BASIC PRINCIPLES OF PHARMACOLOGY For DENTISTRY
BASIC PRINCIPLES OF PHARMACOLOGY For DENTISTRY
BASIC PRINCIPLES OF PHARMACOLOGY For DENTISTRY
PHARMACOLOGY
for Dentistry
Jo-Ann S. Belotindos,RPh,MPH,MPP
College of Pharmacy, SWU-PHINMA
Learning Objectives:
• At the end of the session, the student be able to:
• Define pharmacology, toxicology, drug, pharmacogenomics, pharmacokinetics,
pharmacodynamics.
• Describe the principles of pharmacokinetics and principles of pharmacodynamics.
• Understand the physical nature of drugs
• Describe drug molecule – receptor interaction
2
INTRODUCTION
Definitions Pharmacokinetics
Pharmacodynamics
Permeability /
Absorption
Nature of
Distribution Drugs
Receptors,
Metabolism
Receptors
Elimination sites
Inert binding
sites
3
CASE STUDY
PHARMACOLOGY
= the study of substances that interact with living systems through chemical
processes, especially by binding to regulatory molecules and activating or
inhibiting normal body processes.
5
• these substances maybe chemicals administered to achieve beneficial
therapeutic effect on some process within the patient or for their toxic
effects on regulatory processes in parasites infecting the patient.
6
MEDICAL PHARMACOLOGY
7
TOXICOLOGY
8
9
• New drugs are added every year; they are needed for several reasons:
(1) increasing resistance by bacteria and other
parasites;
(2) discovery of new target processes in diseases
that have not been adequately treated; and
(3) recognition of new diseases.
Furthermore, a dramatic increase has occurred in the number of large
molecule drugs (especially antibodies) approved during the last two
decades.
10
The History of Pharmacology
11
Pharmacogenomics —the relation of the individual's
genetic makeup to his or her response to specific
drugs is becoming an important part of
therapeutics.
13
(3) that all dietary supplements and all therapies promoted as health-
enhancing should meet the same standards of efficacy and safety as
conventional drugs and medical therapies.
14
• That is, there should be NO artificial separation between scientific medicine
and "alternative" or "complementary" medicine.
15
The NATURE of DRUGS:
DRUG
• any substance that brings about a change in biologic function through its
chemical actions.
• the drug molecule interacts as an agonist (activator) or antagonist
(inhibitor) with a specific target molecule that plays a regulatory role in
the biologic system.
• This molecule is called a receptor .
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• Drugs maybe synthesized within the body (eg.
Hormones) or maybe chemicals not synthesized in the
body, ie. Xenobiotics (xenos – “stranger”)
• Poisons are drugs that have almost exclusively harmful effects. (Paracelsus
– famously stated “the dose makes the poison” --- any substance can be harmful if
taken in the wrong dosage)
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The Physical Nature of Drugs
FURTHERMORE…
18
• A drug is often administered at a location distant
from its intended site of action, eg, a pill is given
orally to relieve a headache.
19
The physical nature of drugs:
• drugs maybe:
• solid @ room temp. (ex. aspirin, atropine),
• liquid (ex. nicotine, ethanol),
• gaseous (ex. nitrous oxide, nitric oxide, xenon)
20
To interact chemically with its receptor, a DRUG molecule must have the :
a. appropriate SIZE
21
Drugs interact with receptors by means of chemical
forces or bonds.
These are of 3 major types:
1. COVALENT bonds – are very strong and in many
cases not reversible under biologic conditions.
(Aspirin [NSAIDs] – irreversibly blocks COX)
22
b. electrical charge
c. shape
the shape of a drug molecule must be such
as to permit binding to its receptor site.
Optimally, the drug shape complementary
to that of the receptor site in the same
way that a key is complementary to a lock.
d. atomic composition
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Drug – Receptor Binding
24
DRUG – BODY INTERACTIONS
• PHARMACODYNAMICS – the actions of the drug on the
body.
• These determine the group in which the drug is classified,
and play the major role in deciding whether the group is an
appropriate therapy for a particular symptom or disease.
