INTRODUCTION TO PHARMACOLOGY

1. HISTORY
• Early drug – plants, animals & minerals
• 2700 BB – earliest recorded drug use found in Middle East & China
• 1550 BC – Egyptians created Ebers Medical Papyrus
Castor oil – laxative
Opium – pain
Moldy bread – wounds & bruises
• Galen (131-201 AD) Roman physician; initiated common use of
prescriptions
• 1240 AD – introduction of apothecary system (Arab doctors)
1st set of drug standards & measurements (grains, drams,
minims), currently being phased out
• 15th century – apothecary shops owned by barber, surgeons, physicians,
independent merchants
• 18th century – small pox vaccine (by Jenner)
Digitalis from foxglove plant for strengthening & slowing of
heartbeat Vitamin C from fruits
• 19th century – morphine & codeine extract from opium
Introduction of atropine & iodine
Amyl nitrite used to relieve anginal pain
Discovery of anesthetics (ether, nitrous oxide)
• Early 20th century – aspirin from salicylic acid
Introduction of Phenobarbital, insulin, sulforamides
• Mid 20th century
1940 – Discovery antibiotics (penicilline, tetracycline,
streptomycin), antihistamines, cortisone
 1950 – discovery antipsychotic drug, antihypertensives, oral
contraceptives, polio vaccine

2. DEFINITION & SUBDIVISIONS

Drug – chemical introduced into the body to cause some changes
• WHO def: any product/subs used to modify/explore physiologic
system/pathologic states for the benefit of the patient
Pharmacology – study of the manner in which the function of living system is
affected by chemical agents/drugs
• Science concerned with history, sources, physical & chemical properties
of drugs & the way in which drug affects living system

Subdivisions of pharmacology:
1. pharmacodynamics – study of the biochemical & physiological effects of drugs
& mechanisms of action
• what the drug does to the body
2. pharmacokinetics – deals with the absorption, distribution, biotransformation &
excretion of drugs
• what the body does to the drug
3. pharmacotherapeutics – study of drugs used in the diagnosis, prevention,
suppression, & treatment of diseases
• deals with beneficial effects of the drugs (medicines)
4. pharmacognosy – study of drugs in their original unaltered state; origin of drugs
• source of drugs
• ex: penicillin from penicillium (fungi)
5. Toxicology – study of biologic toxins: study of poison & its effects deals with
deleterious effects of physical & chemical agents (including drugs) in human

Pharmacoeconomics – study of relationship of drugs & economics

Pharmacovigilance – science of collecting,researching, analyzing, & evaluating set of
information about adverse drug effects.
Receptor – a component of the cell that interacts with drug, initiating a chain of
biochemical events leading to drugs’ observed effects
• Human body works through complicated series of chemical reactions & processes
• Important aspects of nursing: understanding how drug ant on body to cause
changes & apply that knowledge in clinical setting
Patients take complicated drug regimen & receive potentially toxic drug
Some manage their own care at home
• Nursing responsibilities regarding drug therapy:
Administering drugs
Assessing drug effects
Intervening to make drug regimen more tolerable
Provide patient teachings about drugs & drug regimen
• Knowing how drug works --- easier to handle --- enhances drug therapy

DRUG NOMENCLATURE
1. CHEMICAL NAME – atomic/molecular structure of drug
2. GENERIC NAME/NON-PROPERTY NAME – original designation given to the
drug when the drug company applies for approval patents
- universally accepted & not capitalized; before drug becomes official, used
in all countries
- protected by law; not capitalized
3. TRADE/BRAND/PROPRIETY NAME – name given by the drug company that
developed it
- followed by the symbol R or TM, 1st letter is capitalized
chemical name – acetylsalicylic acid
generic name – aspirin
trade name – aspilet
COMMON SOURCES /4 MAJOR SOURCES (ORIGINS) OF DRUGS:

1. Animal sources – from organs, organ secretion or organ cells

• Used to replace human chemical not produces because of disease or
genetic problems
• Thyroid drugs & growth hormones preparations – from animal thyroid &
hypothalamus tissue (many of these preparations are now created
synthetically – safer & purer)
• Insulin – from pancreas of animals (hog, cattle, sheep): thru genetic
engineering – cld produce human insulin by altering E. coli bacteria
making it a better product without impurities that come with animal
products
2. vegetable/plant sources – roots, bark, sap, leaves, flowers, seeds of medicinal
plants
• digitalis from wildflower, purple foxglove, dried leaves of plant
• active principles of plants
 alkaloids – alkaline in reaction, bitter in taste, powerful in
physiologic activity
o atropine & scopolamine
o morphine sulfate, cocaine, quinine, nicotine, caffeine
o procaine

