Veterinary Pharmacology - Chapter 4: Pharmacokinetics

Pharmacokinetics

The physiological movement of drugs within the body and includes the mechanisms by which drugs move into, through, and out of the body

Four steps in pharmacokinetics:

- Absorption
- Distribution
- Metabolism or biotransformation
- Excretion

Four basic mechanisms allow drugs to move across cell membranes:

- Passive diffusion
- Facilitated diffusion
- Active transportation
- Pinocytosis/phagocytosis

Passive Diffusion

- The movement of drug molecules (particles) from an area of high concentration to an area of low concentration until equilibrium is reached
- Does not require energy, nor does it expend energy
- The porse in the cell membrane are small, therefore, drugs

Lipophilic

- Means fat loving
- Lipophilic drugs are chemicals that dissolve in fats or oils
- Are able to dissolve in the phospholipid cell membrane because like molecules dissolve in like molecules

Hydrophilic

- Means water loving
- Hydrophilic drugs are chemicals that dissolve in water
- Hydrophilic drugs do not pass through the lipid-rich cell membranes as easily as lipophilic drugs

Drug Ionization

- Affects the movement of the drug
- The ionization or charge of a drug depends on the pH of the liquid in which it is immersed and the pH of the drug

Ionized Drugs

- Have either a positive or a negative charge
- Nonionized drugs have no charge or are considered neutral
- Ionization or neutrality also affects the hydrophilic and lipophilic properties of a drug
- Nonionized drugs tend to be lipophilic
- Ionized drugs

Facilitated Diffusion

- Passive diffusion that utilizes a special carrier moleculre
- This carrier molecule helps the drug across the cell membrane
- No energy is needed

Active Transport

- Involves both a carrier molecule and energy
- Energy is needed in active transport because drug molecules move against the concentration gradient
- Active transport allows drugs to accumulate in high concentration within a cell or body compartment (ex.

Pinocytosis/Phagocytosis (General Information)

- Pinocytosis and phagocytosis are mechanisms of molecule movemnet in which molecules are physically taken in or engulfed by a cell
- Engulfing liquid or solid particles into the cell require energy
- Pinocytosis and phagocytosis are important for the mov

Pinocytosis

Cell drinking" occurs when the cell membrane surrounds and engulfs liquid particles (ex. insulin)

Phagocytosis

- "Cell eating" occurs when the cell membrane surrounds and engulfs solid particles
- Animal cells acquire nutrients by phagocytosis

Drug Absorption

- The movement of drug from the site of administration into the fluids of the body that will carry it to its site(s) of action
- Absorption is the first step in the pasasge of a drug through the body, unless it is introduced directly into the blood via IV

Factors affecting drug absorption

- Drug factors such as:
- Solubility
- Drug pH
- Molecular size
- Patient factors are:
- Animal's age
- Health status

Bioavailability

- The percent of drug administered that actually enters the systemic circulation
- IV and Intra-arterial drugs immediately enter the systemic blood circulation; therefore, are 100% available

Factors that Affect Bioavailability

- Blood supply to the area (muscles have a better blood supply than subcutaneous areas)
- Surface area of absorption (increased surface area means better absorption)
- Mechanism of drug absorption (diffusion versus active transport, etc...)
- Dosage form

pH

- The pH of the drug and the pH of the environment where the drug is administered both play a role in drug absorption
- pH is the measurement of the acidity of alkalinity of a substance
- pH is based on a scale of 0-14 with the lower numbers indicating ac

Acidic vs. Alkaline

The acidic or alkaline nature of the drug itself also helps determine whether a drug is predominately in lipophilic or hydrophilic form

Drug: Weak Acid
Environment: Alkaline

Form: Hydrophilic

Drug: Acid
Environment: Alkaline

Form: Ionized

Drug: Weak Alkaline
Environment: Acid

Form: Hydrophilic

Drug: Alkaline
Environment: Acid

Form: Ionized

Ion Trapping

- Occurs when a drug molecule changes from ionized to nonionized form as it moves from one body compartment to another
- When the drug changes compartments, it may change its ionization and become trapped in that new environment