• However, at the cellular level, drug binding is only the first in what is
often a complex sequence of steps…
26
• Drug (D) + receptor-effector (R) drug-receptor-
effector complex effect
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PHARMACODYNAMIC PRINCIPLES
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PHARMACODYNAMIC PRINCIPLES
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C. Agonists, Partial Agonists, and Inverse Agonists
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D. Duration of Drug Action
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• In the case of drugs that bind covalently to the receptor site, the
effect may persist until the drug-receptor complex is destroyed and
new receptors or enzymes are synthesized.
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PHARMACODYNAMIC PRINCIPLES
E. Receptors and Inert Binding Sites
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For SAS 2
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PHARMACOKINETICS
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• Pharmacodynamics governs the concentration-effect part
of the interaction, whereas;
• Pharmacokinetics deals with the dose-concentration part.
• The pharmacokinetic processes of absorption,
distribution, and elimination determine how rapidly
and for how long the drug will appear at the target
organ.
• The pharmacodynamic concepts of maximum
response and sensitivity determine the magnitude of
the effect at a particular concentration.
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Figure 3 – 1
72 37
PHARMACOKINETICS
=the actions of the body on the
drug.
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2 BASIC PHARMACOKINETIC
PARAMETERS:
1. VOLUME of DISTRIBUTION (V)
- the measure of the apparent space in
the body available to contain the drug.
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• The volume of distribution may be defined with
respect to blood, plasma, or water (unbound drug),
depending on the concentration used in equation.
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• Drugs with very high volumes of distribution have
much higher concentrations in extravascular tissue
than in the vascular compartment, ie, they are not
homogeneously distributed.
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2. CLEARANCE
- the measure of the ability of the body
to eliminate the drug.
42
-maybe defined with respect to blood
(CLb),plasma (CLp), or unbound in water
(CLu), depending on the concentration
measured.
CL = rate of elimination
C
44
FORMULAS:
a. CL renal = rate of elimination (kidney)
C
45
Biological Half-life (t 1/2)
• is the time required to change the amount of drug
in the body by one-half during elimination.
• the most useful in designing drug dosage regimens.
• The time course of drug in the body will depend on
both the volume of distribution and the clearance:
t ½ = 0.7 x V
CL
46
• Half-life useful because it indicates the time required to
attain 50% of steady state—or to decay 50% from
steady-state conditions—after a change in the rate of
drug administration.
47
Drug Accumulation
• With repeating drug doses, the drug will accumulate in
the body until dosing ceases.
• Practically: if the dosing interval is shorter than four
half-lives, accumulation will be detectable.
• Accumulation: inversely proportional to the fraction of
the dose lost in each dosing interval.
• The fraction lost is 1 minus the fraction remaining just
before the next dose. The fraction
remaining can be predicted from the dosing interval
and the half-life.
48
• For a drug given once every half-life, the accumulation
factor is 1/0.5, or 2.
49
Bioavailability
50
• The area under the blood concentration time curve
(AUC) is a common measure of the extent of
bioavailability for a drug given by a particular route.
51
• Check table 3 – 3 Routes of administration, Bioavailability
(%) and general characteristics.
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ROUTES of ADMINISTRATION:
A. ENTERAL:
1. ORAL
= most common and require the most
complicated pathway to the tissues.
= most variable
= offers maximum convenience, but
absorption may be slower and less
complete than when parenteral routes are
used.
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= some drugs are absorb in the stomach but
DUODENUM is often the major site because of its
larger absorptive surface.
= ingestion of foods can influence absorption.
Presence of food in the stomach delays gastric
emptying time (ex. PCN) so that drugs that are
destroyed by acid become unavailable for
absorption.
= most drugs are absorb from the GIT enter the portal
circulation and encounter the liver before they are
distributed into the general circulation.
54
Hepatic ‘First-Pass’ Metabolism
• Affects orally administered drugs
• Drug absorbed into portal circulation, must pass
through liver to reach systemic circulation
• May reduce availability of drug
• Ex. 90% of nitroglycerin is cleared during a single
passage thru the liver.
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2. SUBLINGUAL / BUCCAL
= sublingual (place under the tongue)
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3. RECTAL (suppository)
= offers partial avoidance of the first pass effect.
Because suppositories tend to migrate upward in the
rectum and absorption from this higher location is
partially into the portal circulation.