• glycosides – digitalis
• resin – soluble in alcohol; example – colonic irritant found in laxative
cascara
• gums – used in bulk-type laxatives: some used in certain skin preparations
for their soothing relief
• oils – castor oil, oil of wintergreen
3. Mineral sources – from free elements, both metallic & non-metallic usually in
form of acids bases, salts found in food
 • Dilute HCI – control/prevent indigestion
• Calcium, aluminum, fluoride, iron, gold, potassium
4. synthetic sources – many drugs developed synthetically after chemical in plants,
animals, or environment have been screened for signs of therapeutic activity
• more potent, more stable, less toxic
• steroids – arthritis & other diseases
• sulfonamides/chemotherapeutic agents – kill microorganism slow their growth
• meperidine HCI (Demerol)

DRUG CLASSIFICATION
A. by action
• Anti infectives – antiseptics, disinfectants, sterilants
• Antimicrobials, metabolic, diagnostic materials, vitamins & minerals
• Vaccine & serums, antifungals, antihistamines, antineoplastics, antacids
B. By body system
• CNS – (+)/(-) actions of neural pathways & centers: Phenobarbital
• ANS – governs several bodily functions so that drugs that affect ANS will
at the same time affect other systems functions
• GIT – acts on mascular & glandular tissues: leperamide
• RESPIRATORY SYSTEM – act on resp. tract, tissues, cough center,
suppress, relax, liquefy & stimulate depth & rate of respiration
• Urinary system – act on kidney & urinary tract
• Circulatory system – act on heart, blood vessels, blood; metoprolol

KINDS OF DRUGS
Prescription/legend drug – can be dispensed if with prescription order; with specific name
of drug & dosage regimen to be used by patient
non-prescription drug – can be dispensed over –the-counter/without prescription order
- for self treatment of variety of complaints
- vitamin supplements, cold/cough remedies, analgesics, antacids, herbal
products
- cautions in use of OTC drugs:
1. delay in professional diagnosis & treatment of
serious/potentially serious condition may occur
2. symptoms may be masked making the diagnosis more
complicated
3. clients’ health care provider/pharmacist should be consulted
before OTC preparations are taken
4. labels/instructions should be followed carefully
5. ingredients in OTC drug may interact with prescribed drug
6. inactive ingredients may result in adverse reactions
7. potential for overdose
8. multiple medication users are at risk as more medications
are added to therapy regimen
9. interactions of medications are potentially dangerous
Investigational drug – new drugs undergoing clinical trails
Illicit/street drug – used/distributed illegally for non-medical purposes to alter mood of
feeling

**when drug is taken by mouth, it undergoes 3 phases:

1. pharmaceutic/dissolution
2. pharmacokinetics
3. pharmacodynamics

I. PHARMACEUTIC/DISSOLUTION
- Drug goes into solution so that it can cross the biologic membrane
- Not found in drug administered parenterally
- 1st phase of drug action of agents taken by mouth
 - Additive enhances absorbability of drugs
- EXCIPIENTS: filters & inert substances
Allows drugs to take on particular size & shape
Enhance drug dissolution – potassium (K) --- losartan K (cozaar); sodium (Na)
---cloxacillin Na (Prostaphlin-A)
2 phases:
- Disintegration – breakdown into smaller parts
- Dissolution – futher breakdown into smaller parts in GIT –
absorption; dissolved into liquid
- rate limiting: time it takes drug to disintegrate & dissolve to become available for
body to absorb it
- factors affecting dissolution
 form of drug (LIQUID VS. SOLID) – liquid more absorbed than solid,
already in solution, rapidly available for GI absorption
 Gastric ph (acid vs alkaline) – acidic media (ph=1.2) faster disintegration &
absorption
 Age – young vs elderly – inc ph. Dec absoption
 Enteric coated drugs – resist disintegration in gastric acid
• Disintegration occurs only in alkaline environment (intestine)
• Should not be crushed
• Presence of food – interfere with dissolution & absorption, enhance
absorption of other drugs, may be protectants of gastric mucosa

