pharmacokinetics: ADME Flashcards
What is pharmacokinetics?
The effects of drugs moving through the body.
What are the four key processes in pharmacokinetics? ADME
Absorption
Distribution
Metabolism
Excretion
Absorption
Entry of the drug into the systemic circulation.
Distribution
Spread of the drug throughout the body.
Metabolism
Processing of the drug by the body.
Excretion
Removal of the drug from the body.
What is pharmacodynamics?
The interaction of a drug at “targets” within the body, such as receptors.
How is pharmacokinetics different from pharmacodynamics?
Pharmacokinetics studies how long it takes a drug to reach its target, while
Pharmacodynamics examines the drug’s effectiveness once it reaches its site of action.
What is drug absorption?
The movement of the drug from its site of administration into the bloodstream.
When is a drug considered absorbed?
Once it has entered the bloodstream.
How are orally administered drugs absorbed?
Mucous membranes
stomach
small intestine
T or F: Intravenous (I.V.) bypasses the absorption phase entirely.
True
Why must most drugs pass through cell membranes and why is this important?
To reach their target sites in the body which determines its effectiveness
What is a cell membrane composed of?
Two opposing layers of lipid molecules, forming a lipid bilayer.
What way do the hydrophilic heads of the lipid bilayer face?
Outward
Which way are the hydrophobic tails of the lipid bilayer facing?
Inward toward each other
Is energy required for simple diffusion?
No, it is a passive mechanism.
How do molecules move during simple diffusion?
From an area of high concentration to an area of lower concentration without assistance of a carrier protein.
How does the surface area of a biological membrane affect simple diffusion?
Larger surface areas allow faster diffusion than smaller ones.
How does the concentration gradient influence simple diffusion?
Larger concentration gradients move drugs more quickly than smaller ones.
How does molecule size affect diffusion?
Smaller molecules diffuse faster than larger ones.
How does membrane thickness influence diffusion?
Thinner membranes allow faster diffusion than thicker ones.
How does lipid solubility impact diffusion?
What decreases lipid solubility?
Molecules with higher lipid solubility diffuse faster.
Polarity and ionization can decrease lipid solubility and slow diffusion.
How do molecules move in carrier-mediated facilitated diffusion?
They move from an area of high concentration to one of lower concentration with the assistance of a carrier protein.
What types of molecules are transported by carrier proteins?
Large
polar (and nonpolar)
ionized molecules
Are carrier proteins selective and do they have a maximum rate of activty?
Yes
What is the rate of activity for a carrier protein?
10,000 ions per second.
How are charged ions moved in channel-mediated facilitated diffusion?
Through voltage-gated or ligand-gated channels.
Are channel proteins selective and have a maximum rate of activity?
Yes
What ions are moved by voltage-gated channels?
Ca²⁺, K⁺, Na⁺.
What molecules are moved by ligand-gated channels?
Glutamate, GABAA, Acetylcholine, 5-HT3.
What types of drugs benefit from active transport?
polar and/or not lipid-soluble.
What is required for active transport to occur?
A specialized transport protein and cellular energy.
What are the characteristics of the active transport process?
Saturable (has a maximum rate)
specific
competitive
Can active transport move substances against a concentration gradient?
Yes
How does lipid solubility affect drug movement across biological membranes?
Drugs with higher lipid solubility pass through biological membranes more easily than those with lower lipid solubility.
What is polarity?
Electrical balance of a molecule.
Why might low water solubility be a challenge for drug administration?
Require specially formulated vehicles for injection, making some water solubility desirable.
Which type of drug dissolves easily in water?
Polar drugs.
Which type of drug crosses lipid membranes more easily?
Nonpolar drugs.
What is the typical chemical nature of most drugs?
weak acids or bases existing in equilibrium between ionized and unionized forms.
What is ionization?
The process of gaining or losing electrons.
What are the solubility properties of ionized drug forms?
water-soluble
What are the solubility properties of unionized drug forms?
lipid-soluble
Which form of a drug is more soluble in cell membranes?
Un-ionized drugs
What type of drugs easily penetrate membranes?
un-ionized, non-polar drugs
Acidic drugs are more ionized in a ____ enviornment
basic
environment
Basic drugs are more ionized in an _____ environment
acidic
environment
What is the enteral route of administration?
Administration involving the gastrointestinal system (e.g., mouth, stomach, intestine).
What is the parenteral route of administration?
Administration that doesnt involve the gastrointestinal system, typically involving injection.
What is the topical route of administration?
