Pharmacokinetics

Pharmacokinetics

What the body does to a drug

ADME

Absorption, Distribution, Metabolism, Excretion

7 routes of administration of a drug

* oral
* sublingual
* injection
* inhalation
* transdermal
* topical
* rectal

Sublingual

Tablet underneath the tongue, absorbed directly into blood vessels and into bloodstream

Injection

Intravenously, subcutaneous, intramuscular

Inhalation

Includes intranasal, specific target of the lungs typically

Transdermal

Patches, slowly released into the skin, patches often used for a bout 1 week

Topical

Ointments/creams, only used for local skin effect

Rectal

Used for lower GI tract problems or is oral administration is not possible

Bioavailabiluty

Fraction of administered drug that reaches the systemic circulation

Bioavailability equation

Amount of drug in systemic circulation/Amount of drug administered

What is the bioavailability of a drug delivered intravenously?

100%

What is the main site of absorption for drugs?

Small intestine

4 factors influencing oral absorption of a drug

1) Molecular size/composition

2) Gastric emptying time

3) Intestinal transporters

4) Hepatic metabolism

Ability of a drug to cross membranes can be impacted by what?

Lipid solubility and polarity

What kind of drugs can easily move into cell membranes?

Lipophilic drugs

Cells that are not lipophilic must cross membranes by what?

Moving between cells

If a drug is polar, is it ionized or unionized?

Ionized

Why do polar molecules have more difficulty crossing cell membranes?

They are physically larger molecules

Weakly acidic drugs will do what in an acidic environment?

Remain unionized

Weakly basic drugs will do what in an acidic environment?

Become ionized

Acid is what?

Proton donor

Base is what?

Proton acceptor

Ion trapping

In the 2-compartment model, a drug may become trapped as it shifts compartments moving from a non-ionized state to an ionized state

What is an example of realistic ion trapping?

A mother and fetus, the drug in the mother is a weak base (non-ionized) and is easily transferred to the fetus which makes the drug transfer into the ionized form and it is then trapped in fetal circulation

Gastric emptying time

altering the rate that drug is emptied from the stomach to the small intestine will alter the rate of absorption

What typically delays gastric emptying?

Food

What components of food can bind to drugs and reduce their absorption?

Ca, Mg, Fe - makes drug larger and more difficult to absorb

Labile

Sensitive to acid

If a drug is labile, what would you want to do to increase its effectiveness?

Take the drug without food and decrease the time it is spent in the stomach

If a drug was corrosive to the stomach, what would you want to do to prevent stomach damage?

Take the drug with food so the drug is less likely to damage the stomach

What can you do to a drug in order to protect the stomach/person further?

Coat the drug - will only release at a certain pH level, or will be broken down slower

Intestinal transporters

P-glycoprotein (Pg-P) efflux pumps that push drug from enterocyte back into lumen of intestine

Where is Pg-P found?

Intestines, brain, kidney tubules, liver, placenta

Hepatic metabolism

Drugs take a first pass through the liver before reaching the systemic circulation

Oral absorption through the body steps:

1) Mouth

2) Stomach

3) Small intestine

4) Liver - metabolic enzymes

5) Systemic circulation

What factors are taken into consideration when deciding which route to administer a drug? (5)\`

* Drug properties
* Target
* Onset of action
* Patient characteristics
* Patient compliance

What is the fastest acting drug?

IV

Drug properties

Some drugs cannot withstand harsh environments of the stomach

Target

Systemic or local anesthetic given by injection

Onset of action

What provides the fastest action (within reason)

Patient characteristics

Is oral route available?

Gold standard of providing medication

Oral route, easiest, most accessible to most people

Distribution

The reversible movement of drug between body compartments

Distribution depends on: (4)

* blood flow
* capillary permeability
* protein binding
* tissue binding

Which organs receive drug first? Why?

Liver, brain, kidneys - they have the most blood flow

Capillary permeability

The composition of capillaries determines how freely a drug can move from blood to tissue

Blood brain barrier

Passage of certain drugs is limited due to the tightly packed cells (needs transporter if not lipophilic)

Liver cells and drug entrance

Drugs easily passed through cell membranes in liver because widely spaced

Protein binding

Drugs bound to proteins in blood are unable to diffuse into tissue; some drugs bound extensively to plasma proteins

Tissue binding

Drugs can bind to other tissues like fat and hide out, also can bind to muscle

Which drugs are more likely to be found in fat

Highly lipophilic drugs

Volume of distribution

A theoretical volume in which the total amount of administered drug should be uniformly distributed to account for its plasma concentration

Volume of distribution equation

Dose administered/Plasma concentration

If a drug has a low Vd, what does this suggest?