I. PHARMACOKINETICS – action of body to the drug:

 Study of absoption (taken into the body), distribution (moved into various
tissues), metabolism/biotransformation (changed into a form that can be
excreted) & excretion (removed from the body) of drugs
 What happens to the drug when it enters the body
 “kinetics” movement: deals with drugs actions as it moved through the body
  Also concerned with a drug’s onset of action, peak concentration level, &
duration of action

4 processes involved:
I. Absorption – route of drug takes from the time it enters the body until it is absorbed
in circulating fluids
 Movement of drug molecules from site of administration to circulatory
system
 Movement of drug particles from GIT to body fluids involve 3 processes
 Passive absorption (diffusion) – movement from higher
concentration
o No energy required: occurs when smaller molecules
diffuse across membrane
o Stops when drug concentration on both sides of the
membrane is equal
o Major process through which drugs are absorbed into
the body
 Active absorption – needs carrier (enzymes or protein) to move
against a concentration gradient
o Energy is required: from lower concentration to higher
concentration
o Used to absorb electrolytes (i.e. sodium, potassium) &
some drugs (levodopa)
 Pinocytosis – engulfs the drug to carry it across the membrane
o Transport fat-soluble vitamins (vit.A,D,E,K)
 Factors affecting absorption:
• Drug solubility – lipid soluble drugs pass readily through GI
membrane,
Water – soluble drugs need an enzyme or protein
  Local condition at site of absorption – weak acids less ionized
in stomach
- - - readily pass through the SI
• Pain / stress / solid foods / fatty or hot foods – slows
down gastric emptying time
• Drug concentration – drugs can take several hours/days to
reach peak concentration levels (slow rate: rectal
administration or sustained – release drugs)
• Circulation at site of absorption – poor circulation hampers
absorption (i.e. shock)
 The more blood vessels, the faster the absorption
 Exercise – decrease blood flow to GI – slows
absorption
 Application of heat/massage increases blood flows
at site
 Muscles area selected for IM administration:
• Blood flows faster through deltoid
muscle (upper arm) vs gluteal muscle
(buttocks)
• Gluteal muscle can accommodate larger
volume of drug than deltoid muscle
3. Metabolism – biotransformation: essential for termination of a drug’s biologic activity
so can be easily excreted
• Sites of metabolism
o Liver – main organ for drug metabolism
 Through the drug metabolizing enzymes (microsomal
enzymes, non-microsomal enzymes)
 1st pass effect hepatic 1st pass – some drugs do not directly go
into circulation but pass thru intestinal lumen to liver via portal
vein - - drug metabolized in liver into inactive form - - decrease
 amount of active drugs - - - increase recommended dose for
oral drugs
 Lidocaine – extensive 1st pass – not given orally
o Plasma
o Kidneys
o Membranes of intestine
• Process by which body changes a drug from its dosage form to a more water-
soluble form that can then be excreted
• Can be metabolized in several ways:
o Most drugs metabolized into inactive metabolites (products of
metabolism), which are then excreted
o Other drugs converted to active metabolites – capable of exerting their
own pharmacologic action
 May undergo further metabolism or may be excreted from
body unchanged
 Prodrugs – some drugs administered as inactive drugs which
don’t become active until they’re metabolized
o Permits the body to inactive a potent drug before it accumulates &
produces toxic effects
• Phases of drug metabolism:
o Phase 1: endoplasmic reticulum; introduce/expose a functional group
on the parent compound (i.e. alkylation, alipathic hydroxylation,
oxidation, deamination, hydrolysis, microsomal oxidases)
 Cytochrome p450 inducer – inc drug metabolism, dec
bioavailability
 Cytochrome p450 inhibitor – dec drug metabolism, inc levels
of drug prolonged effect & inc toxicity
o Phase 2 – conjugation reactions that lead to formation of covalent
linkage between parent compound with glucoronic acid, sulfate,
 glutathione or acetate (glucoronidation, sulfation, acetylation);
synthetic reactions
• Factors affecting biotransformation:
o Genetic – some people metabolize drugs rapidly, other more slowly
o Physiologic
 Liver diseases (cirrhosis), heart failure – dec circulation in liver
 Infants – immature livers – dec rate of metabolism
o Area of absorbing surface to which a drug is exposed – (+) chemical
agents may destroy the drug
o Types of transport – diffusion, active, pinocytosis
o Routes of administration – skin absorption slower than IM
 Absorption with in seconds/minutes: sublingual, IV, by
inhalation route
 Slower rate absorption: oral, IM SC routes
o Bioavailability – consideration of highest importance in drug
effectiveness & safety
 Subcategory of absorption
 % of administered drug does that reaches systemic circulation
 Oral route <100%(usually 20-40%); IV route = 100%
 Factors that alter bioavailability:
• Drug form (tablet, capsule)
• Route of administration
• GI mucosa & motility
• Food & other drugs – (+) food - - - pord of gastric acid
– inc drug absorption (i.e. “azole”)
• Changes inliver metabolism, liver disorder – dec liver
function – inc bioavailability
II. distribution – process by which drug becomes available to body fluids & tissues
  the ways a drug is transported from the site of administration to the site of
action (transportation)
 factors affecting distribution:
o size of the organ
o blood flows – drug is quickly distributed to organs with large supply of
blood (heart, liver, kidneys)
 distribution to other internal organs, skin, fat, muscle is slower
o solubility – lipid – soluble drugs can also cross the blood-brain barrier
& enter the brain
o Binding – as drug travels trough the body, it comes in contract with
proteins (albumin). The drug can remain free or bind to protein.
 Portion of drug bound to protein is inactive, no therapeutic
affect
 Free/unbound portion – active - - - - (+) pharmacologic
response
 Highly protein bound drug - > 89% of drug is bound to protein
• Diazepam, piroxicam, valproic acid
 Moderately highly protein bound drugs – (61-89% bound
protein)
• Erythromycin, phenytoin
 Moderately protein – bound drugs – 30-60%
• Aspirin, lidocaine, pindolol, theophyliine
 Low protein-bound drugs - < 30% bound to protein (amikacin,
amoxicillin)

