Four principles of pharmacokinetics
What is pharmacokinetics?
What the body does to the drug
What is biotransformation?
Changing a compound into something more usable by the body
5 Factors that impact the degree of drug absorption
1) route of administration
2) solubility of drug administered
3) conditions at site of absorption
4) degree of ionization of the drug
Why does the solubility of a drug matter in relation to drug absorption?
More lipid soluble, aka lipophilic (lipid LOVING) can pass through cell membranes easily (remember cell membranes are composed of a lipid bilayer).
What effect does ionization have on drug absorption?
Drug absorption is greater if the drug is in non-ionized, lipid soluble form. The ionized form is water soluble and possesses an electrical charge which is repelled by the cell membrane.
Routes of administration: name the fastest to the slowest route in terms of onset
Onset (quickest - slowest) : IV>IM>SC>oral
Routes of administration: name the shortest to the longest route in terms of duration
Duration (shortest to longest) : IV>IM>SC>oral
Advantages of oral route of administration
Disadvantages of oral route of administration
2) Enzymatic destruction
3) ***Patient compliance***
4) Irregular absorption (Influence of food or medications, ***First pass effect***)
5) Size of surface area for absorption and degree of blood flow (Stomach (acid) vs. small intestines (alkaline))
pH compared to pKa determines...
What environment favors the absorption of weak acids?
Gastric fluids. pH 1.5-2.5
examples: ASA, barbiturates
What environment favors the absorption of weak bases?
Small intestines. pH 7-8
examples: Local anesthetics, benzodiazepines
Where are oral drugs mostly absorbed, regardless of ionization, and why?
Oral drugs are mostly absorbed in the small intestine d/t larger surface area and better blood flow.
- The fraction of unchanged drug that reaches the systemic circulation.
- The amount of free drug that binds to target site and produces effect.
What has the greatest effect on bioavailability?
Name the 6 factors that decrease bioavailability
1) ***first pass effect***
2) incomplete absorption from GI tract
3) degree of blood flow to area
4) lipid solubility
5) pulmonary uptake of drug
6) degree of ionization
How is bioavailability calculated?
bioavailability = (area under the curve ORAL/AUC IV)
expressed as a percentage
What is the first pass effect?
drugs absorbed from the GI tract enter the portal vein and pass through the liver before entering circulation.
accounts for the larger difference between oral and IV dosages.
Advantage of sublingual administration
Rapid onset of drug effect. Direct drainage into superior vena cava. it bypasses the liver, and avoids first pass effect.
Advantage of rectal administration
Useful for pediatrics, vomiting, or unconscious patients
Disadvantages of rectal administration
1) unpredictable absorption.
- if inserted into proximal rectum, drug undergoes first pass effect
- if inserted into distal rectum, no metabolism occurs
2) mucosal irritation
Advantages of transdermal administration
1) sustained release provides steady plasma concentration
2) low incidence of side effects and fewer dosing intervals (high patient compliance)
3) avoids first pass effect
Characteristics of transdermal drugs
1) combo water and lipid soluble form
2) low molecular weight
3) absence of histamine release
4) low daily dose
Why do you apply a scopolamine patch behind the ear?
aka post auricular area
it is put there because the external carotid provides good blood flow
What should you consider when applying a transdermal patch?
skin conditions: hydration, body temp, excoriation/thickness, also infants and elderly have thinner skin and greater permeability
Advantages of inhalational administration
- lungs provide large surface area for absorption
- thin alveolar membrane between pulmonary capillaries and alveoli, allowing rapid blood-brain equilibration
- highly lipid soluble and diffusable (also low molecular weight)
Disadvantage of topical administration
potential for systemic toxicity, example: benzocaine
Advantages of intranasal admin
- avoids first apss effect - better bioavailability
- rate of absorption + plasma concentration comparable to IV admin
Dosage for intranasal fentanyl
Advantages of intramuscular administration
1) used when IV access is difficult (pediatrics, mentally challenged
2) rapid absorption
Describe the absorption of drugs administered subQ
- constant and slow absorption
- sustained effect
- use of vasoconstrictors with local anesthetics can prolong effect and slow absorption further
What are the advantages of IV administration?
- 100% bioavailability
- rapid and accurate delivery of drug (titrated to pt response)
- route of choice for anesthesia
What are the disadvantages of IV administration?
