Chapter 1:
Drug Action: Pharmaceutic, Pharmacokinetic, and
Pharmacodynamic phases
Pharmaceutic phase: Drug becomes a solution so it can cross the
biologic membrane.
NO pharmaceutic phase in subQ, IM or IV routes.
Dissolution: First phase of drug action, dissolving of the smaller
particles in the GI fluid before absorption.
Disintegration: Breakdown of a tablet into a smaller particle.
Excipients: Fillers & inert substances, used in drug preparations,
allows drug to take on particular shape & size. Enhances drug
dissolution.
Additives in drugs such as potassium & sodium may increase
absorbability of drug.
Penicillin is poorly absorbed in GI tract due to gastric acid.
NOTE: Infants gastric secretion= higher pH (alkaline) than
adults; infants absorb more penicillin, so dose is LOWER.
Rate limiting: Time it takes for drug to disintegrate and dissolve to
become available for the body for absorption.
Liquid forms are more rapidly absorbed in GI than solids.
Drugs are both disintegrated and absorbed faster in acidic fluids
with a pH of 1 or 2, rather than alkaline.
Slower absorption in very young & older adults, less gastric acid,
primarily absorbed in stomach.
Enteric coated drugs: Resist disintegration in gastric acid of
stomach, no occurrence until it reaches an alkaline environment of the
small intestine.
Remains in stomach for a long time, effect is delayed on onset.
Enteric coated drugs, capsules, sustained-release (beaded)
capsules should not be crushed; alters the place & times of
absorption of the drug.
Food in the GI tract interferes with the dissolution and absorption
of certain drugs; some are enhanced and should be taken w/
food.
May irritate gastric mucosa, so fluid or food is needed to dilute
drug concentration & to act as protectant.
Pharmacokinetic phase: Process of drug movement to achieve drug
action.
Four processes: absorption, distribution, metabolism & excretion.
1. Absorption: Movement of drug particles from GI tract to the
body fluids by passive & active absorption or pinocytosis.
Oral drugs: absorbed into the surface of small intestine through
action of MUCOSAL VILLI, reduced if villi are decreased in number
(disease, drug effect & removal of [Link].)
Passive absorption: Higher to lower concentration through the
process of diffusion (no energy required.)
Active absorption: Protein or enzyme carrier is needed to move
against a concentration gradient. (energy required.)
Pinocytosis: Cells carry drug across membrane by engulfing drug
particles.
GI MEMBRANE: composed of mainly lipid (fat) and protein
lipid-soluble passes rapidly through membrane, water-soluble
needs a carrier.
Nonionized particles pass through cell membrane (no + or
charge)
NOTE: DRUGS THAT ARE LIPID SOLUBLE AND NON-IONIZED ARE
ABSORBED FASTER THAN WATER-SOLUBLE AND IONIZED
DRUGS.
Blood flow, pain, stress, hunger, fasting, food and pH affects
absorption. (see book for examples)
IM drugs are absorbed faster in muscles (more blood vessels, ie,
deltoids)
Hepatic first pass (first-pass effect): Process in which drug passes
to the liver first. (ie, Coumadin (Warfarin) & morphine.)
Some drugs do not do directly into systemic circulation, but
through the intestinal lumen of the liver via portal vein.
Some drugs are metabolized to an inactive form = excretion;
reducing the amount of active drug.
Bioavailability: Percentage of drug dose that reaches the systemic
circulation.
Oral drugs: occurs after absorption & hepatic drug metabolism,
less than 100%; (except for IV ROUTE ); Oral drugs with hepatic
first pass metabolism = 20-40% bioavailability during systemic
circulation. (Higher dose required for desired drug effect.)
Rapid absorption INCREASES bioavailability & drug concentration
= drug toxicity may result.
Slow absorption limits bioavailability, decreases drug
concentration.
Factors that alter bioavailability:
1. Drug form
2. Route of administration
3. GI mucosa & motility
4. Food & other drugs
5. Changes in liver metabolism (dysfunction or inadequate hepatic
blood flow.)
Distribution: When drug becomes available to body fluids and
tissues. Influenced by blood flow, affinity to tissue & protein-binding
effect.
Protein-bound drugs: Bounded to protein (ie, albumin)
High = > 89% | Moderately-high: 61-89% | Moderate: 30-60% |
Low: < 30%
Portion bounded is INACTIVE = not available to receptors.
UNBOUNDED = free, active drugs; causes a pharmacologic
response.
NOTE: TOXICITY MAY OCCUR WHEN TWO HIGHLY PROTEIN BOUND
DRUGS ARE GIVEN AT THE SAME TIME; WHERE THEY COMPETE FOR
BINDING SITE; CAUSING MORE FREE DRUG TO BE RELEASED INTO
CIRCULATION.