DISTRIBUTION

PROTEIN-
BINDING BLOOD BODY TISSUE
FLOW AFFINITY PHARMACOLOGIC
EFFECT
  Elderlies – dec liver size, blppd flow, enzyme production - - - slows
metabolism
 Environment – cigarette smoke may affect rate of some drugs
o Stressful environment – prolonged illness, surgery, injury

III. Excretion/elimination – removal of drug from the body: drug is changed into
inactive form & excreted by the body

 Routes:
o Kidney – main organ for drug elimination: leaves the body through
urine
 Free/unbound/water soluble drugs – filtered in kidney
 Protein bound drug – cannot be filtered in kidney
 (+) kidney dose – dose must be decreased
o Lungs, exocrine (sweat, salivary, mammary) glands, skin, intestinal
tract
 Factors affecting drug excretion
o Urine ph – normal: 4-5.8
 Acid urine – promotes elimination of weak base drugs
• i.e. cranberry juice – dec urine ph - - - (-) elimination of
aspirin
 alkaline urine – (+) elimination of weak acid drug
• overdose aspirin - - - give Nabicarbonate – inc urine ph
- - - (+) excretion of drug
 o glomerular filtration rate (GFR) – dec GFR - - - drug excretion
slowed/impaired
 can result to drug accumulation
 extent of filtration directly proportional to GFR & to fraction of
unbound drug to plasma
• ratio of clearance = fu x GFR - - - cleared by filtration
• ratio of clearance < fu x GFR - - - cleared tubular
reabsorption
• ratio of clearance > fu x GFR - - - cleared by tubular
secretion
o creatinine clearance – most accurate test to determine renal function
 creatinine – excreted in kidney
 dec renal GFR – inc serum creatinine level & dec urine
creatinine clearance
 12-24 hrs urine collection & blood sample
 Normal – 85-135 ml/min; elderly – 60ml/min
 Renal clearance – amount of substance removed from the blood by the
kidneys
 Half-life/elimination half-life (t ½) – time it takes for one half of drug
concentration to be eliminated
o Short t ½ = 4-8 hrs: given several times a day (i.e. penicillin G)
o Long t ½ = > 12 hrs: given 2x or 1x / day (digoxin)

