How a drug is absorbed, distributed, metabolized, and excreted
Mechanism of action of a drug
Routes of Administration
Route of administration via GI tract Includes Oral (PO) and Rectal (PR) Safest and easiest route Least expensive Must pass through GI tract (w/stomach acid, enzymes) & enter portal circulation for 1st-pass metabolism (1st-pass effect)
What is the safest, easiest, and least expensive route of administration for medication?
Enteral aka oral (PO)
Hepatic Portal Vein
A short vein that transports blood containing the medications, etc. to the liver for 1st-pass metabolism, before it’s filtered back into the general circulation
Absorbed in the GI tract, enters portal vein to liver, metabolized, then enters general circulation
Eventually sent back to liver by arterial circulation for more metabolism
Generally speaking, how long does it take once you take a pill to get a peak plasma level so that it can get to the brain?
~ 60 minutes
Route of administration avoiding the GI tract and hepatic 1st-pass metabolism
How long before the drug is distributed throughout the system via inhalation?
Smoking and inhalant drugs of abuse are very reinforcing partially due to _____?
The very fast effects on CNS (about 8 seconds)
Across mucous membranes directly
What are some of the methods of transmucosal administration?
Buccal or sublabial (e.g. nicotine gum)
Sublingual (SL) [e .g. nitroglycerine, alprazolam (XANAX)]
Sprayed into nose or sniffed (e.g. drugs of abuse and nasal decongestants)
What are the methods of injection administration?
Intravenous (IV) or Intra-atrial (IA)
Subcutaneous (SQ or SC)
What is the rate of dispersion for IV injection?
Very fast, seconds, but not as fast as inhalation
What is the rate of dispersion for subcutaneous injection?
Hours, days, months
What is the rate of dispersion for intramuscular injection?
~ 15 minutes
Type of intramuscular injection, allows for slow, controlled release (e.g. Risperdal Consta, Haldol Decanoate)
Injection into area just outside dura mater (outer layer of the meninges that surround CNS)
Used for chronic pain and childbirth
What are the types of parenteral administration?
Inhalation, injection, transmucosal, transdermal,
Liberation Absorption Distribution Metabolism Excretion
release of drug from its dosage form
movement of drug from administration site into the blood
Movement of drug from intra-vascular to extra-vascular space
transformation of drug into compounds that are easier to eliminate (e.g. liver wants to make compounds more water soluble so that they can be excreted in the urine)
elimination of drug or metabolite via renal, biliary, or pulmonary processes
Why are some drugs enteric coated?
Decreases irritation to stomach lining
Delays absorption until the intestine for those drugs that are better absorbed in the intestine (which is more alkaline than the stomach)
Particularly useful for those drugs that are either poorly absorbed or destroyed in acidic environment)
What is the bottom line of liberation and absorption?
TAKE DRUGS AS INSTRUCTED
Why are some drugs instructed to take on empty stomach?
Many drugs are absorbed better in stomach than the intestine (and vice versa)
Reaches desired concentration levels faster when taken on an empty stomach
What are some technologies for controlling release and absorption?
Sustained-release Sustained-action Extended-release Controlled-release Time release technology
What is the point of developing these technologies for controlling release and absorption?
To spread out the action of the drug, decrease side effects, and in general, make drugs more convenient to take (especially in children and stimulants)
Cytochrome P450 (CYP)
System in the liver that is the main system of enzymes that inactivate drugs
What are the most important CYP enzymes?
1A2, 2C9/19, 2D6 (30%), 3A4 (55%)
Three different groups of metabolizers
Rapid or extensive (i.g. normal)
Different ethnic/racial groups vary in certain these enzymes, leading to ___________
varying degrees of metabolism and effects
What are some considerations that you need to make with elderly population?
- Overall, may be twice as sensitive to drugs, so the dose needs to be halved, usually
- Polypharmacy is common, thereby leading to many drug-drug interactions
What are some changes that influence metabolism in the elderly?
- Decreased hepatic (liver) & renal (kidney) function
- May have less effective barriers to absorption (GI, blood-brain-barrier)
- May have increased body fat
- May have more sensitive receptors
- Hepatic changes (decreased CYP2C19, hepatic mass, and circulation)
What are some sex differences to consider with medication metabolism?
- Females may have more sensitive receptors
- Possible hormone interactions
- Combined with phamacokinetics factors (e.g. more body fat, lower body weight), females may be twice as sensitive as males (dose may need to be halved)
What are the factors involved in inter-individual variability?