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Parenteral Route
• Intravenous*
• Intramuscular
• Subcutaneous
• Intradermal
• Intrathecal
• Intraarticular
*Fastest delivery into the blood circulation
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B. PARENTERAL:
= use for drugs that are poorly absorbed from the
GIT.
= example: INSULIN (unstable in GIT)
= use for treatment of unconscious patient – which
requires rapid onset of action under circumstances.
= provides the most control over the actual dose of
drug delivered to the body.
= 3 major parenterals:
IV
IM
SC
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1. INTRAVASCULAR (IV)
= IV is the most common.
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2. INTRAMUSCULAR (IM)
= can be aqueous solution or specialize depot preparation (
often a suspension of drug in a non aqueous vehicle like
ethylene glycol or peanut oil)
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= as the vehicle diffuses out of the
muscle, the drug precipitates at the site of injection.
Then the drug dissolves slowly, providing a sustained
dose over an extended period of time.
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3. SUBCUTANEOUS (SC)
= offers slower absorption than the IM route; slower
than IV
= large volume bolus doses are less feasible but
heparin does not cause hematomas when
administered by this route.
= minimizes the risks associated with IV injections.
= First-pass metabolism is avoided.
examples: epinephrine ( act as local
vasoconstrictor and decreases removal
of a drug such as LIDOCAINE, from the site
of administration); insulin
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Topical Route
• Skin (including transdermal patches)
• Eyes
• Ears
• Nose
• Lungs (inhalation)
• Vagina
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OTHERS:
1. INHALATION
= provides rapid delivery of a drug across
the large surface area of mucous
membrane of the respiratory tract and pulmonary
epithelium.
= effective and convenient for patients
with respiratory complaints.
examples: Budesonide (Budecort inhaler)
Flixotide (Fluticasone propionate)
Easily volatilized many anesthetics
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2. INTRANASAL
= examples: Desmopressin is administered
intranasally in the treatment of diabetes insipidus.
= Calcitonin, a peptide hormone, for the treatment of
osteoporosis is also available in nasal spray.
= Cocaine, generally taken by sniffing
3. INTRATHECAL / INTRAVENTRICULAR
= introduces drugs directly to the cerebrospinal fluid
(CSF).
= examples; Methotrexate for ALL
Amphotericin B to treat
cryptococcal meningitis
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4. TOPICAL
= use when local effect of the drug is desired.
= this route includes application to the skin or to the
mucous membrane of the eye, nose, throat, airway, or
vagina for local effect.
examples:
Clotrimazole, treatment of dermatophytosis
Atropine, instill directly to the pupil to
dilate eyes and permit
measurement of refractive errors.
67
5. TRANSDERMAL
= achieves systemic effects by application of drugs
to the skin.
= the rate of absorption varies, depending on the
physical characteristics of the skin at the site of
application.
ex. Nitroglycerin patch
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Reasons for different Routes of
Administration:
70
Extraction ratio & First-pass effect
• Systemic clearance is not affected by bioavailability.
However, clearance can markedly affect the extent of
availability because it determines the extraction ratio.
• Other drugs that are highly extracted by the liver include
isoniazid,morphine, propranolol, verapamil, and several
tricyclic antidepressants.
• Drugs with high extraction ratios will show marked
variations in bioavailability between subjects because of
differences in hepatic function and blood flow.
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• For drugs that are highly extracted by the liver, bypassing
hepatic sites of elimination (eg, in hepatic cirrhosis with
portosystemic shunting) will result in substantial increases
in drug availability.
• For drugs that are poorly extracted by the liver (for which
the difference between entering and exiting drug
concentration is small), shunting of blood past the liver will
cause little change in availability.
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THE TIME COURSE of DRUG EFFECT
plasma concentrations.
• DELAYED EFFECTS
• CUMMULATIVE EFFECTS
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DELAYED EFFECTS
• Changes in drug effects are often delayed in relation to changes in plasma
concentration.
• This delay may reflect the time required for the drug to
distribute from plasma to the site of action.
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• Some drugs bind tightly to receptors, and it is the half-
life of dissociation that determines the delay in effect,
eg, for digoxin.
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CUMULATIVE EFFECTS
• The renal toxicity of aminoglycoside antibiotics (eg,
gentamicin) is greater when administered as a constant
infusion than with intermittent dosing.
