Principles of Pharmacology



Principles of Pharmacology

Drug Metabolism

A. Characteristics

1. chemical change in a drug

2. forms more water soluble metabolites

3. usually terminates drug action

B. Types of non-synthetic (phase 1) reactions

1. oxidation reactions – Mostly by cytochrome P450

a. types of microsomal oxidations

1) aromatic hydroxylation

2) aliphatic hydroxylation

3) epoxidation

4) N-, O-, and S-dealkylations

5) N-hydroxylation (not P450)

6) N-oxidation (not P450)

7) oxidative deamination

8) sulfoxide formation

9) desulfuration

b. broad selectivity of cytochrome P-450

1) multiple forms

2) mechanistic broad selectivity

a. classification based on sequence similarity

1) 40% families

2) 59% subfamilies

b. regulation of P450 expression

1) enzyme induction

a. transcriptional activation

b. also stabilization of mRNA, protein, and increased protein synthesis

2) polymorphisms

a. are frequently silent

b. expression polymorphisms

c. polymorphisms in structural gene

c. CYP1A

1) inducible by polycyclic hydrocarbons – large compounds that look like cholesterol

2) found in cigarette smoke

3) 1A1 – inducible

4) 1A2 constitutively expressed - little expression in extrahepatic tissues

5) CYP1A1 polymorphisms

a) Ah receptor polymorphism

b) polymorphisms in structural gene

6) CYP1A2 polymorphisms

a) detected by caffeine metabolism

b) CYP1A2 is expressed only in liver, but appears to be associated with cancer at distal sites

d. CYP2A

1) hormonally regulated forms

2) 2A1 - increased in female and young male rats

3) 2A2 - not found in female rats

4) 2A6 in humans

5) CYP2A6 polymorphism

a) significant ethnic variability

b) variant 2A6 alleles

c) coumarin 7-hydroxylation

f. CYP2B - induced by phenobarbital

1) 2B1 inducible in liver but constitutive in lung

2) 2B2 constitutive and inducible

3) 2B6 human P450 isozyme

g. CYP2C – constitutive hormonally regulated isozymes

1) gender specific expression in rodents

2) regulated by growth hormone levels

3) CYP2C19 polymorphisms

a) there are 7 different 2C isozymes in human

b) mephenytoin metabolism is marker activity

1) 3 – 5 % of Caucasians

2) 20 – 25% of Asians

c) CYP2C19 metabolizes many drugs of pharmacologic significance

1) omeprazole, imipramine, propranolol, hexobarbital, diazepam, etc.

2) taxol

h. CYP2D6 – human P450 isozyme – exhibits polymorphisms

1) debrisoquine

polymorphism in 4-hydroxylation

autosomal recessive trait

related to increased cancer risk – extensive metabolizers were more susceptible to cancer

P450 2D appears to have an abnormal substrate binding site

2) dextromethorphan

3) codeine

i. CYP2E1

1) ethanol-inducible isozyme

2) production of reactive oxygen species - toxicity

3) polymorphisms

4) role in cancer

5) role in alcohol-related liver dysfunction

j. CYP3A

1) hormonally regulated P450 isozymes

2) CYP3A4 major isozyme found in humans

3) no discernable polymorphisms

4) 10% of patients show poor response to immunosuppressant therapy with the 3A4 substrate cyclosporine

k. non-microsomal oxidations

1) alcohol dehydrogenase

2) aldehyde dehydrogenase

3) xanthine oxidase

4) tyrosine hydroxylase

5) monoamine oxidase

2. reduction

a. location of reductases

1) microsomes

2) cytosol

3) anaerobic microorganisms in the gut

b. types of reduction reactions

1) azoreduction

2) nitroreduction

3) ketoreduction

3. hydrolysis

a. a. esterase

b. 1) succinylcholine apnea

a) due to an esterase deficiency

b) enzyme appears to have an altered affinity for esters

c) affects about 1 in 3000

b. amidase

c. epoxide hydrolase

B. synthetic (phase II) reactions

1. conjugation reactions

a. glucuronidation

1) found in endoplasmic reticulum

2) reacts with hydroxyl, amine or carboxylic acid functions

b. sulfate conjugation

1) found in the cytosol

2) reacts with alcohols, phenols, and aromatic amines

3) saturable

d. acetylation

1) found in the cytosol

2) reacts with primary amines

c. 3) Acetylation polymorphism

a) differences not due to differences in quantity of enzyme

b) in U.S. mostly slow acetylators (0.72)

