Pharmacokinetics Flashcards
4 properties that determine how rapidly and for how long the drug will appear at the target organ
Absorption, distribution, metabolism, excretion
Routes of administration is determined by which two things?
Properties of the drug (solubility, ionization) Therapeutic objectives (rapid onset, chronic administration, setting at which its used)
2 major routes of administration
Enteral (mouth) and parenteral (not by mouth)
The most simplest and common method of administration
Enteral- by mouth. Swallowed (most common) or placed under tongue.
Advantages and disadvantages to oral administration
Easily self administered
Easily to overcome overdose
Large surface area of absorption in GI tract
Low incidence of infection
Complicated pathway to absorption
Harsh environment of stomach (acidic)
Metabolism by liver happens before it reaches blood stream
Major site of absorption by oral administration?
Mainly small intestine. Some stomach.
Advantages to sub-lingual administration
Rapid absorption
Easily administered
Low incidence of infection
Avoid stomach and first pass metabolism
Preferred route of enteral administration for drugs that undergo extensive first pass metabolism.
Sub-lingual
How does Parenteral administration work?
Introduction of drugs directly across the body’s barrier defenses into systemic circulation or other vascular tissue. Bypasses GI tract.
Used for drugs that are poorly absorbed from the GI tract, if you have an unconscious patient, or need fast.
Parenteral advantages and disadvantages
Pros: Highest bioavailability
Not subject to first pass metabolism
Provides the most control over dosage delivered
Cons:
Can’t get it back
Can cause pain, fear
Infection risk higher
Bioavailability
Amount of drug available for the body to use.
Determined by comparing plasma levels of a drug after a particular route of administration with levels after IV injection.
Area under curve (AUC) oral/ AUC injected
3 major parenteral routes
IV, AV
SC
IM (intramuscular)
Most common parenteral route
IV.
Intramuscular can be which two types?
Aqueous solutions- fast absorption
Depot preparations- slow absorption
-Suspension of drug in a non-aqueous vehicle. Vehicle diffuses out of muscle leaving the drug to precipitate at the site of injection.
Subcutaneous
Injection under the skin. Slower than IV but less risks.
Often combined with epinephrine (a vasoconstrictor) which will decrease the removal of the drug from the site of administration
Other routes of administration
Inhalation: Breathing in. Rapid delivery (almost as fast as IV)
Intranasal
Intrathecal (CSF)
Intravitreous
Topical
Transdermal (through skin. Patch. Variation of absorption rate)
Rectal (minimizes fast pass metabolism. Good for meds that induce vomiting or in a vomiting patient)
Absorption
Transfer of a drug from its site of administration to the bloodstream.
Absorption is completed for __
an IV or IA drug. All other routes have lower absorption and thus lower bioavailability.
Examples of passive diffusion
- Passive diffusion of a water soluble drug through an aqueous channel or pore. No carrier.
- Passive diffusion of lipid soluble drug dissolved in membrane.
Most drugs are either ____ or ___
Weak acids (HA) or weak bases (BH+)
pKa is a property of a ____
pH is a property of a ___
Compound (the drug)
Solution
pKa is a measure of
The strength of the compound/drug interaction with a proton
Low pKa= drug is acid
Higher pKa= drug is basic
Weak acids will be non-ionized in environments with ____ pH
Low pH. Acids like acid. Absorbs better in stomach
Weak bases will be non-ionized in environments with __ pH
High pH. Bases like bases. Absorbs better in sm intestine.
How does blood flow influence absorption
Higher blood flow = greater absorption
Ex: higher blood flow in sm intestine than stomach
How does total surface area influence absorption
Greater surface area= greater absorption
Ex: SA of sm intestine is 100x that of stomach
How does contact time influence absorption
If drug moves quickly, it will not be well absorbed.
Drugs will remain in stomach longer and not make it to small intestine due to sympathetic input (exercise, medications) or presence of food.
What does expression of p-glycoprotein do?
It is a transporter protein that DECREASES absorption.
Cells with high expression of it will not absorb drug easily. The cell will take it in, travel somewhere else, then kick it out.
Bacteria use this protein to their advantage.
Also involved in drug resistance.
Also found in the liver, kidneys, placenta, intestines, and brain capillaries.
5 Factors that affect bioavailability
First pass metabolism Solubility of the drug Chemical stability Formulation of the drug (size, coatings, binders) Concentration
First pass metabolism (affects bioavailability)
Drugs absorbed from the GI tract enter the hepatic circulation before systemic circulation. Even one pass through the liver can alter many drugs. IV drugs will eventually make way to liver after going through the rest of the body first.
In order to be readily absorbed, what solubility should the drug have? (affects bioavailability)
Lipid soluble but have some solubility in aqueous solutions.
Hydrophilic drugs are poorly absorbed- cannot travel through membrane with carrier molecule.
Extremely hydrophobic drugs are poorly absorbed because they cannot dissolve in aqueous body fluids.