The drug is mostly intravascular and highly bound to plasma proteins

If a drug has a high Vd, what does this suggest?

The drug is distributed everywhere in the body

Metabolism 2 main purposes:

1) Makes drug more hydrophilic to facilitate excretion

2) Changes the activity of a drug - usually inactivates it

What is metabolism carried out by in the liver?

Enzymes

Prodrug

Drugs that are activated by metabolism (codeine to morphine)

2 types of enzymatic reactions:

I) Phase I

II) Phase II

Phase I enzymatic reaction

Oxidation/reduction reaction

Purpose of the oxidation/reduction reaction to drugs

Makes drug more polar/soluble in order to excrete it, uses P450 (CYP450) enzyme family

Phase II enzymatic reactions to drugs

Conjugation reaction

Conjugation reaction purpose

Results in highly polar, inactive molecule that is ready to be excreted

Conjugation reaction involves

Addition of a chemical group to the drug; glucuronic acid, sulfate, glutathione, amino acid, acetate

Clearance

The volume of blood from which a drug is irreversibly removed per unit of time (mL/min)

Excretion

Irreversibly loss of the drug

Excretion ways (4)

* feces
* urine
* sweat
* breast milk

Processes that impact renal excretion

* Filtration
* Secretion
* Reabsorption

Filtration

Kidney only filters free drug (not plasma protein bound)

Secretion

Occurs at proximal tubule, via transporters, competetive

Reabsorption

Occurs unless drug is very polar

Net drug removed =

Filtered + secreted - reabsorbed

First order kinetics

Constant fraction of drug is eliminates per unit of time, linear

Rate of elimination is proportional to what?

Plasma concentration

Zero order kinetics

Constant amount of drug eliminates per unit of time, not linear if drug amount is increased

Elimination half-life

the amount of time it takes for 50% of a drug to be eliminates from the body

Drugs with short half lives are dosed more or less frequently?

More frequently

How many half-lives does it take for a drug to be considered gone from the body?

5

Why is a drug with a short half-life advantageous?

It leaves the body quickly

Why is a drug with a long half-life advantageous?

It stays in the body longer; needs to be given less often

What two organs play a key role in drug elimination?

Kidneys and liver

Sources of variability of drugs in patients (3)

* drug interactions
* age
* genetics

Most common reasons for drug interactions

Metabolic; involving CYP450 enzymes and results in activity of CYP450 enzyme induced or inhibited

3 Pharmacokinetic interactions in regards to metabolism

1) Enzyme inhibition - competitive

2) Enzyme inhibition - allosteric inhibition

3) Enzyme induction - allosteric induction

Enzyme inhibition - competitive metabolism

One drug binds more avidly, other drug is displaced

Enzyme inhibition - competitive metabolism result

Decreased metabolism of drug A, increased levels of drug A in body (toxicity)

Enzyme inhibition - allosteric inhibition metabolism

Drugs can inhibit other enzyme systems, aside form their own

Enzyme inhibition - allosteric inhibition metabolism result

Decreased metabolism of drug A, increased levels of drug A in body

Enzyme induction - allosteric induction metabolism

Drugs usually induce other enzyme systems, not their own

Enzyme induction - allosteric induction metabolism result

Increased metabolism of drug A, decreased levels of drug A in body

Enterohepatic recycling

Phenomenon where drug cycles between gut and liver because bacteria are able to reactivate the drug (estrogen)

Young absorption

* reduced peristalsis, may reduce rate of absorption
* increased gastric pH

Young distribution

reduced plasma proteins, less plasma protein binding and more drug is free to cross membrane and act at receptors

Young metabolism

Metabolic enzymes not fully developed, reduced ability to eliminate drugs through liver

Young excretion

Renal function impaired, reduced ability to eliminate drugs through kidneys

Old person absorption

* reduced peristalsis, may reduce rate of absorption
* reduced blood flow, may reduce extent of absorption
* increased gastric pH

Old person distribution

* less fluid in body, higher fat proportion


* distribution of hydrophilic drugs reduced
* distribution of hydrophobic drugs increased

Old person metabolism

Impaired hepatic metabolism due to reduced blood flow, reduced liver size, reduced liver enzymes

Old person excretion

Renal function declined, reduced ability to eliminate drugs through kidneys