Nurses role: Check clients plasma protein & albumin levels.. decrease
in plasma protein decreases protein binding sites = free drugs in
circulation.
2. Metabolism or Biotransformation: Can occur in GI tract or
liver (primary site)
Inactivated by liver enzymes; converted by hepatic enzymes
to inactive metabolites or water-soluble substances for
excretion.
Lipid-soluble drugs = liver metabolism
Diseases: Cirrhosis & hepatitis alters metabolism = inhibits
the enzymes in liver.
If metabolism rate decreases, excess drug accumulation can
occur = toxicity.
Half-life (t ): Time it takes for one half of the drug concentration to
be eliminated; affected by metabolism and elimination.
Example: 650mg of aspirin = life of 3 hoursit takes:
3 hours for first half -life to eliminate 325mg
6 hours for the second half-life 162mg
9 hours for third half-life 81mg
12 hours for fourth half-life 40.5mg
15 hours for fifth half-life 20.25mg
18 hours for sixth half-life 10mg
Short: 4-8 hours
Long: 24 hours or longer (ie, digoxin)
3. Excretion or Elimination: Main route are the kidneys (urine.) (Bile,
feces, lungs, saliva, sweat & breast milk.)
Filters our free-unbound, water-soluble and unchanged
drugs. PROTEIN BOUND = NOT EXCRETED through kidneys.
Lungs: Eliminates volatile drug substances and products
metabolized to CO2 and water.
Urine pH varies from < 4.5-8 (Acidic=weak base drugs,
alkaline=weak acid drugs.)
Kidney disease: decreases glomerular filtration rate (GFR)
or decreased renal tubular secretion = excretion slowed
down/impaired.
Decrease blood flow alters excretion.
Creatinine clearance (CLcr): Test to determine renal
function; compares level of creatinine in the urine w/
creatinine level in blood.
Varied with age and gender; lower in older adults &
females (decreased muscle mass.)
Pharmacodynamic Phase: Drug concentration & its effects on the
body.
Primary: Desirable (ie, treat symptoms of allergy)
Secondary: Desirable or undesirable. (ie, CNS depression = drowsiness
con: driving, pro: sleeping)
Dose response: Relationship between minimal vs. max amount
of drug dose needed to produce desired [Link].
Onset: Time it takes to reach minimum effective concentration (MEC)
after drug is administered.
Peak: When drug reaches its highest blood or plasma concentration
Duration: Length that the drug has pharmacologic effect.
IMPORTANT: BELOW MEC DRUG DOSING NOT ACHIEVED; ABOVE MTC
= TOXICITY.
Receptor theory: Protein in nature found in cell membrane; proteins,
glycoproteins, proteolipids, & enzymes.
Four receptor families:
1. Kinase-linked receptors: Ligand-binding domain for drug
bindingcell surface.
2. Ligand-gated ion channels: Channel spans the cell
membrane, channel to allow flow of ion in & out of cells. (ions:
sodium & calcium.)
3. G protein-coupled receptor systems: 3 components:
4. receptor -> G protein binds w/ GTP -> effector (enzyme or ion)
(drug -> receptor -> Gprotein -> effect)
5. Nuclear Receptors: In cell nucleus; rapid activation through
transcription
Lock & key theory: Drugs act through receptors by binding to the
receptor to produce a response or to block a response. Activity is
determined by how well drug binds to a specific receptor. The better
the drug fits at receptor site, the more active the drug is. See figure 15
Agonists: Drugs that produce a response (ie, Isoproterenol stimulates
beta1 & beta2 receptors.)
Antagonists: Drugs that block a response (ie, Cimetidine blocks
histamine receptors, preventing excessive gastric acid secretion.)
Nonspecific drugs: Affects various sites and have properties for
nonspecificity.
Cholinergic receptors: Located in bladder, heart, blood
vessels, lungs and eyes. (ie, Bethanechol prescribed for
postoperative urinary retention to increase bladder contraction
drug stimulates the cholinergic receptor located in bladder &
urination occurs by strengthening bladder contraction. Heart rate
decreases, BP decreases, gastic acid secretion increases,
bronchiles constrict, pupils dilate.) See fig 1-6
Nonselective drugs: Acts at different receptors & have properties of
nonselectivity.
(ie, Chlorpromazine acts on the norepinephrine, dopamine,
acetylcholine, and histamine receptors and various responses results
from these receptors.)
Categories of Drug Action:
1. Stimulation or depression: Rate of cell activity & secretion
increases. Cell activity & function reduced.