• It is the accumulation of aminoglycoside in the renal
cortex that is thought to cause renal damage.
• The effect of many drugs used to treat cancer also
reflects a cumulative action.
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The Target Concentration Approach to
Designing a Rational Dosage Regimen
• MAINTENANCE DOSE
• Drugs are administered to maintain a steady state
concentration in the body.
(just enough drug is given in each dose to replace the drug
eliminated since the preceding dose)
• Clearance is
the most important pharmacokinetic term to be
considered in defining a rational steady-state drug dosage
regimen.
• At steady state, the dosing rate (“rate in”) must equal the
rate of elimination (“rate out”).
• LOADING DOSE
• Promptly raises the concentration of drug in plasma to the target
concentration.
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Plasma Protein Binding: Is It Important?
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• Drug displaced from plasma protein will be distribute
throughout the volume of distribution, so that a 5%
increase in the amount of unbound drug in the body
produces at most a 5% increase in pharmacologically
active unbound drug at the site of action.
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• The clinical importance of plasma protein binding
is only to help interpretation of measured drug
concentrations.
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Factors affecting protein binding:
1. Albumin concentration: Drugs such as phenytoin,
salicylates, and disopyramide (weak acid drugs) are extensively
bound to plasma albumin. Albumin levels are low in many
disease states lower total drug concentrations.
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3. Capacity-limited protein binding:
84
4. Binding to RBCs:
drugs such as cyclosporine and tacrolimus bind
extensively inside RBC.
A decrease in RBC concentrationwill cause whole blood
concentration to fall.
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Pharmacokinetic Processes
“LADME” is key
Liberation Metabolism
Absorption Excretion
Distribution
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Liberation
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Absorption
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Pharmacokinetics: Distribution
The transport of a drug in the body by the bloodstream to its site of
action.
• Rate of perfusion
• Ability to cross membranes
• Blood-brain barrier
• Placental barrier
• Plasma Protein-binding
• Water soluble vs. fat soluble
• Areas of rapid distribution: heart, liver, kidneys, brain
• Areas of slow distribution: muscle, skin, fat
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Blood-Brain Barrier
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Pharmacokinetics: Metabolism
(Drug Biotransformation)
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• Metabolic products are often less
pharmacodynamically active than the parent drug
and may even be inactive.
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Pharmacokinetics:
DRUG EXCRETION
- is the process by which a drug or metabolite is eliminated from the
body.
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Routes of elimination:
1. KIDNEY = most important organ for excretion of drugs.
= primary site
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For SAS 1
Pharmacodynamics
97
Pharmacodynamics
• Receptor interaction
• Enzyme interaction
• Nonspecific interactions
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RECEPTORS
• The component of a cell or organism that interacts with a drug and
initiates the chain of biochemical events leading to the drug`s
observed effects.
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RECEPTORS...
1. Largely determine the quantitative relations
between dose or concentration of drug and
pharmacologic effects (affinity for binding);
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• Most receptors are proteins.
• "orphan" receptors - so
called because their ligands are
presently unknown, which may prove to be useful
targets for the development of new drugs.
102
• Other classes of proteins that have been clearly
identified as drug receptors include Enzymes, which
may be inhibited (or, less commonly, activated) by
binding a drug (eg, dihydrofolate reductase, the
receptor for the antineoplastic drug Methotrexate);
103
RECEPTOR RESERVE OR SPARE
RECEPTORS
104
SPARE RECEPTORS…
105
meaning....
106
Drug Mechanisms
•Receptor interactions
•Non-receptor mechanisms
107
Receptor Interactions
Agonist Receptor
Agonist-Receptor
Interaction
108
TYPES of DRUG-RECEPTOR
INTERACTIONS:
a. AGONIST – drugs that bind to and activate the
receptor which directly or indirectly brings about the
effect.
a.1 FULL AGONIST – drugs bind to receptors and activate
them but do not evoke as great a response
109
Agonists and Antagonists
b. ANTAGONIST
A drug is said to be an antagonist when it binds to a
receptor and prevents (blocks or inhibits) a natural
compound or a drug to have an effect on the
receptor. An antagonist has NO
activity.
