NUR 3031-002 Pharmacokinetics Lecture

Pharmacokinetics

The study of drug movement through the body or what the body does to the drug

The four pharmacokinetic processes: ADME

Administration/Absorption

Distribution

Metabolism

Excretion

Drug Absorption

Time from administration to entrance into the bloodstream

When is the onset of action determined?

Onset of action is largely determined by the rate of absorption

How is the intensity of effect determined?

Intensity of effect determined by the extent of absorption

What is Bioavailability?

Bioavailablity is the % of dose that enters blood

IV = 100%, PO <100%

Absorption

Diffusion of a molecule from an area of high concentration to an area of low concentration

• The extent of movement depends on the ability of drugs to pass to and from the major spaces of the body: intracellular, intravascular, and interstitial.

• Drugs can pass freely netween wide junctions, or gaps, in a capillary wall

Where can drugs pass?

Freely between wide junctions, or gaps, in a capillary wall.

Sometimes they must pass across membranes through channels or pores, transport systems, or through direct penetration

For a drug to pass through direct penetration, what must happen?

The drug must be lipid soluble, nonpolar, or nonionized

Mechanisms of Drug Transport: Passive Diffusion

Lipophilic

Small Size

Mechanisms of Drug Transport: Active Transport

Electrolytes

Mechanisms of Drug Transport: Carrier Proteins

Structurally selective

Hormones

Mechanisms of Drug Transport: Endocytosis

Immune Complexes

Rules of Drug Absorption: Liquids

Liquids absorb faster than pills

Rules of Drug Absorption: Food

Food in the stomach impairs absorption

Rules of Drug Absorption: Location of Absorption

Most absorption occurs in the duodenum

Sometimes, the skin, mucous membranes, and lungs serve as additional sites of absorption.

Rules of Drug Absorption: Administration

IM/SC administration results in faster absorption

Routes of Administration: Parenteral

Parenteral is the space between the eccentric canal and the surface of the body (outside of the GI tract)

• IM

• IV

• SubQ

Routes of Administration: Parenteral Locations

Intravenous (IV)

Intramuscular (IM)

Subcutaneous (subQ)

Routes of Administration: Enteral

Using the GI tract

Routes of Administration: Parenteral (IV) Implications for absorption:

No barriers to absorption

Direct pattern of absorption

Routes of Administration: Parenteral (IV) Advantages

Rapid onset, control of level of drug, ability to administer large volumes of fluid

Routes of Administration: Parenteral (IV) Disadvantages

• Expensive

• Inconvenient

• Can't take it back

• Infection

• Fluid overload

• Embolism

Routes of Administration: (IM) and (subQ) Implications for absorption:

No barriers to absorption

Rapid or slow

Water solubility of the drug

Blood flow to the site of injection

Routes of Administration: (IM) and (subQ): Advantages

Good for meds with poor water solubility

Used for the administration of depot preparations

Routes of Administration: (IM) and (subQ): Disadvantages

• Discomfort

• inconvenience

• Painful

• infection

• nerve damage

Routes of Administration: Oral (PO): Implications for Absorption

Solubility/Stability of the drug

Gastric and Intestinal pH

Gastric emptying time

Presence of food

Co-Administration of other drugs

Coatings on the drugs

Routes of Administration: Oral (PO) Advantages

Easy, convenient, safe

Additional routes of administration

Topical: Transdermal; Sublingual

Inhalation

Suppository

Direct injection to the site of action

Factors Affecting Absorption

- Route

- Formulation of drug: dyes, binders, coatings, solubilizers, liposomal preparation

- Particle size

- Acid-base properties

- Temperature

- Blood flow

Distribution

Drugs exit blood vessels through capillary walls to reach sites of action.

Dependent on blood flow, vascular permeability, cardiac output, etc.

What are hard(er) to enter spaces: BBB

Tight junctions between cells block most drugs from entering the brain

- In infants, this barrier isn't fully formed yet, which allows more drugs to cross. They also have a higher risk of CNS effects.

What are hard(er) to enter spaces: Blood-Testes Barrier

Tight junctions block many drugs from entering the testes.

What are hard(er) to enter spaces: Placenta

Not a true barrier; most drugs can cross to the fetus due to lipid solubility

Distribution: Protein Binding

Many drugs bind to albumin (a plasma protein) like a temporary parking spot

What is a bound drug in protein binding?

A bound drug is inactive. It can't reach its target, be metabolized, or be excreted while attached.