Chemical stability (affects bioavailability)
Drugs must be formulated to withstand acidity of the stomach and actions of the enzymes. If not, should not be taken orally.
Formulation factors of a drug (affects bioavailability)
Particle size (smaller is easier)
Binders
Enteric coatings (coating could be acid stable if med is not)
Salt form
Concentration (affects bioavailability)
Absorption can be increased by increasing concentration of drug- but only up to a certain point.
Bioequivalence
Two drugs that demonstrate comparable bioavailability and similar times to achieve peak blood concentrations. Does not have to do with how effective the drug is!!!
Therapeutic equivalence
Two drugs that are comparable in efficacy and safety.
Drug distribution
The process by which a drug diffuses from systemic circulation into the extracellular fluid and/or the cells of the tissues.
What 4 things is drug distribution dependent on?
Blood flow, capillary permeability, protein binding, and lipid solubility of the drug
Brett can play sports
Where is the quickest blood flow to? Where is the slowest?
Brain, liver, and kidneys is fastest/greater.
Slowest blood flow to adipose tissue.
The ability of a drug to diffuse out of capillaries is determined by
The structure of the capillary wall and chemical structure of the drug.
Typical structure of a capillary?
Different from organ to organ.
Single layer of endothelial cells resting on a BM. No surrounding smooth muscle or elastic tissue
Some have slit junctions and fenestrations. Exposes the BM and allows for transport out of the capillary.
Capillary structure in the brain
No junctions or fenestrations (zonulae occludens) EXCEPT 5 areas. Those 5 areas are exposed to drugs that the rest of the brain may not be.
Where are the largest slit junctions in capillaries?
Liver and spleen. Allows for large plasma proteins to pass thru.
How can drugs pass into the brain?
The drug must be able to pass through the endothelial cells or be transported in by specific transporters.
Lipid soluble molecules readily pass through into the CNS.
What is the delayed equilibration of drug between mother and fetus?
10-15 mins.
What capillaries in the eye are fenestrated?
Choroid and ciliary process.
Iris and retina capillaries are impermeable and no back flow from Schlemm’s canal.
- most systemic drugs have a difficult time getting into the eye.
Do lipophilic or lipophobic molecules readily pass through membranes?
Lipophilic
How does protein binding affect drug distribution?
Binding of drugs to plasma proteins makes the molecule too large to pass through any membrane. This is called its non-diffusible form. Will slow transfer out of circulation- traps in capillaries.
The binding is usually reversible.
What is the main plasma protein that binds drugs for protein binding?
Albumin. Causes drugs that are bound to become pharmacologically inactive. AKA drugs will not have the effect you would expect.
Albumin affinity for drug and or drug affinity for albumin differ between drugs
Volume of distribution
Hypothetical volume of fluid into which a drug is dispersed. Cannot measure.
Does volume of distribution remain constant or change over time
Remains constant.
Once a drug enters the body, it has the potential to distribute into any one of the three functionally distinct compartments of body water. What are the 3 bodies of water?
Plasma compartment- blood vessel or circulation
Must pass through capillary wall to make it to:
Extracellular fluid/Interstitial fluid
Must pass cell membrane to make it to:
Intracellular fluid
If molecules are in the plasma compartment, their volume of distribution is said to be? And what are properties of the drug molecule?
Low. Usually large molecular weight drugs or drugs that bind extensively to plasma proteins and are trapped within the vascular compartment.
Plasma volume is 6% of body weight
If molecules are in the plasma AND extracellular fluid/interstitial space, their volume of distribution is said to be? and what are properties of the drug molecule?
Medium Volume of Distribution
Molecule has low molecular weight, and hydrophilic (lipophobic). Can move through capillaries into interstitial fluid, but cannot pass lipid membranes of cells.
Plasma + interstitial fluid = 20% of body weight
If molecules are in the plasma AND extracellular fluid AND intracellular, their volume of distribution is said to be? What are properties of the drug molecule?
High V.
Drug has low molecular weight and is hydrophobic (lipophilic).
Distributes into about 60% of body weight total.
Volume of distribution (L) =
Amount of drug in body (dose) in mg / Plasma concentration AKA amount in blood in mg/L
Concentration is determined by injection of standard dose and them measurement of plasma concentration
When the volume of distribution is calculated, we assume no elimination. In reality, drugs are eliminated and plasma concentrations have 2 phases. What are they?
Distribution phase
Elimination phase
*Most drugs show an exponential decrease in concentration with time during the elimination phase.
What are the effects of a large Volume of distribution?
Most of the drug is in extra-plasmic space and is unavailable to excretory organs.
Can lead to an increased half life and extend the duration of action of a drug.
Drug elimination depends on the amount of drug delivered to:
The liver or kidney per unit of time
Main site for drug metabolism? And others
Main: Liver
Others: Kidney and intestines.
Metabolism can either be first or zero order kinetics.
First order Kinetics: Rate of metabolism is proportional to concentration of the free drug. Increases as conc increases.
