Pharmacokinetics
A quantitative approach to describe the behavior of a drug in the body.
What does body do to the drug?
Pharmacodynamics
Impact of drugs in the body.
What does the drug do to the body?
Four pharmacokinetic phases
(1) absorption (4) excretion
(2) distribution
(3) metabolism
Absorption
Movement of drug from its site of administration into the bloodstream.
Absorption is not always desired
As with inhaled or topical steroids
Routes of administration
Oral, topical, IV, rectal, ears, eyes
Passage of drugs across membranes
(1) channels or pores: small drugs (2) transport system: selective molecular carriers(3) direct penetration: lipid soluble (most common)
Plasma concentration curve
ADME, drug is absorbed and peaks when distribution occurs, then drug metabolizes and is excreted over time.
Bioavailability
Fraction (%) of drug available in bloodstream after administration
100% bioavailability
IV, IM&SC ( usually, but absorption may be delayed)
Oral route
Must go through ADME, while injections just metabolize, but both routes calculated and compared (AUC)
Patient Variables that Affect Absorption
Infant skin more absorbent, Broken, rashy, hot, sweaty, moist more absorbent, patient w/bowel resection, diarrhea or constipation, stomach acidity, presence or absence of food
Chemical factors that affect absorption
Liquid solubility: a drug must be lipid soluble. Rate of dissolution, Surface area: larger area>faster absorption, Blood flow: greater blood flow=faster rate of absorption.
Clinical relevance of bioavailability
Explains why normal IV dose is the same as normal oral dose for some drugs, but not others. Some drugs are not effective if given by different routes. Some drugs are not effective given orally, rectally, or topically. Some drugs taken with food, others on
Distribution
Movement of drug into the various body fluids and tissues.
Volume do distribution (vd)
Mathematical concept describing the amount of drug in the body in relation to the concentration of drug in the plasma.
Vd
Useful in estimating the loading dose necessary to achieve adequate plasma levels.
Drug Distribution
Blood brain barrier (BBB): only lipid soluble drugs can cross and reach CNS
Placental barrier: lipids soluble can cross and reach developing fetus
Breast milk: most drugs can enter nursing mother's milk
Fluid areas & lipid tissues
Protein binding
Some drugs are bound to plasma proteins mostly albumin. Drugs inactive while bound.
The amount of drug bound at a given time is expressed as a percent. As the free drug is cleared, some of the bound drug will become unbound to maintain a constant percenta
Variables Affecting Vd & Distribution
Body composition, Obese patients have larger Vd, changes in body weight or composition alters Vd, malnourished patients, neonates and elderly have more permeable BBB
Metabolism
Biotransformation- chemical alteration of the parent compound usually resulting in enhanced excretion, or sometimes active metabolites.
Metabolism
Enzymatic process. Usually occurs in the liver.
Metabolism
First- pass metabolism: drugs absorbed in the small intestine are first exposed to the liver and maybe extensively metabolized before reaching systemic circulation.
Metabolism
1st-pass metabolism can greatly lower
% bioavailability .
Metabolism
Prodrug: inactive compound that must be metabolized in order to become active
Metabolism
PHASE 1 Reactions- Hepatic microsomal enzyme system: Cytochrome p450 (CYP2D6. CYP3A3/4)
Metabolism
PHASE 2 Usually no change with age more water soluble and bioavailable through kidneys
Exerction
process by which the drug is eliminated from the body. Some drugs are excreted after metabolism. Some drugs are excreted "Unchanged". KIDNEY (main), Bile, Intestine, Lung, Saliva, Skin
Drug Clearance
a general term used to describe the volume of blood which is completely cleared of a drug per unit of time (tells how much blood cleared from drug). Includes the combination of metabolism of excretion by any route.
Half-life (t 1/2)
time required for the drug's plasma concentration to be reduced by one-half. Takes 4-5 half-lives for a drug to be considered "cleared" (clinically cleared). Most drugs follow "linear kinetics." That is, the half-life is concentration and dose independent
Variables that Affect Clearnce
Neonates have immature/underdeveloped metabolic pathways & renal function. Infants &children have high liver metabolism and excretion rates. There is a natural decline in some liver enzyme activity and in renal excretion with age. Hepatitis or alcohol abu
Dose Response Relationship
Relationship between size of dose and intensity of response
Therapeutic Window
Minimal effective level: levels lower, Maximal safe level: higher than the max, toxic levels: dramatic adverse effects, even death
THERAPEUTIC INDEX
therapeutic window" is a measure of the drug's safety. it is the relationship between beneficial & adverse effects of a medication. Refer to notes pg. 6
HALF-LIFE vs. DURATION OF EFFECT
Duration of Action length of time a drug can be expected to exhibit its pharmacological (therapeutic) effect. Half-life specifically refers to plasma concentrations only, while duration of effect refers to the pharmacological action (blood levels). Durati
POTENCY vs. EFFICACY
potency is rarely of clinical importance. Example: Pepcid 20mg will produce the same clinical effect as Zantac 150mg. Thus, Pepcid is more potent than Zantac. but both drugs are equally effective. Potency does not matter.
Efficacy
the ability of a drug to produce a desired therapeutic effect (how well it works)
Potency
measure of the amount of drug (dose, mg) required to produce a given degree of effect.