What is a free drug in protein binding?

A free drug is active, only unbound drugs produce effects.

Clinical Relevance of Protein Binding

Two drugs can compete for the same albumin-binding sites. If one displaces the other, more free drug is suddenly released -> risk of toxicity, even without a dosage change

Plasma Binding Proteins: Bound Drugs

A bound drug is inactive because of its large size.

- Drug Reservoir

- Released as free drug is utilized

Half-life of Bound Drug

Bound drugs usually have a longer half-life

- Epinephrine 15% bound; half-life is < 5 minutes

- Warfarin 99% bound, half-life is almost 40 hours

Low Plasma Blinding Proteins

Low plasma-binding proteins can increase free drug toxicity.

Areas of Potential Tissue Deposit

- adipose tissue

- 15-50% body weight

- muscle

- bones and teeth

- placenta

- mammary tissue

Consequences of tissue deposits

- Drug reservoir: Anabolic steroids detected long after the last dose.

- Lipid-soluble drugs can cause toxicity if rapid weight loss occurs

- Some drugs may need a loading dose to saturate tissue deposits and establish MEC

Metabolism

Biotransformation- the chemical alteration of a drug's structure

Main site of metabolism if the Liver

Where is the main site of metabolism?

The liver

Special Considerations for Metabolism: First Pass Effect

- Rapid inactivation of some oral drugs as they pass through the liver after being absorbed.

- Parenteral administration will bypass this effect

Special Considerations for Metabolism: Nutritional Status

- Adequate nutritional status provides the required cofactors for the hepatic drug-metabolizing enzymes to function

Special Considerations for Metabolism: Competition between drugs

- Two or more drugs that use the same metabolic pathway may cause a decrease in the metabolism of one or more.

Special Considerations for Metabolism: Age

Infants' livers are not fully developed, which affects their metabolism

Special Considerations for Metabolism: Induction of Drug Metabolizing Enzymes

Some drugs can cause the liver to synthesize more drug-metabolizing enzymes

- This causes an increase in the metabolism of the drug

- Also, increases the metabolism of other drugs

Special Considerations for Metabolism: Inhibition of drug metabolizing enzymes

Decrease rates of drug metabolism

Prodrug:

A biologically inactive compound that can be metabolized in the body to produce a drug

E.g: Codeine into morphine

Therapeutic Consequences of Metabolism

- Accelerated renal excretion of drugs

- Drug inactivation

- Increased therapeutic action

- Activation of "prodrugs"

- Increased toxicity

- Decreased toxicity

Excretion

The removal of drugs from the body

Types of excretion: Renal drug excretion:

Glomerular Excretion

Passive Tubular Reabsorption

Active Tubular Secretion

Factors that modify renal drug excretion

1. pH-dependent ionization

2. Competition for active tubular transport

Non-Renal Routes of Drug Excretion

-Breast milk

-Bile

-Enterohepatic reticulation

-Lungs

-Sweat

-Saliva

Time course of Drug Response: Serum/Plasma Drug Levels

Drug levels are highly predictive of therapeutic and toxic responses

Time course of Drug Responses: Therapeutic Range

- Falls between the MEC and toxic concentration

- Enough drug is present to produce a therapeutic response

- Narrow vs. wide -- Think safety IMPLICATIONS

Minimum Effective Concentration (MEC)

The minimum plasma drug level at which therapeutic effects will occur

Toxic Concentration

The level at which toxic effects occur

Onset of Action

Time from when the drug is administered to when it reaches the minimum effective concentration

- How long it takes to start to have an effect

Duration of Action

Time from when the drug first reaches the minimum effective concentration to when it falls below the minimum effective concentration

- How long does the effect last

Drug Half-Life (t1/2)

The time required for the amount of drug in the body to be decreased by half

Plateu

When a steady level of the drug has been achieved

- When the amount of drug eliminated between doses equals the dose administered.

-It takes four to five half-lives to achieve a plateau

Peak and Trough: Peak

Peak is the highest blood level of a drug

Peak and Trough: Trough

The lowest blood level of a drug

Loading vs Maintenance: Loading Doses

Loading doses are used when a plateau must be achieved quickly

Loading vs Maintenance: Maintenance

Maintenance is smaller doses used once the plateau is achieved

Reducing fluctuations in drug levels

Administer a continuous infusion

Administer a depot preparation

Reduce the size of a dose and the dosing interval