2. Replacement: Replaces essential body compounds.
3. Inhibition or killing of organisms: Interferes with bacterial
cell growth. (ie, penicillin)
4. Irritation: ie, Laxatives irritate inner wall of the colon;
increasing peristalsis & defacation.)
Drug action: Lasts for hours, days, weeks, or months. Length depends
on drugs half-life.
Therapeutic Index: Estimates margin of safety of drug through ratio
that measures the effective (ED) (50% in humans & animals) & lethal
dose (LD)(50% in animals); the closer the ratio to 1, the greater the
toxicity.
Low therapeutic index: Narrow margin of safety; drug dose
adjustment may be needed & plasma drug lvls need monitoring
due to small safety range b/w ED & LD.
High therapeutic index: Wide margin of safety; less danger of
toxic effects; no need for monitoring.
Therapeutic Range (window): Drug concentration in plasma should
be b/w the MEC & MTC. When therapeutic range is given, it includes
both protein-bound and unbound portions of drug. If narrow, plasma
drug lvl should be monitored; if drug is not considering highly toxic,
monitoring not required. See table 1-3 for more info.
Peak drug level: Highest plasma concentration of drug at a specific
time. Indicates rate of absorption. Blood sample should be drawn at
proposed peak time depending on route of administration. (ie, IV
peak time = 10minutes.) If peak if too low, no therapeutic
effect is achieved. Too high = toxicity.
Trough drug level: Lowest plasma concentration of a drug. Measures
the rate of elimination. Must be drawn immediately before next dose of
drug is given regardless of route. (Before & after administration) Too
high= toxicity.
NOTE: PEAK & TROUGH ARE REQUESTED FOR DRUGS WITH
NARROW THEREPEUTIC INDEX AND ARE CONSIDERED TOXIC.
(ie, Aminoglycoside antibiotics.)
EXAMPLE: If dose is q6h (4 x a day) make sure trough is above MEC
If above MEC then pt. has problem with elimination. Nurse should
INCREASE the interval to q8h.
EXAMPLE:
600mg of Clarix, if concentration too low; increase the dose to increase
the peak.
If trough is too high, increase the interval.
If trough is too low, decrease the interval or increase the dosage of the
drug.
NOTE: If increasing frequency, you need to decrease the dose,
thus, lowering down the peak.
Loading dose: Large initial dose given to achieve a rapid minimum
effective concentration (MEC) in the plasma. After initial dose,
prescribed dose/day is ordered. (ie, Digoxin, requires [Link] when first
prescribed.)
Side effects: Physiologic effects not related to desired drug effects.
(desirable or undesirable.) Results mainly from drugs lacking
specificity. (ie, Benadryl (desirable effect) drowsiness during bedtime.)
Some are expected in drug therapy...not always a reason to
discontinue drug therapy.
Nurses role: Teach client to report side effects.
Adverse reactions: Not the same as side effectMORE SEVERE
AND ALWAYS UNDESIRABLE. Must always be reported and
documented. (ie, anaphylaxis (cardiovascular collapse.)
Toxic effects or toxicity: Can be identified through monitoring
plasma therapeutic range of drug. When drug levels exceeds t. range,
toxic effects are likely to occur from overdosing or drug accumulation.
(drugs with narrow TI are closely monitored.)
Pharmacogentics: Scientific discipline study of how the effect of a
drug action varies from a predicted drug response due to genetic or
hereditary factors/influence.
Different genetic makeup=different response to drug dosage or
drug therapy.
Can alter metabolism of drug (can be enhanced or diminished.)
Sensitivity to drugs depend on genetics. (ie, African Americans
do not respond as well as Caucasians to some antihyperthensive
meds, ACE inhibitors.)
Tolerance: Decreased responsiveness over the course of therapy.
Tachyphylaxis: Rapid decrease in response to the drug; acute
tolerance. (ie, Narcotics, barbiturates, laxatives, psychotropic agents.)
Prevention should always be part of therapeutic regimen.
Placebo effect: Psychological benefit from a compound that may not
have chemical structure of a drug effect; effective in 1/3 of persons
who take placebo compound.
Nurses role: Must tell participants of placebo use during any drug
trials.
Determinants that affect drug therapy:
Clinical factors:
Age & weight
Present health disorder
Other disease entities
Client drug compliance
Administration:
Drug form
Route of drug administration
Multiple drug therapy (polypharmacy)
Drug interactions
Pharmacokinetics:
Absorption
Distribution
Metabolism
Excretion
Pharmaodynamics:
Onset, peak and duration
Therapeutic rage
Side effects, adverse reactions