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 DeliveryWith „Tailored Particles“

Liposome Technology: Making Hydrophobic Molecules Bioavailable

Microcapsules

Externally Triggered Drug Release Devices

Pulmonary Drug Delivery: Making Use of 100 m2 Surface

Transcytosis: a natural uptake path

Inhalers

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 cavityremaining 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

Cleavage of ester bond

Cleavage of amide bond

Reduction of azoand nitro groups

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

Aminothiazole prodrugActive metabolite(imidazolthiazole)

Tetramisole, an AcceptableActive Analog

• Stable after oral administration

• Bioavailable at target site

• Antiparasitic activity N

N

S S

progenitor

Tetramisole

Targeted Acceleration of Metabolism for Short Duration of Action

Fentanyl(long-acting)

Rapifen(short-acting)