1. Lecture Contents -- Unit 4
The Basics of Pharmacology
Drug delivery
Absorption and distribution
Metabolism
Excretion
Case studies: teramisole and rapifen

2. Pharmacokinetics: A Highly Specialized Science

3. 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

4. From the Pill to the Intestines

5. From Absorption To Excretion

6. Barrier Penetration By Drugs

7. Multiple Doses, Half-Life, Drug Cumulation, and Steady-State

8. Sustained Release (SR) Formulations

9. The Capsule: Flexible, Pre-Programmed Intestinal Release

10. Drug Delivery With „Tailored Particles“

11. Liposome Technology: Making Hydrophobic Molecules Bioavailable
Microcapsules

12. Externally Triggered Drug Release Devices

13. Pulmonary Drug Delivery: Making Use of 100 m2 Surface
Inhalers
Transcytosis: a natural uptake path

14. Transdermal Route Advantages
Non-invasive
No infection risk
Pain-free
Drug delivery rate profiles can be pre-programmed
Convenient -- high patient compliance
Simplifies handling of geriatric patients

15. Transdermal Delivery: The „Patch“

16. 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

17. 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)

18. Transdermal Delivery: Iontophoresis
Requirements for iontophoretic drug delivery:
Low molecular weight
Hydrophilic
Carries a charge at near-neutral pH

19. 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

20. Drug Distribution in the Body: „How To Reach The Target“
Compartment model:
Muscle
Fatty tissue
Intestine
Blood
Peripheral organs
Brain
Effective capacity can vary acutely (dehydration) or as a consequence of body remodeling (age)

21. Exchange Between Body Compartments

22. Dynamics of Drug Distribution

23. Drug Metabolism: The „Biofate“
Four main metabolic patterns:
Oxidation
Reduction
Hydrolysis
Conjugation Phase II
Phase I

25. Oxidative Metabolic Reactions
Hydroxylation
S-oxidation
Dealkylation
Deamination (monoamine oxidase)
Formylation (alcohol dehydrogenase)

26. Reductive and Hydrolytic Metabolic Reactions
Reduction of azo and nitro groups
Cleavage of ester bond
Cleavage of amide bond

27. Conjugation / Coupling Reactions
Addition of molecules naturally present in the body:
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

28. Drug Excretion: „How To Get Out“
Urine
Feces
Skin (sweat)
Respiratory tract

29. Renal Excretion

30. 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
Active metabolite (imidazolthiazole)
Aminothiazole prodrug

31. Tetramisole, an Acceptable Active Analog
Stable after oral administration
Bioavailable at target site
Antiparasitic activity
progenitor
Tetramisole

32. Targeted Acceleration of Metabolism for Short Duration of Action
Fentanyl (long-acting)
Rapifen (short-acting)