Administration where drugs are applied directly to the skin.
Examples of Enteral administration
Sublingual
Oral
Rectal
What are the advantages of sublingual and buccal drug administration?
Rapid onset (sublingual faster than buccal)
Complete absorption
Avoids the first-pass effect
What are the disadvantages of sublingual and buccal drug administration?
Enzymes in saliva may degrade the drug
Compliance can be difficult
Limited to drugs that are sufficiently potent and easily absorbed
What are the advantages of oral drug administration?
Convenient
Economical
Non-invasive, often safer route
Requires no special training
What are the disadvantages of oral drug administration?
Slow onset of effects
Drug delivery can be erratic and incomplete
May cause GI tract irritation (e.g., nausea, vomiting, gastric bleeding)
Highly dependent on patient compliance
Increased risk of drug-drug and drug-nutrient interactions
Many drugs degrade in the GI environment
Exposes drugs to the first-pass effect
What is the pH and surface area of the stomach?
pH: 2-3; Total surface area: less than 1 square meter.
What is the pH and surface area of the small intestine?
pH: 6-7; Total surface area: greater than 250 square meters.
What is first-pass metabolism?
The elimination of a fraction of a drug during its first passage through the liver, preventing it from reaching the target organ.
Can first-pass metabolism be saturated?
Yes, the liver’s ability to metabolize the drug can reach its maximum capacity.
Why does first-pass metabolism occur?
Because oral drugs enter the hepatic portal system after gut absorption.
Which drugs are affected by first-pass metabolism?
Any oral drug metabolized in the liver or the gut.
What are the advantages of rectal administration?
Can be used when patients cannot take oral medications.
Suitable for pediatric patients.
Partially avoids first-pass metabolism.
What are the disadvantages of rectal administration?
Absorption from solid dosage forms can be erratic.
Many patients have an aversion to rectal administration.
What are the advantages of intravenous (IV) administration?
Rapidly achieves target concentration in blood.
Precise delivery of dose.
Doses are easy to titrate.
What are the disadvantages of intravenous (IV) administration?
Risk of toxicity due to high initial concentration.
Risk of infection.
Requires trained personnel.
What are the advantages of subcutaneous (SC) administration?
Little training required for SC injection.
Avoids harsh GI environment.
What are the advantages of intramuscular (IM) administration?
More consistent dosing than oral administration.
Faster onset than oral dosing.
Sustained effects possible with certain drugs (depot).
What are the disadvantages of subcutaneous (SC) and intramuscular (IM) administration?
SC cannot be used with large injection volumes (>2 ml).
Potential pain and tissue damage.
Variability in absorption from different injection sites.
What are the advantages of topical administration?
Minimizes systemic side effects when used for local effects.
Avoids first-pass effect.
What are the disadvantages of topical administration?
Cosmetically unappealing.
Can demonstrate erratic absorption.
What are the advantages of pulmonary and intranasal administration?
Very rapid onset of action.
Avoids first-pass metabolism.
Dose can often be easily titrated (vapors and gases).
What are the disadvantages of pulmonary and intranasal administration?
Aversive odors.
Bulky/expensive equipment (vapors and gases).
What is drug distribution?
The passage of drugs from the bloodstream to various tissues.
What factors influence drug distribution?
Ability to cross biological barriers.
Physicochemical properties of drugs.
Blood flow to tissue.
Plasma proteins binding (ability of drug to exit the vascular system).
T or F: Drugs constantly move between different body compartments until they are eliminated.
True
What does perfusion refer to in drug distribution?
how much blood a tissue receives.
When is perfusion-rate important in drug distribution?
When biological membranes are not a barrier to distribution:
small and highly lipophilic drugs
loose cellular membranes.
Does Perfusion rate differs depending upon tissue type?
Yes, with a direct correlation between tissue perfusion and distribution time.
rapidly perfused tissues
brain, liver, kidney
less rapidly perfused tissues
muscle
skin
poorly perfused tissues
fat
Permeability refers to?
how well a drug
crosses biological membranes
factors of drugs that affect permeability
Polar drugs
Size
Ionization
T or F: Membrane permeability can vary depending upon tissue type.
True
Distribution is limited by permeability when?
Drug is ionized, polar and water soluble
When a selective barrier restricts drug access
(e.g. BBB)
Distribution is limited by perfusion when?
Drug is unionized, nonpolar and water soluble
Membrane is highly permeable
What blood proteins can bind drugs
preventing them from reaching target sites?
Plasma Binding Proteins
What are 3 examples of plasma biding proteins?
