Physiologic Factors

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PHARMACEUTICAL INDUSTRY
Drug Discovery
- natural sources, synthesis/modification
biological properties
Preclinical Studies
- pharmacology, pharmacokinetics
preformulation
- chem/phys properties
- analytical assays
Formulation
development of dosage form
 large-scale manufacturing

Clinical Trials
Approval for Distribution
Post-Marketing Surveillance
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CHEE 440
Definitions
drug - Any substance or mixture of substances manufactured, sold or represented
for use in:
a) the diagnosis, treatment, mitigation or prevention of a disease, a disorder, an
abnormal physical state or the symptoms thereof in humans or animals
b) restoring, correcting or modifying organic functions in humans or animals
c) “disinfection” in premises in which food is manufactured, prepared or kept
pharmaceutics - the area of study concerned with the formulation, manufacture,
stability, and effectiveness of dosage forms
pharmacology - the science of the properties of drugs and their effects on the
body
pharmacokinetics - the study of the kinetics of absorption, distribution,
metabolism, and excretion of drugs and their corresponding pharmacologic
response in animals/man
clinic - a facility or area where ambulatory patients are seen for special study and
treatment
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CHEE 440
Introduction
Drugs seldom administered alone
• contain additional ingredients called excipients
Need for dosage forms:
• provide safe and accurate delivery
• protect drug from environmental and in vivo degradation
• provide rate-controlled action
• conceal bitter/salty taste, offensive odor
• allow for administration by the desired route
Objective of dosage form design
• achieve a predictable therapeutic response to a drug
included in a formulation which is capable of large scale
manufacture with reproducible product quality
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CHEE 440
Excipients
Purpose
Example
pH control
citric acid, NaCO3
preservative
NaBenzoate, phenol
antioxidant
surfactant
ascorbic acid,
NaBisulfite
alcohol, sterilized
water
cetyl alcohol
ointment base
petrolatum, PEG
flavor
peppermint oil,
menthol
solvent
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CHEE 440
Routes of Administration
Considering only systemic delivery, wherein the objective is to get
the drug into the blood stream. There are essentially two classes
of delivery approaches:
 enteral
• oral (peroral), rectal, buccal and sublingual
 parenteral
•
•
•
•
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injection (s.c., i.v., i.m.)
transdermal
nasal
pulmonary
CHEE 440
Bioavailability
 extent of absorption and the rate at which an administered
dose reaches systemic circulation in its active form
tissue, lymph
intravenous
drug in
dosage form
oral
liver
blood plasma
bound  free
site of
action
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CHEE 440
excretion
metabolism
Absorption
Affected by:
1. Physiological factors
 route of administration
 drug distribution
2. Drug chemical physical properties
 dissolution rate (solids)
 hydrophilicity/hydrophobicity
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CHEE 440
Oral
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CHEE 440
Oral Absorption
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CHEE 440
Oral
gastric emptying
 volume of gastric contents determines [drug]
 time dosage form/drug spends in stomach influences
absorption
 liquids emptied faster than solids
 acids slow gastric emptying
 natural triglycerides inhibit gastric motility
 eating influences transit
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CHEE 440
Drug Absorption
oral administration plasma concentration time profile
absorption
phase
elimination phase
plasma
conc’n
time after administration
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CHEE 440
Therapeutic Window
 therapeutic response is dependent on drug achieving an
adequate plasma concentration (Cp)
Cp
time after administration
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CHEE 440
Oral
advantages
 patient compliance
 cheap compared to other routes
 transit time is consistent among individuals
disadvantages
 hepatic first-pass effect
 possible enzymatic degradation/acid degradation
 effect too slow for emergencies
 presence of food retards absorption
 short window of time for absorption
B. Amsden
CHEE 440
Rectal
Rectal route:
 lined with one or more layers of epithelial cells
•
•
•
•
luminal side covered with mucus layer
contains a small amount (1-3 ml) of fluid
fluid has low buffering capacity
abundantly vascularized
 drug absorption primarily by passive diffusion
• avoids some first pass clearance
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CHEE 440
Buccal and Sublingual
Avoids exposure to GIT.
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CHEE 440
Parenteral
i.v.
plasma
conc’n
time after administration
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CHEE 440
Parenteral
i.m. and s.c.
 not all drugs fully absorbed
 tissue more acidic than most tissues
 blood flow is important
 good supply of capillaries
 drug absorption function of diffusion rate
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CHEE 440
Transdermal
rate limiting step is diffusion through stratum corneum
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CHEE 440
Transdermal
Factors affecting absorption
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CHEE 440
Transdermal
Limitations
 drug must be potent
 drug must be effective when delivered slowly over a long
period of time
 benefits over existing methods?
Drug qualifications
 narrow therapeutic window
 subject to extensive first-pass degradation
 taken many times/day
 unpleasant side-effects
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CHEE 440
Transdermally Delivered Drugs
drug
B. Amsden
MW
pKa m.p. log
(g/mol)
(˚C) (Ko/w)
efficacious
blood level
(ng/mL)
scopolamine
303
7.8
59
1.24
0.04
clonidine
230
8.2
140
0.83
0.2-2.0
nitroglycerin
227
13.5
2.05
1.2-11.0
estradiol
272
176
2.49
0.04-0.06
fentanyl
337
8.4
83
2.93
1
nicotine
162
6.16 < -80
testosterone
288
153
3.31
10-100
progesterone
314
131
3.57
1-3
CHEE 440
10-30
Nasal
advantageous for drugs poorly
absorbed orally
for some peptides and small
molecules, bioavailability
comparable to injections
drugs:
lypressin, desmopressin,
vitamin B-12, progesterone,
insulin, calcitonin, propanolol
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external
naris
CHEE 440
Pulmonary
- large contact surface (surface area > 30 m2 )
- extensive blood supply (2000 km of capillaries)
- thin membrane separating air from blood
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CHEE 440
Conventional Dosage Forms
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CHEE 440
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