MECHANISM OF ACTION (receptors)
Receptor Theory
a drug produces an effect by combining with some specific molecular constituent (receptor). The function of the receptor or cell is modified to produce a measurable effect.
Agonist
a drug that mimics some natural compound by binding with the receptors & stimulating some cellular response.
Antagonist
a drug that binds with a receptor, blocks the receptor from stimulation, and prevents it from being triggered normally.
Affinity
measure of the strength of attraction between a drug and its receptor. describes the tightness of the bond. A drug with a high affinity to a certain receptor is very likely to elicit that response. A drug with a low affinity, is less likely to elicit that
Selectivity
refers to the degree to which a drug acts upon one site relative to all possible sites. Usually, the more selective a drug is, the fewer adverse effects it will cause. Some keys fit multiple locks--how adverse effects cause side effects.
Adverse Drug Reactions (ADR)
any undesired, unintended response to a drug.
Exaggerated drug response
i.e. a blood pressure medication that unexpectedly bottoms out the patient's blood pressure.
Adverse effect
undesired pharmacological effects of a drug; usually dose related
Toxicity
harmful of destructive effects of a drug often seen when therapeutic doses are exceeded, the drug is used for a longer period of time than is recommended, or the drug is not properly monitored. Many use the terms toxicity & adverse effect interchangeably.
Drug interaction
that causes increased adverse effects of decreased efficacy.
ADR REACTIONS
Exaggerated drug response
Adverse effect
allergic or hypersensitivity reaction
toxicity
drug interactions
Drugs are poisons with therapeutic adverse effects
Intolerance
adverse effect of a drug that limits its usefulness, or acceptance in a patient (side effects).
Drug Allergy
immune system mediated response, non-dose related, unpredictable.
Rash, hives, itching
Anaphylactic reaction: bronchoconstriction. swelling of lips, face, throat, tongue, severe hypotension
ADRs/Drug Interactions/Patient Specific Variables
HIGH RISK DRUGS: are those with a narrow therapeutic index, high incidence of adverse effects, or high incidence of allergic reactions.
HIGH RISK PATIENTS: are those that would be least likely to tolerate adverse effects or loss of arrthymias, or epilepsy
Interpatient Variability in Drug Responses
Allergy history
age
weight
disease states
genetics
polypharmacy
compliance
Concept of placebo
Drug-drug interactions
modification of the effects of one drug by the prior of concomitant administration of another.
4 Mechanism of drug interactions
1. direct chemical interactions
2. pharmacokinetic interactions
3. pharmacodynamics interactions
4. combined toxicity
Direct chemical interaction
(Precipitation, inactivation)
Pharmacokinetic Interaction
Altered GI Absorption (altered pH, altered intestinal flora, chelation, mucosal damage)
Pharmacokinetic Interaction
Altered pH (acidic) Non-ionized form of drug is more lipid soluble & easily absorbed. Ex: ketoconazole/antacids requires acidic environment for absorption
Pharmacokinetic Interactions
Altered intestinal flora(therapeutic) ex: digoxin/antibiotics
Pharmacokinetic Interactions
Chelation
Chemical bonding that prevents absorption
Ex: ciprofloxacin/ polyvalent cations ( Mg++, Fe+++), Calcium bind and not absorb----separate by 2 hours.
Cholestyramine/digoxin or thyroid ( don't absorb together)
Pharmacokinetic interaction
Drug induced Mucosal Damage
Chemotherapy agents
Altered distribution
Protein Displacement
Drugs bound to plasma proteins are pharmacologically inactive & exist in equilibrium between bound and unbound forms.
Any drug which is also protein bound may upset this equilibrium when added to or deleted from a patient' s drug regimen.
Usually only cli
Altered metabolism
Concurrent administration of two drugs metabolized by the same liver enzyme system can cause increase or decreases in blood levels of one or both agents.
Most of these interactions involve the cytochrome p450 system, which has multiple enzyme subsets (alt
Enzyme induction
Increased metabolism =lower drug levels= loss of efficacy
Caused by one drug inducing( speeding up) the shared metabolic pathway
Enzyme inhibition (most common type of DI)
Decreased metabolism = higher levels= increased effects, adverse effects, & toxicity .
Caused by competition for the same metabolic pathway
Altered renal excretion
Decreased cardiac output---decreased renal blood flow----decreased drug filtration----decreased drug excretion
Pharmacodynamic interactions (Synergistic/Antagonistic DI)
Synergistic Effects: occurs when the effects of two drugs are greater than would have been predicted from each of their effects alone. 1+1=3
Pharmacodynamic Interaction
Antagonistic Effects: occurs when the effects of two drugs are less (cancel out) than predicted from their effects when given alone. 1+1=0.
Strategies to Prevent DIs
Medication history
Most common drug interaction & adverse effects
Avoid use of unnecessary drugs
Select a non-interacting medication
Separate chelating or pH interacting drugs (antacids) by at least 2 hours.
Monitor more closely when adding or deleting po
Drug-Food Interactions
Taken with food, some on empty stomach, grapefruit juice, caffeine can increase theophylline toxicity.
FDA Pregnancy Categories
A--Human studies show no fetal risk.
B--Animal studies show no fetal risk.
C--Either animal studies do show fetal effects or no studies exist.
D--Evidence of human fetal harm exists
X--Contradicted! Risk to fetus clearly outweighs any possible benefit.