- possible adverse reaction due to high drug level (narrow therapeutic window)
- requires vigilance
- need for patient IV access
Describe the first pass effect of the lungs
- percentage of drug taken up by the lungs after IV admin
- serves as a temporary reservoir --> drug released back into blood circ as plasma conc decreases.
Describe what the cell wall membrane (CWM) is composed of
bilipid layer composed of cholesterol and phospholipids.
Describe the CWM role in drug administration
- selectively inhibits passage of certain drugs
- lipid soluble drugs easily dissolve in CWM
- relatively impermeable to water soluble drugs
What is Fick's law?
there is a concentration gradient, and molecules attempt to create equilibrium on both sides
What is carrier mediated diffusion?
occurs via transmembrane protein carrier. glucose is transported this way
What is active transport?
requires ATP. can move against concentration gradient.
example: Na+/K+ pump
What is pinocytosis?
large molecule engulfed by CWM.
Drug characteristics that determine crossing a cell membrane
1) molecular size
2) degree of ionization
3) relative lipid solubility of ionized and nonionized forms
4) binding to tissue proteins (only unbound can cross cell membranes)
uptake of drugs across the cell membrane is influenced by...
regional blood flow and concentration gradient
Factors affecting transfer of drugs across cell membranes
1) molecular size - smaller agents traverse easier. molecule wt < 200 transfers easily.
2) ***lipid solubility - high lipid solubility (lipiphilic/hydrophobic)
3) degree of ionization - influences the extent that a drug can cross cell membranes. ionized = H2O soluble = repelled by CWM + excreted by kidneys
What is the degree of ionization determined by?
- whether the drug is an acid or a base
- pH of the environment
- pKa of agent
pH is equal to...(equation)
pH = -log10 [H+]
pH is equal to the negative log to the base ten of the molar hydrogen ion concentration.
example: pH decrease from 3 to 2, causes ten fold increase in hydrogen ions
What is the Henderson-Hasselbalch equation used to calculate?
It is used to calculate the ratio of non-ionized to ionized drug at each pH. Used to estimate degree of drug absorption
pH = pKa + log acid/base
What is pKa?
Dissociation constant of an agent. ratio of ionized to non-ionized substance (drug) in a solution.
- rate that substance will dissociate into its ion form when placed in a solution.
- expressed as log of equilibration constant for the dissociation of an acid or base.
Why are most drugs formed as salts?
Increases solubility and absorption
What happens to drug absorption when a patient is acidotic?
Drugs are more likely to ionized and can be less effective.
What happens if you put ASA into the small bowel?
it will ionize and not be effective. it is an acidic drug, going into an alkaline environment (small bowel)
What effect does adding bicarb to a local anesthetic have?
hastens absorption and speed of onset. non-ionized
Describe ion trapping
- degree of ionization varies across membranes that separates fluids with different pH. non-ionized portion traverses CWM, ionized portion becomes trapped. can happen with pregnancy, and drugs cross the placenta and become trapped
Drugs binding to albumin are usually...
acidic drugs such as ASA, dilantin, barbiturates
Drugs binding to alpha-acid glycoproteins (AAG) are usually...
basic drugs such as diazepam, midazolam, opioids, local anesthetics
What is volume of distribution?
Theoretical volume that drugs have to distribute in body
How does protein binding influence drug clearance?
- unbound fraction is subject to hepatic metabolism.
- unbound fraction undergoes glomerular filtration.
- highly bound drugs are metabolized and excreted slower
How and when do drug-protein bonds dissociate?
drug-protein complex is maintained by a weak bond (ionic, hydrogen, van der Waals), easily reversible.
- dissociates when plasma conc is low after hepatic or renal clearance of unbound drug. essentially serves as a storage reservoir.
describe protein binding's selectivity and competition
- binding of drugs to protein is nonselective
- drugs with similar characteristics can compete for same binding site
- when two drugs are competing for same binding site then this can increase the amount of free drug leading to potential toxicity
What are some examples of highly protein-bound drugs?
coumadin, phenytoin, propanolol, propofol, fentanyl, diazepam, midazolam
What are some patient-related factors that impact protein-binding?
- severe hepatic or renal disease
- aging (decreased albumin, less binding sites = more free drug)
- acute/chronic inflammatory diseases (trauma, surgery, burns, acute MI, RA, crohns, cancer)
What is the relationship between lipid solubility and protein binding?
The more lipid soluble a drug, the more likely it is to bind to protein