c) Japanese have a higher percentage of rapid acetylators, whereas peoples of Middle Eastern descent, Scandanavians and Finns have more slow acetylators

d) slow acetylators more likely to exhibit toxic effects

e) specific acetylation disorders

1) Isoniazid-induced neurotoxicity – slow acetylators

2) Isoniazid-induced hepatitis – rapid acetylators

3) Drug-induced lupus erythematosus – slow acetylators

4) Arylamine induced bladder cancer – higher incidence in slow acetylators

5) colorectal cancer – higher incidence in rapid acetylators particularly when associated with rapid CYP1A2 phenotype

d. methylation

1) found in both the cytosol and the endoplasmic reticulum

2) S-adenosyl methionine is the methyl donor

3) reacts with hydroxyl, sulfhydryl, and amine functions

e. glutathione conjugation

1) superfamily of genes found on 11 chromosomes

2) found in the cytosol and mitochondria (kappa) of liver and numerous other tissues

3) exists as a functional dimer

4) mu, pi, sigma (tyrosine) and theta (serine)

5) drug binds to glutathione (glu - - cys-gly)

6) can ultimately form mercapturic acids

7) reacts with:

a) aromatic hydrocarbons (epoxides)

b) arylamines

c) organic halides

a) phenols

b) some have ligand-binding capabilities (ligandins)

8) alpha class GSTs are inducible by ingestion of high levels of brussels spouts

9) polymorphisms

a) four classes – GSTM1 to GSTM4

b) GSTM1 is polymorphic (*0, *a, and *b)

1) null gene, increased risk of cancer

2) essentially absent in 20 – 50% of all individuals

c) GSTP1 (four allelic variants)

d) ethnic component

1) higher percentage of null gene in Asians than Caucasians

2) lower percentage in blacks

e) links between GSTM1 null phenotype and pituitary adenomas, head and neck cancer, malignant melanoma, colorectal cancer and bladder carcinoma

f) association of lack of GSTM1 with lung cancer in heavy smokers

g) appears to be linked to a combined GSTM1 null and CYP1A1 Msp I.

f. glycine conjugation

1) found in both the cytosol and mitochondria

2) reacts with aliphatic acids and aromatic carboxylic acids

3) can be saturated

4) developmentally induced

Factors that Affect Drug Metabolism

Age

A. Developmental changes

B. Changes with senescence

Induction and Inhibition by Foreign Compounds

A. Administration of drugs and chemicals can induce P450 and other drug metabolizing enzymes

1. phenobarbital and other drugs

2. polycyclic hydrocarbons and carcinogenesis

3. ethanol

B. Inhibitors of drug metabolism

1. ethanol

2. cimetidine

Dietary factors

A. charcoal broiled beef

B. vitamin deficiencies

C. brussel sprouts

D. grapefruit

Species differences

A. quantitative differences

B. qualitative differences

Clinical Pharmacokinetics

Compartmental Modeling

A. One compartment model

B. Two compartment model

C. Intravenous Bolus (One compartment model)

1. Elimination rate constant

2. Half-life

3. Relationship between elimination rate constant and half-life

t1/2 = 0.693/kel

4. Zero order kinetics

C. Single Extravascular Administration

1. Elimination rate constant is calculated the same way as for an i.v. bolus

2. Absorption rate constant

3. Effect of absorption rate

D. Intravenous Bolus (Two compartment model)

1. calculation and significance of the disposition rate constant

2. distribution rate constant

E. Single Extravascular Dose (Two compartment model)

Volume of Distribution

A. Apparent volume into which a drug distributes in the body

B. How it is calculated

1. Inject a known quantity of drug as an i.v. bolus

2. Take blood samples at various times after injection

3. Plot data on a semilogarithmic plot and extrapolate back to t = 0 to calculate the concentration prior to elimination

4. Take values and plug into the following formula:

VD = __amount of drug___ = X0/Cp

plasma concentration

C. Factors affecting volume of distribution

Clearance

A. Total clearance

1. ClT = kel * VD

2. ClT = X0/Area under the curve

3. ClT = Clliver + Clkidney + Clother

B. Hepatic clearance

1. Extraction ratio

2. Relationship between Cl

C. Renal clearance

Bioavailability

A. area under the curve

B. time to peak drug concentration

Intravenous Infusion

A. Conditions

1. constant rate of drug administration (zero order)