- Genetics (PM vs RM vs URM)
- Environmental factors
Types of DDI’s
What is the most common type of DDI?
What is an example of synergistic effect?
Thyroid hormone + antidepressant
What can antagonistic drug effects lead to?
Decrease in therapeutic effect, as in taking a stimulant + depressant at the same time
- One drug (or food) may alter absorption of another.
- One drug may alter protein binding
When are additive drug effects considered good vs bad?
If the additive effect is therapeutic, it’s good.
If the additive effect is a side effect, it’s bad.
A drug can _______ or _________ enzyme(s) that metabolizes itself or other drugs.
Most important effects of inhibition or induction?
Those that involve CYP enzymes in the liver, the primary site of drug inactivation/metabolism
What is the result of inhibition?
increased plasma levels of substrate of a particular drug, which can lead to increased SE’s or toxicity.
In terms of safety, which is the bigger problem? Inhibition or induction?
How quickly can DDI’s occur?
almost immediately, within hours to days & can cause toxicity
Why do drugs inserts instruct you not to take the drug with grapefruit juice?
The oils in the grapefruit juice inhibit CYP3A4 in an irreversible fashion, causing increased plasma levels of 3A4-metabolized drugs (meaning the inhibition can last as long as 3 days)
- As many as 85 drugs can be affected from DDi’s with grapefruit juice, including Abilify and Celexa
What is the bottom line for us as clinicians with regard to DDI’s?
You must always instruct patient to ask doctor and pharmacist about potential drug-drug interactions for their medications, including food, OTC drugs, herbs, and supplements
Drug concentration is at its highest
Drug concentration is at its lowest
How do sustained release formulations affect peak and trough levels of drugs?
Decreases peaks and troughs, which typically translates into decreased side effects
Metabolism rate is a constant fraction of remaining drug.
An absolute amount is eliminated per hour (regardless of the concentration of the drug in blood)
What is an example of a zero-order kinetic substance?
Average = 10cc(ml) of 100% ETOH/hour (1 drink equivalent)
Steady State (SS)
plasma drug concentration does not change with repeated (or continuous) same dose administration
Drug in rate = drug out rate
Half Life (T1/2)
The time required for plasma concentration to decline by 50% of drug after one dose.
SS dosing is achieved with regular interval dosing after how many half lives?
How many half lives does it take for most of a substance to be eliminated?
What is the typical regimen of drug administration?
To take the drug at the end of each half life.
Lethal dose in 50% of animal test subjects
Dose that produces desired effect in 50%
Therapeutic index (TI)
Measure of relative safety
What is the formula for TI?
TI = LD50/ED50
Less safe and possibly fatal with overdose
Toxic dose in 50% of human subjects
Formula for Safety Index
Range between minimum effective concentrations for desired & adverse effects, the concentration level that is high enough to have a therapeutic effect and low enough to avoid adverse effects
Therapeutic Drug Monitoring (TDM)
Correlating plasma concentration with effects within a specific patient (e.g. blood draws to measure the levels of Lithium in bloodstream)
What is the point of TDM?
May help increase therapeutic effects or to avoid toxic side effects
Increased dose required for a response
Pharmacokinetic (metabolic) tolerance
More enzyme available to metabolize drug, resulting in increased dose required to maintain same level
Receptors decrease in number or sensitivity, resulting in increased dose required to maintain same response (down-regulation)
What are the two types of tolerance?
Pharmacokinetic (increased enzymes)
Pharmacodynamic (decreased receptors or sensitivity)
Physical or psychological withdrawal symptoms occur when drug is discontinued
True or False: Physical dependence only occurs with tolerance, abuse, or substance dependence
FALSE; physical dependence can occur without tolerance, abuse ,or substance dependence
What is the general rule for discontinuing medication?
Never discontinue (D/C) a psychotropic abruptly but to titrate off slowly
every day (should be written out)
every night at bedtime
twice a day
three times a day
four times a day
g or gm
prescription, technically means “take”
i, ii, iii, iv, etc.
one, two, three, four, etc.
Activates receptor just as a natural NT does
Blocks action of a natural NT by binding to the receptor, thereby preventing the natural NT from binding (but has NO EFFECT on the receptor)
exerts the same but weaker effect as a full agonist; but this is a complex mechanism that at times can result in a net agonist effect and at other times in a net antagonist effect in the same brain
exerts opposite effect as full agonist (causes the receptor to do the opposite thing as it would if the natural NT has bound to it)
Increases effectiveness of NT without binding to the receptor
Decreases the effectiveness of NT without binding to the receptor