Oral vs. Parenteral Drug Forms

- Absorption is further affected by the choice of oral or parenteral route of administration
- Solid drugs administered orally must first be broken down and then dissolved in gastric or intestinal fluids before they can be dissolved
- Parenterally adminis

Patient factors affecting drug absorption:

- Blood Flow
- Pain
- Stress
- Hunger
- Fasting
- Food consumption
- pH

Drug Distribution

- The physiological movement of drugs from the systemic circulation to the tissues
- the goal of drug distribution is for the drug to reach the target tissue or intended site of action

Factors that affect drug distribution:

- Membrane permeability
- Tissue perfusion
- Protein binding
- Volume of distribution

Membrane Permeability (Drug Distribution)

- Has a great effect on drug distribution
- Blood capillaries are only one cell layer thick and have fenestrations or small holes between cells to allow drug molecules to move in and out of the capillaries
- Exceptions: Blood-brain barrier (no fenestratio

Tissue Perfusion (Drug Distribution)

- Tissue perfusions affects how rapidly drugs will be distributed
- Tissue perfusion is the relative amount of blood supply to an area or body system
- Fast perfusion - brain, heart, liver, kidneys
- Slow perfusion - fat, skin

Protein Binding (Drug Distribution)

- Some drugs bind to proteins in the blood (particularly albumin)
- Proteins are large and cannot leave the capillaries, so the drug-protein complexes become trapped in the circulation
- Free or unbound drugs are able to leave the capillaries
- Liver dise

Volume of Distribution (Drug Distribution)

- How well a drug is distributed throughout the body based on the concentration of drug in the blood
- Drug concentration in blood will be lower if the drug has a large volume to distribute itself through

Biotransformation (aka Drug Metabolism)

- The chemical alteration of drug molecules by the body cells of patients to a metabolite that is in an activated from an inactivated form, and/or a toxic form
- The goal of biotransformation is to make drugs more water soluble so that they can be more ea

Primary site of biotransformation

- The Liver
- Other sites of biotransformation include
- Kidneys
- Small intestines
- Brain and neurological tissue
- Lungs
- Skin

Ways drugs interact with each other include:

- Altered absorption
- Competition for plasma proteins
- Altered excretion
- Altered metabolism

Altered absorption

One drug may alter the absorption of other drugs (ex. Antacids)

Competition for Plasma Proteins

Drug A and Drug B may both bind to plasma proteins

Altered Excretion

Some drugs may act directly on the kidney and decrease the excretion of other drugs (ex. Diuretics)

Altered Metabolism

The same enzymes may be needed for biotransformation of both drugs

Tolerance

The decrease response to a drug resulting from repeated use
An animal that develops tolerance requires a larger dose of drug to achieve the effect originally obtained by a smaller dose

Drug Elimination (Excretion)

Removal of a drug from the body

Routes of drug elimination include:

- Kidneys
- Liver
- Intestine
- Lungs
- Milk
- Saliva
- Sweat

Renal Elimination

- Glomerular filtration occurs at the level of the nephron and works by pushing water and small molecules through a tuft of capillaries called the glomerulus, similar to pushing things through a sieve

Tubular Secretion

- Active transport across the convoluted tubule membrane that moves certain molecules from blood into the urine filtrate
- Is generally a more rapid process of elimination than glomerular filtration

Hepatic Elimination

- Drugs excreted by the liver usually move by passive diffusion from the blood into the liver
- Once in the liver, they are secreted into the bile
- The bile is then secreted into the duodenum
- If lipophilic drug -- goes back to the liver
- If hydrophili

Drug Action

- Drugs can form a chemical bond with specific cell components on target cells within the animal's body
- These specific cell components are called receptors
- Receptors are three-dimensional proteins that are usually located on the cell membrane, but may

Affinity

- The strength of binding between a drug and its receptor
- The better the drug fits at the receptor site, the more biologically active it is

Agonist

A drug that binds to a cell receptor and causes action

Antagonist

A drug that inhibits or blocks the respose of a cell when the drug is bound to the receptors