Lecture Contents -- Unit 4 The Basics of Pharmacology 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, Pre-Programmed 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 Non-invasive No infection risk Pain-free Drug delivery rate profiles can be pre-programmed 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: 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 Conjugation Phase II Phase I

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: 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“ 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 Active metabolite (imidazolthiazole) Aminothiazole prodrug

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

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