110
111
Drug Antagonism – one drug decrease or
inhibits action of another drug
TYPES of ANTAGONISM:
• Pharmacological
• Competitive
• Non-competitive
• Physiologic
• Chemical
112
b.1 Pharmacologic antagonism:
b.1.1 Competitive antagonist
= antagonist binds with the same
receptors as the agonist.
= a pharmacologic antagonist that can be
overcome by increasing the dose of an
agonist.
= “surmountable” / reversible
= examples, Propranolol = Norepinephrine;
Morphine = Naloxone
b.1.2 Non-competitive or Irreversible antagonist
= binds to another site of receptors.
= a pharmacologic antagonist that cannot be overcome by increasing the dose
of agonist.
= ”non-surmountable” / irreversible
= example, Phenoxybenzamine (an irreversible 𝛼 −
adrenoceptor antagonist)
114
Physiologic Antagonism
• Examples:
• antagonism of the bronchoconstrictor action of HISTAMINE (mediated
@ histamine receptors) by EPINEPHRINE`S bronchodilator action
(mediated @ beta adrenoceptors)
115
b.3 Chemical antagonism
=a type of antagonism where a drug counters the
effects of another by simple chemical reaction /
neutralization (not binding to the receptor)
= examples:
1. Calcium sodium edetate form insoluble complexes
with arsenic / lead
117
SECOND MESSENGERS
118
119
There are 3 major classes of second
messengers:
• cyclic nucleotides (e.g., cAMP and cGMP)
120
cyclic nucleotides (e.g.cAMP & cGMP)
121
(PHOSPHOINOSITIDES)
inositol trisphosphate (IP3) and diacylglycerol
(DAG)
• bind to G protein-coupled receptors (GPCRs) that activate the
intracellular enzyme phospholipase C (PLC).
122
Drug Mechanisms
•Receptor interactions
•Non-receptor mechanisms
123
Non-receptor Mechanisms
1. Actions on Enzymes
• Enzymes = Biological catalysts
• Speed chemical reactions
• Are not changed themselves
• Drugs altering enzyme activity alter processes catalyzed by the enzymes
• Examples
• Cholinesterase inhibitors
• Monoamine oxidase inhibitors
124
Non-receptor Mechanisms
• Mannitol
125
Non-receptor Mechanisms
126
Non-receptor Mechanisms
127
Non-receptor Mechanisms
5. Anti-metabolites
• Enter biochemical reactions in place of normal substrate “competitors”
• Result in biologically inactive product
• Examples
• Some anti-neoplastics (anti-cancer)
• Some anti-infectives (antimicrobials)
128
Therapeutic Index
129
Drug-Drug Interactions
130
• Consequences of drug interactions:
131
• Examples -- positive, beneficial drug interaction effects:
• propranolol + hydralazine (reflex tachycardia
(undesirable) caused by hypotensive hydralazine-mediated
response is prevented by propranolol-mediated b-adrenergic
receptor blockade
132
• Adverse effects -- toxic reactions
• one drug may interact with another to
impede absorption
• one drug may compete with another for the
same plasma protein-binding sites
• one drug may affect metabolism of another
by either enzyme induction or enzyme
inhibition
• one drug may change the renal excretion
rate of the other.
133
DRUG-DRUG INTERACTIONS
T ricyclic antidepressants
H2 antagonist ( Tagamet )
E thanol
rythromycin
M AO inhibitors
A minophylline
D igoxin, Dilantin, Diuretics
W arfarin
A zole ( antifungal )
R ifampin
134
FOOD-DRUG INTERACTIONS
• DRUG • FOODS to AVOID
1. ANTACIDS bran and whole grain breads
(Ca carbonate)
136
• SYNERGISM
= occurs if two drugs with the same effect, when given together,
produce an effect that is greater in magnitude than the sum of the
effects when the drugs are given individually.
137
CO TRIM OXAZOLE
TRIMETHOPRIM + SULFAMETHOXAZOLE
138
• POTENTIATION
139
Pregnancy Considerations
140
Pregnancy Categories table 59-2
141
Drug Classification
• By chemistry
• electrolytes
• By mechanism
• Beta blockers
• benzodiazepines
• By disease
• antihypertensives
• Antiemetics
142