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Pharmacology Review
• Pharmacology is the study of substances that
interact with living systems through chemical
processes
• Especially by binding regulatory molecules and
activating or inhibiting normal body processes
Drug
• Most drugs interact with a molecule or protein
that play a regulatory role in living systems
Drugs must have specificity
• Drugs that interact with receptors must be
appropriate size, charge, and shape to interact
with a given receptor
Drugs must have delivery
• A drug must be able to be transported to site
of action
Drugs must have elimination
• Drugs must be removed and excreted at a
reasonable rate
The Nature of Drugs
• Most drugs are weak acids or weak bases
pKa
• The pKa is the pH at which the molecule or
drug is balanced between the uncharged (lipid
soluble) and the charged (water soluble) form
The Nature of Drugs
• Most drugs are weak acids or weak bases
because only subtle changes in pH are
required to shift them back and forth:
• - lipid soluble (easily passes cell membranes)
• - water soluble (does not pass without
transport)
Henderson-Hasselbach
• Log [RH]/[R] = pKa-pH
pH
• Potential of hydrogen ion (proton) in water
• pH = 7 neutral
• pH> 7 basic
• pH< 7 acidic
pH
• Physiologic pH is about 7.35
• - slightly alkaline
The Nature of Drugs
• Drugs interact with receptors by means of
chemical forces or bonds
Nature of Receptors
• Most receptors are proteins which mediate
the action of endogenous chemical signals
Affinity
• How tightly the receptor binds to the drug
Receptors
• Receptors are responsible for selectivity of
drug action
The Nature of Drugs
• Drugs interact with receptors by means of
chemical forces of bonds:
• Covalent – very strong,usually irreversible
The Nature of Drugs
• Drugs interact with receptors by means of
chemical forces or bonds:
• - Electrostatic – pretty strong
•
- ionic groups (+ and – attract)
•
- hydrogen bonds
The nature of drugs
• Hydrophilic or lipophilic – weak
Drug-Body Interactions
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Pharmacodynamics
- actions of drugs on the body
Pharmacokinetics
- actions of the body on the drug
Pharmacodynamic Principles
• Agonist drugs bind to and activate the
receptor
• - opening ion channel
• - initiating second messenger
Pharmacodynamic Principles
• Antagonists bind to receptor and prevent
activation of the receptor
Agonist
• An agonist is any drug that binds to a receptor
and activates the receptor
• In many receptors, agonist leaving the binding
site deactivates the receptor
• In other receptors, agonist permanently
activates the receptor
Pharmacologic Antagonist
• A pharmacologic antagonist is any drug that
binds to a receptor and prevents the
activation of the receptor
Competitive Antagonist
• A competitive antagonist is any pharmacologic
antagonist that “competes” with the binding
of agonist at binding site
Noncompetitive Antagonist
• A noncompetitive antagonist is any
pharmacologic antagonist that binds to a site
on the receptor other than the agonist binding
site
Chemical Antagonist
• A chemical antagonist is any drug that binds
directly to an agonist and deactivates the
agonist
Physiologic Antagonist
• Physiologic antagonism means the drug is
reduced by other physiologic pathways.
• Epinephrine is the physiologic antagonist of
histamine
Pharmacodynamic Principles
• Effect of drug may persist long after drug
dissociates from receptor
Natural Curves
• The interaction between a drug or ligand and
it’s receptor can be described by a curve
• Because drugs mimic the natural regulatory
processes, their effect follows a natural curve
Drug Concentration and Response
• Response usually increases in proportion to
dose
• As dose increases, response increment
diminishes
• At some dose there is no further increase in
response
Agonist Dose/Response Curve
Potency vs Efficacy
Efficacy – refers to the effect of a
drug. The more effect, the more
efficacious the drug
Potency – refers to the
concentration of a drug needed for
the effect. The less the
concentration required, the more
potent the drug.
Potency and Efficacy
- are used interchangeably by
medical personnel
Quantal Dose Effect Curves
• Quantal dose effect curves implies a binary or
on/off response to a drug
• Either the effect is achieved or not achieved
EC 50
• EC 50 is the concentration of drug required to
achieve half of the expected response
ED 50
• ED 50 is the dose of the drug required to
achieve half of the expected response
TD 50
• TD 50 is the dose of the drug required to
achieve toxicity in half of the subjects given
the drug
LD 50
• LD 50 is the dose of the drug required to be
lethal to half of the subjects given the drug
T½
• T1/2 or half life is the amount of time required
to lower the concentration for the drug by half
Route of administration
• How the drug is administered affects
bioavailability
Bioavailability
• Bioavailability describes the concentration of
drug in systemic blood in relation to the
amount of drug given
PO
• PO – by mouth
• - blood from the GI tract goes directly to the
liver first
• - rarely 100%
IV
• IV – intravenous
• - drug goes directly into the bloodstream
IM
• IM – intramuscular – into muscle
• - to out of muscle deposited to blood
SC
• SC – subcutaneously – under skin
• - out of subcutaneous fat deposited to blood
PR
• PR – by rectum
• - to liver via GI blood
Inhalation
• Inhalation – directly to lungs
• - to bloodstream
Transdermal
• Transdermal – applied to skin, crosses skin to
systemic blood supply
• e.g. nicotine patches
Topical
• Topical – applied to skin, action intended
locally at the site of administration
Intranasal
• Intranasal – into and across nasal mucosa
• - to bloodstream
• - to base of brain (pituitary)
Intrathecal
• Intrathecal – into the cerebrospinal fluid
• - foramen magnum – hole skull/spine
• - to brain via CSF
Epidural
• Epidural – outside of the spinal dura
• - spinal anesthesia
Intraarticular
• Intraarticular – into the joint space
• - steroid injection into knee
First Pass Effect
• The first pass effect:
• - all drugs absorbed by GI tract enter the
portal blood supply and go directly to the liver
• - the liver metabolizes many drugs before they
enter into systemic blood supply
Prodrug
• Many drugs are administered in their inactive
forms
• When drugs make their first pass through the
liver, they are converted into their active
forms
Permeation
• Permeation is the penetration of drug into the
tissues
Mechanisms of Permeation
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Aqueous diffusion
Lipid diffusion
Special carriers
Endocytosis and exocytosis
Transformation
• Transformation is the chemical changing of
the drug by the body
Transformation
• Liver transformation
• Peripheral transformation
• GI transformation
Phase I Reactions
Oxidation
• Phase I involves conversion to water soluble
metabolites
• - CYP
• - Cytochrome P450
Phase II Reactions
Conjugation
• If not polar enough, they will undergo Phase II
reactions during which they are conjugated to
highly polar groups
• In reality many substances can undergo either
transformation in any order
Elimination
• Elimination is the removal of drug from the
body
Renal vs. Hepatic Elimination
• Not all drugs need to be transformed by the
liver to be eliminated
• Urination – elimination by kidneys
• Defecation – hepatic elimination via bile
• Most drugs require both
Volume of Distribution
• Amount of drug in body relative to
concentration of drug in blood
Clearance
• The rate of elimination in relation to the drug
concentration
• CL = Rate of elimination/Concentration
Drug Accumulation
• Whenever drug doses are repeated, the drug
will accumulate until dosing stops
• If the dosing interval is shorter than 4 halflives accumulation will occur
Maintenance Dose
• Dosing Rate = Clearance x Target
Concentration
Loading Dose
• Loading Dose = VD x TC