II. PHARMACODYNAMICS – refers to action of drug to the body

 What happens to the body in response to the drug
 Effects of drugs on the cell’s biological & physiological functions &
mechanisms of action
 Interactions between chemical components of living systems & foreign
chemicals including drugs that enter these system
 Mechanism of action: means by which a drug produces alteration in function
of their action
 Drug actions:
a. To replace/act as substitute for missing chemicals
b. To inc or stimulate certain cellular activities
c. To depress/slow cellular activities
d. To interfere with functioning of foreign cells (i.e. invading
microorganisms/neoplasms) – chemotherapeutic Agents
 Theories of Drug Actions
a. Drug-receptors interaction – certain portion of drug molecule (active
site) selective combines with some molecular structure (reactive site)
on the cell to produce a biologic effect
 Receptor site – drugs act at specific areas on cedil memb.; react
with certain chemicals to cause an effect with in cell
 “lock & key theory” – specific chemical (key) approaches a cell
membrane & finds a perfect fit (the lock) at receptor site –
affects enzymes system within a cell – produce certain effects
 Specificity – selectivity theory
 Drug action may be:
• Agonists – drugs that produce a response
o insulin reacts with specific insulin receptor site
to change cell membrane permeability - - - (+)
movement of glucose into cell
• competitive antagonist – act with receptor sites to block
normal stimulation producing no effect
o curare – use on spear in Amazon to paralyze
prey & cause death: occupies receptor sites for
Acetylcholine (needed in muscle contraction &
movement) - - - prevents nerve stimulation
causing paralusis
 o noncompetitive antagonist - prevent reaction of
another chemical with different receptor site on
that cell
b. drug-enzymes interaction – interferes with enzyme systems that act as
catalyst from various chemical reations
 enzyme systems – cascade effect; one enzyme activating
another - - - causing cellular reaction
 if single step in one of enzyme system is blocked – normal cell
function is disrupted
 ex: acetazolamide (diamox) – diuretic that block carbonic
anhydrase – alters H+ & H2O exchange systems in kidneys &
eye
c. nonspecific drug interaction – act by biophysical means that do not
affect cellular enzymatic reactions
d. selective toxicity – all chemotherapeutic agent would act only on 1
enzyme system needed for life of a pathogen or neoplastic cell & will
nor affect healthy cells
 ex: penicillin
 unfortunately most of it cause destruction of normal human
cells

Drug response may be:

1. primary – always desirable / physiologic effects
2. secondary – desirable or undesirable
ex: diphenhydramine (benadryl) – 1st effect: antihistamine, treat symptoms of
allergy; 2: CNS depression - - - drowsiness
desirable: when given at bedtime: undesirable: when client is driving

Classification of drug action:

1. rapid – few seconds to minutes (IV, SL, inhalation)
2. intermediate – 1-2 hrs after administration (IM, SC)
 3. Delayed/slow – several hrs after administration (rectal, oral)

Parameters of Drug Action:

1. onset of action – latent period: interval between time drug is administered & 1st sign
of its effect
• time it takes to reach the minimum effective concentration (MEC) after a drug
is administered
• time from drug administration to 1st observable effect _T0 – T1)
2. duration of action – period from onset until drug effect is no longer seen
• length of time the drug exerts pharmacologic effect (T1 – T3)
3. peak action – drug reaches its highest blood / plasma concentration (T0 – T2)

Termination of action – point from onset at which drug effect is no longer seen
Minimal effective concentration – lowest plasma concentration that produces the desire
effect
Peak plasma level – highest plasma concentration attained from a dose
Toxic level – plasma concentration at which a drug produces adverse effects
Therapeutic range – range of plasma concentration that produces the desire effect without
toxicity (range between minimal effective concentration & toxic level)
Loading dose – bolus of drug given initially to attain rapidly a therapeutic plasma
concentration
• large initial dose; when immediate drug response is desired
• given to achieve a rapid MEC in the plasma
• i.e. digoxin - - - requires LD
Maintenance dose – amount of drug necessary to maintain a steady therapeutic plasma
concentration
Dose response – relationship between minimal vs. maximal amount of drug dosed needed
to produce desired drug response
• i.e. some clients respond to lower drug dose while others need a high
dose
Maximal efficacy (maximum drug effect) – all drugs give a maximum drug effect
(maximal efficacy)
• i.e. simvastatin 40mg vs rouvastatin 10mg

