General Principles
in
Pharmacology
Ma. Victoria M. Villarica M.D.
Basic Principles:
• Pharmacology – study of substances that
interact with living systems to produce an
effect
• Pharmacotherapeutics – drugs used in the
diagnosis, treatment and prevention of
diseases
• Toxicology – toxic effects of drugs
• Pharmacognosy – drugs in their unaltered
state
• Pharmacogenetics
• Pharmacoeconomics
• Drug – substance that brings about
change through its’ chemical action
• Physical properties of a drug:
a. physical nature of a drug
b. drug size
c. chemical forces – covalent, electrostatic,
hydrophobic
Basic Pharmacologic concepts:
1. Pharmacokinetics – body → drug
- “ drug-concentration” relationship
4 processes:
A. absorption – rate → circulating fluids
factors: drug solubility, drug
concentration, local conditions, blood
flow, surface area
Routes of drug administration:
a. enteral – oral , rectal
b. parenteral – IV, IM, SC, intraperitoneal,
intrathecal, intraarterial, inhalational, otic,
optic
c. topical
B. distribution – site of administration →site
of action
factors: size of the organ, blood flow,
solubility, binding
Permeation – how a drug transverses the
plasma membrane
• Passive diffusion, active transport,
facilitated diffusion, pinocytosis
C. metabolism – biotransformation; liver
2 phases:
1. phase I – introduce or expose a
functional group
e.g. dealkylation, oxidation, reduction,
hydrolysis, deamination, cytochrome p450
2. Phase II – formation of covalent linkage
between the functional group on the
parent compound; cytosol
e.g. glucoronidation, sulfation, acetylation
Factors
Inducer
Inhibitor
D. excretion – elimination; kidneys
Factors
2 Basic Parameters of
Pharmacokinetics
1. Volume of distribution (Vd) – amount of
apparent space in the body able to
contain a drug
Vd = amt of drug in body / concentration (C)
2. Clearance (Cl) – ability of the body to
eliminate a drug
Cl = rate of elimination / C
Clearance:
a. capacity-limited elimination – varies,
depending upon concentration of the drug that
is achieved; saturable; dose/concentration
dependent
e.g. phenytoin, ethanol, aspirin
rate of elimination = Vmax x C
Km x C
Vmax – maximum elimination capacity
Km – drug conc. at w/c rate of elimination is
50% of Vmax
“pseudo-zero order kinetics” – elimination is
independent of concentration
b. Flow dependent elimination – dependent
on the rate of delivery of the drug to the
organ
“high extraction” drugs
“first order kinetics” – a constant fraction of
drug is eliminated/unit of time; not
saturated
“zero-order kinetics” – a constant amount of
drug is eliminated/unit of time; saturable
Other parameters:
• Half-life (t ½) – time required to change
the amount of drug by ½
t ½ = 0.7 x Vd
Cl
• Drug accumulation – drug interval is
shorter than 4 t ½ , accumulation is
detectable
Accumulation factor = 1/ 1 – fraction
remaining before next dose
•Bioavailability – fraction of unchanged drug
reaching the circulation; extent of absorption
varies
first pass elimination
ER =
C liver
Q (hepatic blood flow)
• Steady state – achieved when rate of
elimination = rate of administration
rate in = rate out
• Area under the curve (AUC) – 1st order
elimination; time concentration profile after
a dose; C is constant
•Minimum effective concentration
• Loading dose = Vd x desired plasma conc.
bioavailability
- initial dose that is given
• Maintenance dose =
Cl x desired plasma conc.
bioavailability
• Therapeutic index (TI) – dose to produce
desired effect
• Intermittent dose: peak – high pts. of
fluctuations (toxic effects)
troughs – low pts. of fluctuations (lack
drug of effects)
2. Pharmacodynamics – drug →body
• Receptors
inert binding site – binds with a drug w/out
initiating events leading to any of the
drug’s effects; buffers concentration
gradient that drives diffusion
active site – recognition site
Principles:
a. Concentration effect curve – response to
low dose increases in direct proportion to
dose; however, as dose increases, the
response increment diminishes that
finally, doses may be reached at w/c no
further increase in response can be
achieved
b. Receptor-effector coupling – transduction
process that occurs between occupancy
of the receptors and drug response
•
•
Spare receptor
Receptor antagonists – prevent agonist from
binding and activating receptors
• 2 classes:
a. competitive antagonist
b. irreversible antagonist – unavailable
chemical antagonist – protamine and warfarin or
heparin
Physiologic antagonist – steroids and insulin
• Receptor agonist – full agonist and partial
agonist
Signaling mechanism and drug action
1. Intracellular receptors for lipid soluble agents –
NO, hormones, corticosteroids, sex hormones,
vit D, thyroid hormone
2. Ligand regulated transmembrane enzymes –
insulin, growth factor
3. Cytokine receptor – JAK enzyme, STAT;
growth hormone, erythropoietin, interferon
4. Ligand-gated channels – ACTH, GABA
5. G-proteins and 2nd messengers – cAMP, Ca,
cGMP
Relation between drug dose and clinical response
A. Graded dose response
pharmacologic potency – EC50 and
ED50
maximal efficacy – extent or degree of
an effect that can be achieved by the
patient
B. Quantal dose effect responsemargin of safety;
indicates variability of responsiveness; ED50,
LD50, TD50, TI = TD50
ED50
Variations in drug responsiveness:
- mechanisms involve alteration in
concentration of a drug and changes in the
receptor
• Hyporeactive
• Hyperreactive
• Tolerance - ↓ responsiveness due to
continued drug administration
• Tachyphylaxis – rapid, diminishing
responsiveness
Basic and Clinical Evaluation of a
New Drug
• 1st step – discovery of a potential molecule
(chemical modification, random screening of
natural products, rational drug design,
biotechnology and cloning)
• 2nd step – drug screening → LEAD compound
• 3rd step – preclinical and toxicity testing;
limitations
(acute and chronic toxicity, teratogenicity,
carcinogenicity, mutagenicity, investigative
toxicology)
• 4th step – evaluation in humans ; factors
Phases of clinical trial:
• Phase 1 – 25-50 healthy volunteers
• Phase 2 – 10-200 patients with target
disease
• Phase 3 – larger population; difficult
phase; NDA is submitted and approval
takes place 3 yrs or more
• Phase 4 post-marketing surveillance;
apply for a patent (20 yrs.)
Maraming Salamat