4 - PHA 4107 Week 2 Pharmacokinetics II (Jan 18)

What are the 2 types of drug elimination from the body

1. Metabolism - enzymatic conversion of a drug into another

2. Excretion - elimination of an unchanged drug or its metabolites from the body

2 phases of metabolism

Goal: increase size and polarity of compounds

Phase:

1. Addition of reactive group (-OH,-NH2,-SH) or polar group

   • reactions: oxidation, hydroxylation, reduction

   • Many reactions catalyzed by cytochrome P450 family

2. Conjugation of the reactive group w/ a highly charged, water soluble substrate (e.g., glucuronic acid)

   • reactions: glucuronidation, acetylation, conjugation w/ AA

What are the 4 things that drug metabolizing enzymes could do?

1. Convert active to inactive

2. Activate prodrugs (e.g., tamoxifen)

3. Increase therapeutic action (e.g., codeine to morphine)

4. Decrease toxicity

Where are metabolism processed drugs excreted?

• more readily excreted through kidneys or in bile

Cytochrome P450 enzymes

• large family of heme-containing enzymes that metabolize drugs and endogenous compounds

• Each enzyme family has its distinct substrate specificities

• Drug metabolizing enzymes (CYP 1-3) are at highest concentration in the liver

  • CYP 3A4 most common enzyme subtype in drug metabolism

CYP450 can display _____

Polymorphism — a trait that demonstrates a different activity in >1% of the population

What do PM, EM, and URM stand for?

1. PM: poor metabolizes

2. EM: extensive metabolizes

3. Ultra rapid metabolizer

What is CYP 2D6 required for?

The activation of codeine

What happens when PM take codeine vs URM?

PM: decreased responsiveness to typical doses

URM: suffer from overdoses

What enzyme are drug levels reduced by?

CYP 3A4

Grapefruit juice is an example of a ____ inhibitor, causing an increase in the amount of drug that reaches the liver

CYP 3A4

Special conditions of metabolism

Stereoselectivity: drug metabolizing enzyme may act on diff stereoisomers

• ex. Warfarin ( given as a racemic bc S isomer is 4x as potent as R isomer)

Routes of excretion: Urine

Major route of elimination

3 steps:

1. Glomerular filtration (low MW drugs filtered from blood to urinary filtrate)

2. Passive tubular reabsorption (lipid soluble drugs move back into the blood from a conc gradient)

3. Active tubular secretion (certain drug transporters pump drugs into urine)

Factors that modify excretion:

1. pH dependent ionization

2. Competition for active tubular transport

3. Decreased kidney function

Routes of Excretion: Bile/Feces

Important for excretion of large water soluble compounds. Higher MW.

Enterohepactic cycling: a process when a drug enters the intestine in bile and is reabsorbed into the circulatory system through blood vessels

Routes of Excretion: Expired Air

• common for gaseous drugs (anesthetics)

• Less common for soluble drugs

Routes of Excretion: Breast Milk

• lipid soluble drugs (RARELY polar)

• May risk nursing infants through exposure

Routes of Excretion: Skin

• small amounts of drug via sweat (e.g., benzoic acid)

• Can cause mild dermatitis

Routes of Excretion: Hair

• small amounts excreted through hair (e.g., meth)

• Used forensically rather than therapeutically

Routes of Excretion: Saliva

• pH of saliva varies from 5.8-8.4 therefore unionized lipid soluble drugs excreted passively

• Bitter taste in mouth

• Some drugs inhibit saliva secretion causing dryness

• E.g., caffeine

Difference between first and zero order kinetics

First: a constant FRACTION of the dose eliminated in a given time period

Zero: a constant AMOUNT of the dose is eliminated in a given time period

What is clearance?

A measure of the removal of drug from the body. Typically expressed as the volume of plasma removed in a given time (mL/min)

What range does the therapeutic window fall between?

Between the minimum effective concentration (MEC) and the toxic concentration

• drugs with wide ranges are safe

Plateau

When amount of drug eliminated equals the amount of drug administered

How many half lives will there be for a consistent dose/interval?

5

Loading dose

Large initial dose used to achieve immediate therapeutic effect when time to plateau is too long

Maintenance dose

Smaller dose given after loading dose to maintain drug concentration in the therapeutic range

Pharmacodynamics

The study of what drugs do to the body and how they do it

Dose-response relationship

Relationship between dose and intensity of the response produced

Determines:

• min amount of drug to produce a response

• Max response

• How much to increase dose to produce desired increase in response

4 primary receptor families

1. Cell membrane embedded enzymes/kinase receptors

2. Ligand-gated ion channels

3. GCRPs

4. Transcription factors

Affinity

The measure of how tightly a drug binds to its receptor

Efficacy

A measure of the action of a drug once binding has occurred - determines max response to a drug

Efficacy vs potency

Efficacy: largest effect drug can produce

Potency: amount of drug needed to produce a given effect (lower the dose, higher the potency)

POTENCY OF A DRUG IMPLIES NOTHING ABOUT ITS MAX EFFICACY

When a drug binds to a receptor, it can act in several manners

1. Agonists

   • mimic action of endogenous regulator molecules

2. Antagonists

   • block receptor action

3. Partial agonists

   • Mimic agonist effects but also appear to antagonize the effect of full agonists

4. Inverse agonists

   • bind to a receptor and induces the opposite effect as an agonist

Receptor Regulation

Agonist

• repeated exposure to agonists can desensitize receptors, especially in the case of GCRPs

• Desensitization is due to phosphorylation

• Down-regulation: when the # of receptors decreases from regulation of receptor gene expression

Antagonist

• repeated exposure to antagonists can initially increase response to the receptor

• Called supersensitivity

• Up-regulation: Chronic exposure can increase the number of receptors

Drug tolerance

1. Pharmacodynamic: due to receptor down-regulation

2. Pharmacokinetic: due to accelerated drug elimination

Drug efficacy vs safety

• ED50: the dose required to produce a therapeutic response in 50% of the population (considered standard dose)

• LD50: the average lethal dose (kills 50% of the population)

Therapeutic index

Measure of drug safety

Ratio: LD50/ED50

• Large = safe drug

• Small = unsafe drug