Drug-response relationship:
Biologic half-life (t1/2) = time required to reduce to ½ amount of unchanged drug that is
in the body
• short t1/2 drugs need to be administered more often than one with a
longer t1/2
Lethal dose (LD50) – dose lethal to 50% of animals tested
Effective dose (ED50) – dose required to produce therapeutic effect on 50% animals
tested
Therapeutic index (TI) – ratio between LD50 and ED50; the closer the ratio is to 1, the
greater the danger involved in giving the drug to humans
• estimates the margin of safety of a drug through the use of a ratio that
measures the effective (therapeutic or concentration) dose (ED) in 50%
of persons/animals (ED50) & lethal dose in 50% of animals (LD50)
TI=LD50/ED50
• low therapeutic index: narrow margin of safety; might need to adjust
drug dose & plasma drug levels need to be monitored
• high therapeutic index: wide margin of safety less danger of producing
toxic effects

4 Categories of Drug Action:

1. stimulation/depression
• stimulation – inc rate of cell activity/secretion from the gland
• depression – dec cell activity & function of a specific organ
2. replacement – replaces essential body compounds; i.e. insulin
3. inhibition/killing of organism – interfere with bacterial cell growth ; i.e. antibiotics
4. irritation – i.e. laxative – irritate inner wall of colon - - - inc peristalsis - - - inc
defecation

Drug potency – relative amount of drug required to produce desired response

• also used to compare a drug
dose response curve – graphical representation of relationship between dose of drug &
response it produces
• low dose – low response
• dosage increased produce slight increase response, as dose further increases, drug
response increases markedly, at certain point however, inc dose yield little or no
inc in response - - - drug have reached Maximum Effectiveness

Factors Affecting Dose Response Curve:

- nurse must be aware that human factor has tremendous influence on
what actually happens when it enter the body
- no 2 people react in exactly the same way to any given drug
1. weight heavier patient – larger dose to get therapeutic effect (more tissue to
perfuse & inc receptor site in some reactive tissues)
- dec weight – dec dose
2. age – children (immune system for handling drugs) & older adults
- older patients: less absorption, distribution between fewer plasma
proteins & less efficient perfusion: geriatric dosages
- nurse should monitor closely for desired effects (may adjust dose)
3. toxicity
4. pharmacogenetics – effect of a drug action that varies from a predicted drug
response because of genetic factors or hereditary influence
• people have different genetic makeup – do not always respond identically to a
drug dosage or planned drug therapy
• ex: African – Americans do not respond as well as whites to some classes of
antihypertensive medications
5. route of administration
 6. emotional factors
7. pre-existing disease state – liver disease
8. drug history – drug interaction – synergistic/excretion
9. tolerance
10. cumulative effect
11. drug- drug interaction
12. BMR – inc BMR – inc drug metabolism & excretion

Drug Interaction
1. Additive effect – 2 drugs with similar actions are taken for a doubled effect
(desirable/undesirable) (1 + 1 = 2)
• Ibuprofen + paracetamol + added analgesic effect
2. Synergistic – combined effect of 2 drugs is greater than sum of the effect or each
drug given alone (1 + 1 = 3)
• Aspirin + codeine = greater analgesic effect
3. potentiation – a drug that has no effect enhances the effect of a 2nd drug (0 + 1= 2)
4. Antagonistic – one drug inhibits the effect of another drug (1 + 1 = 0)
• Tetracycline + antacid = dec absorption of tetracycline

SIDE EFFECTS
• Physiologic effects not related to desired drug effects
• All drugs have side effects
 Desirable: diphenhydramine (Benadryl) at bedtime – s/e:
drowsiness
 Undesirable
• Result mostly from drugs that lack specificity
• Might be used interchangeably with adverse reactions
• Not a reason to discontinue drug therapy
• Nurse’s role: teach clients to report any side effects
ADVERSE REACTIONS
• More severe than side effects
• Range of untoward effects (unintended, occurring at normal doses) of drug
that cause mild-severe side effects: anaphylaxis (cardiovascular collapse)
• Always undesirable
• Must always be reported & documented because they represent variances
from planned therapy.

TOXIC EFFECT/TOXICITY
• Can be identified by monitoring the plasma (serum) therapeutic range of the
drug
• Narrow TI (aminoglycoside & antibiotics) – therapeutic range is monitored
• When drug level exceeds therapeutic range, toxic effects are likely to occur
from overdosing or drug accumulation.