Albumin
Glycoprotein and lipoproteins
Globulin
Albumin is associated with which drugs?
acidic drugs
Glycoprotein and lipoproteins are associated with which drugs?
basic drugs
Globulin is associated with which drugs?
Endogenous substances
Only the ______________ drug is available for pharmacologic effect and for metabolism
free (unbound)
What are some highly protein bound drugs?
Ibuprofen (Advil)
Naproxen (Aleve)
Warfarin
Diazepam (Valium)
Heparin
Fluoxetine (Prozac)
Doxycycline
in plasma protein binding, small change in binding results in ____________ change in free drug concentrations
large
Plasma protein binding is important for drugs with _____________ therapeutic window
narrow
What is volume of distribution?
Reflection of the amount left in the blood stream after all the drug has been absorbed
if drug is ‘held’ in the blood stream and doesn’t get to other tissues it will have a _______________ volume of distribution
Small
if very little drug remains in blood stream because it accumulates and is stored in deep tissues it has a __________ volume of distribution
Large
What does a low Volume of Distribution (Vd) indicate about a drug’s location in the body?
Most of the drug is found in the bloodstream and is likely bound to plasma proteins.
T or F: Many acidic drugs have a low volume of distribution
True
If the Vd is close to total body fluids (20-40 liters) what does it indicate?
The drug is distributed throughout the fluid compartments of the body.
If the Vd is larger than total body fluids (>40 liters) what does it indicate?
The drug is bound in peripheral tissues.
What is the primary function of the Blood-Brain Barrier (BBB)?
To protect the brain from foreign substances in the blood.
How does the structure of the BBB differ from other body membranes?
It has high cerebral blood flow and allows only lipid-soluble drugs to cross.
the blood brain barrier is present in what percentage of brain capillaries?
85%
The blood brain barrier does not exist in which areas?
hypothalamus
pituitary gland
brainstem area
How are brain capillaries different from capillaries in the rest of the body?
structurally closed, making them selectively permeable to blood contents.
What must blood contents cross to enter neurons in the brain?
capillary wall and a layer of astrocyte cells
How do most drugs distribute across the placenta?
By passive diffusion.
Which types of drugs cross the placenta easily?
Non-ionized and small-sized drugs.
What effects can some drugs have on the fetus?
fetal death
birth defects
drug dependence
respiratory depression in neonates.
Which drugs have difficulty crossing the placenta?
Highly-ionized or very large-sized drugs.
What is the usual effect of biotransformation on a drug?
It usually inactivates the drug.
How can biotransformation activate a drug?
By transforming an inactive prodrug into an active drug (e.g., aspirin, some benzodiazepines).
T/F: Biotransformation can generate toxic metabolites
True, Ex: Acetaminophen
How does biotransformation affect drug properties?
It makes drugs more polar and ionized.
What are examples of phase 1 / nonsynthetic reactions during drug metabolism? (3)
Hydrolysis
Reduction
Oxidation
What is hydrolysis
Splitting water atom
oxidation involves the ___________ of electrons
loss
What is the function of Cytochrome P450?
mediator of metabolism of most drugs
reduction involves the __________ of electrons
gain
Phase II Conjugation Reactions
- Synthetic reaction
- Glucuronide
- Acetyl
- Glycine
- Glucuronidation
what is Glucuronidation?
a major mechanism used by the liver to detoxify molecules.
what factors alter metabolism?
Induction
Reduction
Age
Biological sex
Genetics
Nutrition
Environmental toxin exposure
what is elimination?
the irreversible removal of the parent drug from the body and termination of its effects
What are the two major organs for drug elimination?
kidneys and liver
What are the three mechanisms of elimination in the kidney?
Glomerular Filtration
Tubular Reabsorption
Tubular Secretion
glomerular filtration
the movement of substances from the blood within the glomerulus into the capsular space
The enterohepatic cycle
Elimination of conjugated drugs through bile into the intestine.
Pulmonary Elimination
Gas molecules move out of blood and into lungs to be eliminated in expelled air
For most drugs degree of receptor binding / magnitude of drug effect is related to _____________________
plasma concentration
Elimination processes usually follow what?
first order kinetics
Elimination usually slower process than what?
absorption or distribution
Zero order drug kinetics
Constant amount of drug eliminated per unit of time
What has zero order kinetics?
alcohol
first-order kinetics
Rate of elimination is a constant percentage of total drug in the plasma
half life
Amount of time required for the concentration of drug to fall by 1/2