2. proportional elimination of drug (first order)

B. Css = infusion rate/ClT

C. Adjustments to dosage – the Css is directly proportional to the infusion rate (dose)

D. Time required to achieve Css

E. Relationship between i.v. infusion and i.v. bolus

F. Effect of alteration in infusion rate

Repeated intravenous injections

A. Relationship between frequency of administration and Css

Left panel – A drug with a t1/2 = 5 h is administered after virtually all of the drug is eliminated. Right panel – A drug with a t1/2 = 5 is administered about once every half-life. Note the greater accumulation of drug and decreased fluctuations.

B. Relationship between dose and Css

C. Relationship between t1/2 and Css

The above graph depicts two drugs that are administered with the same frequency, but have different half-lives. The drug with the shorter half-life reaches its steady state concentration more rapidly. The drug with the longer half-life exhibits a much greater accumulation in the blood and shows smaller fluctuations (on a percentage basis).

D. Loading dose

Repeated extravascular administration

Principles of Pharmacology

Pharmacokinetics Problem Set

January 2009

1. A patient was administered an analgesic drug by a single 12 mg intravenous injection. Blood samples were then taken at various times and the following results were obtained.

What type of pharmacokinetic model is followed by this data? Calculate the t1/2, the elimination rate constant and the apparent volume of distribution for the drug. What is the total body clearance for this drug?

2. You have decided to administer the drug described in question #1 by intravenous infusion at a rate of 3.7 mg/min. How long will it take before steady state is attained? What is the Css after intravenous infusion? The drug was administered to the patient for 10 days, after which administration was discontinued. What would the drug concentration be 9 hrs. after administration was stopped?

You want to give the drug orally in four separate doses, and you know that 20% of the drug will be inactivated by first pass metabolism. What dose of this drug would you prescribe if you wanted to achieve a steady state plasma concentration of 0.29 mg/L.

3. A new drug used in the treatment of asthma was administered by i.v. infusion at a rate of 1 (g/min. A graph of the infusion is shown.

a. What is the half-life of this drug?

b. Also calculate the elimination rate constant, the volume of distribution, and total body clearance for this drug.

c. The drug is eliminated 20% by renal and 80% by hepatic mechanisms. If there is a 50% hepatic failure, then what is the new steady state concentration?

d. If the drug was administered by oral administration how many hours would be required to attain steady state?

e. If the drug (no hepatic failure) when taken orally has only a 40% bioavailability when compared to the intravenous route, then what oral dose would be required to attain a steady state concentration of 2 (g/ml (the drug is to be administered every 12 h).

f. Provide a possible explanation for the low bioavailability of this drug.

4. Blood ethanol data were obtained from a patient on admission and at various times afterward. The following graph of the data was obtained.

What is the pharmacokinetic model? Calculate the rate of disappearance of the drug.

Answers

1. One compartment Model

t1/2 = 3 hrs

kel = 0.231/ hr

Vd = 375 liters

ClT = 86.6 Liter/h or 1444 ml/min

2. Css = 2.56 µg/ml

12 – 15 hrs to attain steady state

C9 hrs = 0.32 µg/ml

Dose = 31.4 mg/hr = 753.6 mg/day (or 4 x 188 mg)

3. t1/2 = 10 hrs (from graph)

kel = 0.0693/hr

ClT = 50 ml/min

Vd = 43.3 liters

ClR = 10 ml/min

ClH = 40 ml/min

with 50% hepatic failure, ClH is decreased to 20 ml/min

therefore ClTmodified = 30 ml/min

Css = 33µg/liter

Recalculate time to achieve steady state:

t1/2 = 16.7 hrs

time to steady state = 66 - 83 hrs

Calculation of oral dose 180 mg every 12 hrs

4. zero order decay

20 mg (100 ml)-1(hr)-1

for zero order reactions v = kel, therefore kel = 20 mg/100ml/hr.

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Total Body Volume

A

A

A

absorption

elimination

Central compartment

Peripheral compartment

A

A

A

A

distribution

absorption

elimination

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