYP Cycle

NADPH donates an electron to the flavoprotein P450 reductase, which in turn

reduces the oxidized P450- drug complex

Step 3 CYP cycle

A second electron is introduced from NADPH via the same P450 reductase,

which serves to reduce molecular oxygen and to form an “activated oxygen”-

P450-substrate complex

Step 4 CYP cycle

This complex in turn transfers activated oxygen to

the drug substrate to form the oxidized product

Metabolized drug dissociates.

What do CYP isoforms metabolize

1. many endogenous substances including prostaglandins, lipids, fatty acids,

and steroid hormones

2. metabolize (detoxify) exogenous substances including drugs

Troleandomycin and clotrimazole is induced by what enzyme

CYP3A

Ethanol is medicated by what enzyme

CYP2E1

Isosafrole is induced by

CYP1A2

5-10% of caucasians are poor metabolizers of type of substrates

CYP2D6

The incidence of poor metabolizers of CYP2C19 drugs is what in asian and caucasian populations

20% asian

4% caucasian

phase 2 biotransformation conjugation reactions

• glucuronidation

• acetylation

• glutathione conjugation

• glycine conjugation

• sulfation

• methylation

• water conjugation

What is the location of non-microsomal enzymes

primarily hepatic (liver); also, plasma & gastrointestinal tract

Non-microsomal enzymes catalyze all conjugation reactions except

glucuronidation

What do nonspecific esterases in liver, plasma, GIT do

hydrolyze drugs containing ester linkages

conjugation reactions are usually

detoxification reactions

conjugates

• more polar

• easily excreted

• typically inactive

Therapeutic doses acetaminophen

glucuronidation + sulfation to conjugates

(95% of excreted metabolites)

5% due to alternative cytochrome P450 depending glutathione (GSH)

conjugation pathway

What is the enzyme for Ac-Glucronide to Ac-Sulfate

UDP- glucuronosyltransferase

What is the antidote for acetaminophen toxicity

 N-acetylcysteine

protects patients for hepatoxicity and death followed by acetaminophen overdose

Influence of age on drug responses - Variation in drug responses is usually due to

diminished cardiac output

• reduces hepatic perfusion - decreases delivery of drug to liver for metabolism

• can prolong the duration of action of drugs

Age - increased body fat

increases Vd

promotes accumulation of highly lipid-soluble agents

ex. diazepam (Valium) , thiopental (pentothal)

Neonates have reduced hepatic metabolism and renal excretion due to 

relative organ immaturity

elderly patients exhibit 

differences in absorption, hepatic metabolism, renal clearance and volume of distribution.

Grapefruit juce contains chemicals that are potent inhibitors of

CYP3A4 localized in intestinal wall mucosa

Cruciferous vegetables such as brussels sprouts, cabbage, cauliflower and

hydrocarbons present in charcoal-broiled meats can induce

CYP1A2

Calcium present in dairy products can chelate drugs including commonly used

tetracyclines and fluoroquinolone antibiotics.

Drug interaction

when one drug affects the pharmacological response of a second drug given at the same time

Drug interactions may be due to

pharmacodynamic effects

pharmacokinetic effects 

Direct pharmacodynamic interaction

Drug A blocks the target site of Drug B,

there by diminishing or antagonizing the effect of Drug B

ex. b-adrenoceptor antagonists diminish the effectiveness of b-

receptor agonists, such as salbutamol or terbutaline.

Indirect pharmacodynamic indirect interaction

Drug A alters the levels of an endogenous

substance (could be increase or decrease) that subsequently affects

action of Drug B

1. Diuretics (certain ones) ¯ plasma K concentration, which can enhance some

actions of digoxin and predispose to glycoside toxicity.

2. Monoamine oxidase inhibitors (MAO I) inhibit NE metabolism and ­ NE

level. This could produce interactions with certain drugs, such as ephedrine

or tyramine that work by releasing stored norepinephrine.

metabolize catacholamines

3. H1-receptor antagonists, such as mepyramine, commonly cause

drowsiness as an unwanted effect. This is more troublesome if such drugs are

taken with alcohol and may lead to accidents at work or on the road.

Distribution

A. Displacement of a drug from binding sites in plasma or tissues by another

drug transiently increases the concentration of free (unbound) drug

B. Above is followed by increased elimination, producing a new steady state

where total drug concentration in plasma is decreased but the free drug concentration is similar to that before introduction of the second 'displacing' drug.

The main mechanism by which one drug can affect the rate of renal excretion of another

by inhibiting tubular secretion; by altering urine flow and/or urine pH; by altering protein binding, and hence filtration.

1) Inhibition of tubular secretion:

Probenecid inhibits penicillin secretion and thus prolongs its action. It also inhibits the excretion of other drugs, including azidothymidine (AZT)

2) Alteration of urine flow and pH:

• Loop and thiazide diuretics indirectly increase proximal tubular reabsorption of Li+ (which is handled in a similar way as Na+) and this can cause Li+ toxicity in patients treated with lithium carbonate for mood disorders.

• The effect of urinary pH on the excretion of weak acids and bases is put to use in the treatment of poisoning but is not a cause of accidental interactions.