Zero order Kinetics: Rate of metabolism is constant over time. Dose Independent. Ethanol.
phase I of metabolism
Converts lipophilic molecules to more polar molecules. Often uses cytochrome p-450 (CYP450) system in the liver. (Most common)
Other reactions include oxidations, dehydrogenations (ethanol), deamination, hydrolysis
CYP450 system
Enzymes located in most cells. Mainly in liver and GI tract. Used for phase 1 of metabolism. Exhibit genetic variability.
Are CYP450 enzymes specific for one particular substrate during phase 1 metabolism?
No. 1 enzyme might be responsible for metabolizing many different drugs.
How can CYP450 enzymes be a source of drug-drug interactions?
Inducers: Drugs that increase CYP activity, leading to a decreased plasma level of many drugs.
Inhibitors: Drugs that decrease CYP activity, leading to an increased plasma level of drugs,
Phase II reactions of metabolism
Most are conjugation- make drug molecule larger.
Attaches an endogenous substrate to molecule to form highly polar conjugate.
Glucuronidation is the most common and important. Makes lipophilic molecules more readily excitable in urine.
Phase II reaction. Conjugations. What endogenous substrates can be attached to drug molecules?
Glucuronic acid, sulfuric acid, acetic acid or an amino acid.
Glucuronidation
Apart of phase II reactions during the metabolism process. Most common and important reaction. Makes lipophilic molecules more readily excretable in the urine.
Do all drugs undergo phase I and II reactions during metabolism?
No. Some may skip Phase I or undergo phase II first.
Individual differences in rates of drug metabolism could be due to: (4)
- Genetic factors- enzyme polymorphisms.
- Diet and environmental factors. Certain foods (grapefruit, cigarettes), age and sex.
- Drug interactions
- Diseases
Drugs may be removed from the body by which routes?
Kidney (most common)
Liver- biotransformation or bile
lungs
Most common place for metabolism to take place and elimination?
Metabolism: Liver
Elimination: kidney
What influences the passage of drugs into the glomerular filtrate?
Only molecular size.
Charge, pKa, lipid solubility, and pH do not matter.
Characteristics of drug molecules that can enter through the glomerus vs the PCT
Glomerulous: Free drugs can travel through into bowman’s space.
PCT: Larger drugs not transferred into the filtrate leave glomeruli thru efferent arterioles, but then can be actively secreted back into the kidney or go back to bloodstream(esp if not ionized)
Ion trapping in the kidney
Manipulate pH of urine to increase elimination of certain drugs. Idea is to charge compound so it cannot exit/travel through the membranes.
Increase pH for weak acids
Decrease pH for weak bases.
Why would you want to ion trap in the kidney?
As drugs move towards DCT, concentration is high and favors diffusion out of the nephron.
Clearance (CL)
Predicts the rate of elimination in relation to drug concentration
CL= 0.693 x Volume of distribution (mg) / half life (Hr)
In general, the elimination of a drug obeys ___ order kinetics
First. Rate of metabolism is proportional to concentration of the free drug. Increases as conc increases.
Steady State concentration
Plasma level increases until elimination rate equals infusion rate. Just as much drug coming in as going out.
Steady state is directly proportional to ___ and inversely proportional to ___
Directly proportional to infusion. Increase infusion of IV, steady state concentration will increase.
Inversely proportional to rate of clearance. High clearance = low steady state.
Describe steady state graph
Time on X, plasma concentration of drug on Y.
A faster rate of infusion does not change the time needed to achieve steady state. Only the steady state concentration changes with faster infusion.
Consumption is that it takes __ half lives for a drug to reach SS concentration and to be completely eliminated
5
Is half life or time it takes to achieve steady state affected by rate of infusion
No. rate of infusion only affects concentration of SS.
If a drug has a half life of 24 hours, when will the full effects be reached?
5th day. half life x 5
Why might the half life change?
Usually due to disease states. Anything that affects CL or V.
Fixed dose/ fixed time regiments
Result in time dependent fluctuations in the circulating level of a drug. Better to use smaller doses at shorter intervals than larger doses at longer intervals.
Regardless, SS is the same.
Maintenance Dose
Dose of the drug administered to establish the desired steady state concentration for therapeutic effectiveness.
Must account for bioavailability if given enteral.
Dosing rate =
CL x Target concentration
Maintenance dose=
Dosing rate/ bioavailability x dosing interval
Loading dose=
V x target concentration
What is the loading dose
We need target conc to be pretty high, pretty quickly to have an effect. Achieve rapid therapeutic levels. Can be any method of administration.
Caution: Toxic reactions can occur if drug has a rapid rate of absorption (Like for IV infusion. Should prob go slower on this! don’t want too high of a conc for SS)
___ is the most important factor determining drug concentrations
Clearance. Make sure they have good kidney and liver function- or it could cause complications.
Clearance is determined by dose, organ blood flow, and kidney/liver function.
Clearance is determined by which 3 things
dose, organ blood flow, and kidney/liver function.
