Download Lecture Contents -- Unit 4 - Vienna University of Technology

Lecture Contents -- Unit 4
• The Basics of Pharmacology
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Drug delivery
Absorption and distribution
Metabolism
Excretion
Case studies:
teramisole and rapifen
Pharmacokinetics:
A Highly Specialized Science
Drug Delivery: „How To Get In“
• Oral (p.o. = per os)
• Injection
– intravenous (i.v.)
– intramuscular (i.m.)
– subcutaneously (s.c.)
• Transdermal
– Iontophoresis
– enhanced diffusion
• Mucosal
– nasal or pulmonary
– sublingual
– rectal, vaginal
From the Pill to the Intestines
From Absorption To Excretion
Barrier Penetration By Drugs
Multiple Doses, Half-Life, Drug
Cumulation, and Steady-State
Sustained Release (SR) Formulations
The Capsule: Flexible, PreProgrammed Intestinal Release
Drug Delivery
With „Tailored Particles“
Liposome Technology: Making
Hydrophobic Molecules Bioavailable
Microcapsules
Externally Triggered Drug
Release Devices
Pulmonary Drug Delivery:
Making Use of 100 m2 Surface
Inhalers
Transcytosis: a natural uptake path
Transdermal Route Advantages
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Non-invasive
No infection risk
Pain-free
Drug delivery rate profiles can be preprogrammed
• Convenient -- high patient compliance
• Simplifies handling of geriatric patients
Transdermal Delivery: The „Patch“
Utility of Transdermal Patches
• Wherever constant delivery of limited
amounts (<200mg/day) of drug at constant
rate is required over prolonged periods:
– Hormone replacement therapy (HRT)
– Chronic pain (cancer): fentanyl
• Can be the only applicable route of
administration for compounds with
unfavorable pharmacokinetics
Skin Penetration Enhancers
• Solvents (alkanols, glycols, acetamide, ...)
• Ionic compounds (monoalkylphopsphates,
lauroylcholine, ascorbate, ...)
• DMSO and related cyclic sulfoxides
• Azone and related compounds (azacycloalkanes
and -alkenones, ...)
• Fatty alcohols, fatty acids, liposomes
• Complexing agents (macrocyclic lactones,
ketones, and anhydrides; unsaturated cyclic ureas)
Transdermal Delivery: Iontophoresis
Requirements for iontophoretic drug delivery:
•Low molecular weight
•Hydrophilic
•Carries a charge at near-neutral pH
Biodegradable Implants:
Post-Surgery Treatment of Glioma
Carboxyphenoxy propane:sebacic acid (polifeprosan 20)
in a 20:80 copolymer [poly(CPP:SA)20:80]
Directly implanted into brain cavity
remaining after surgery
Delivered agent: carmustine
http://www.guilfordpharm.com/products/gliadel.htm
Drug Distribution in the Body:
„How To Reach The Target“
• Compartment model:
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Muscle
Fatty tissue
Intestine
Blood
Peripheral organs
Brain
• Effective capacity can vary acutely (dehydration)
or as a consequence of body remodeling (age)
Exchange Between Body
Compartments
Dynamics of Drug Distribution
Drug Metabolism: The „Biofate“
• Four main metabolic patterns:
– Oxidation
– Reduction
– Hydrolysis
Phase I
– Conjugation
Phase II
Oxidative Metabolic Reactions
Hydroxylation
S-oxidation
Dealkylation
Deamination
(monoamine oxidase)
Formylation
(alcohol dehydrogenase)
Reductive and Hydrolytic
Metabolic Reactions
Reduction of azo
and nitro groups
Cleavage of ester bond
Cleavage of amide bond
Conjugation / Coupling Reactions
• Addition of molecules naturally present in
the body:
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Glucuronidation (in the liver; e.g., alcohols)
Acylation (e.g. sulfonamides)
Glycination (e.g. nicotinic acid)
Sulfatation (e.g. paracetamol, morphine)
• Metabolite is generally more hydrophilic
 facilitated renal excretion
Drug Excretion: „How To Get Out“
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Urine
Feces
Skin (sweat)
Respiratory tract
Renal Excretion
Case Study: An Antiparasitic Drug
• Starting point: An aminothiazole is an effective
deworming agent in chicken but not in mammals
• Explanation: A rather unstable metabolite,
imidazothiazole (which is not formed in
mammals) is the actual antiparasitic agent
Aminothiazole prodrug
Active metabolite
(imidazolthiazole)
Tetramisole, an Acceptable
Active Analog
• Stable after oral administration
• Bioavailable at target site
• Antiparasitic activity
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progenitor
Tetramisole
Targeted Acceleration of Metabolism
for Short Duration of Action
Fentanyl
(long-acting)
Rapifen
(short-acting)