Chemotherapy is the science of selective toxicity. The goal of chemotherapeutic treatment is to selectively attenuate or destroy pathogenic micro-organisms or cells with minimal side effects to the host. These targeted cells or organisms may be bacteria, viruses, protozoans, fungi, helminths, or tumor cells. In order to achieve selective toxicity, the target for chemotherapeutic agents may be unique to the target population, may be structurally different in the target population from the form in the host population, or may be more essential in the target population than in the host population. We will explore the targets and the mechanisms of action of various classes of chemotherapeutic drugs, and will relate both the therapeutic effects and the adverse effects of these drugs to those targets and mechanisms.

The first task in learning this material is to recognize the drug names and to assign them to a class, based on target cell or organism, or mechanism of action, or both. For some classes of drugs, such as the penicillins and the cephalosporins, this will be a simple task. For other groups the memorization is more challenging. Once assigned to a class, one should recall the general characteristics of that class: pharmacokinetics (i.e. absorption, distribution, metabolism, excretion), pharmacodynamics (i.e. mechanism of action, spectrum of activity, resistance), and adverse effects. Often a single drug will be described as the prototype for a class. You should learn everything about the prototype drug and then learn how each member differs from the prototype. Please note that the designation "prototype" simply denotes a model drug with characteristics typical for the group. This does not imply relative clinical importance.

This study guide will outline organization of the material to be presented, and the key concepts to be understood and applied. These sections will be cross-referenced with chapters from the Katzung text. An asterisk denotes that only portions of a chapter are relevant to the topic. Following this outline you will find a drug list for this unit.

I. General Principles of Chemotherapy (Chapter 51):

Note: Although these chapters address antimicrobial chemotherapy, many of the same basic principles apply to antiparasitic and anticancer chemotherapy as well.

• Understand the concept of selective toxicity — what it is and how it may be achieved
• Recognize and understand the different types of targets for chemotherapeutic drugs, and how these mechanisms relate to selective toxicity
• Know the definitions of chemotherapeutic spectrum and chemotherapeutic index and how they relate to selective toxicity
• Understand the role of the host in chemotherapy
• Be aware of both general and specific pharmacokinetic barriers to effective chemotherapy
• Understand the difference between bacteriostatic and bactericidal, and how this relates to drug choice and dosage intervals
• Know general mechanisms for resistance to chemotherapeutic drugs, and appreciate how the use of these drugs selects for resistant populations
• Know the indications for combination chemotherapy
• Know the rationale behind chemoprophylaxis
• Understand the appropriate and inappropriate uses of chemotherapeutic drugs

II. Antibacterial Chemotherapy:

A. Inhibitors of cell wall synthesis (ICWS) (Chapter 43)

• Understand the structure and function of the bacterial cell wall
• Know the multiple sites of inhibition by antibacterial agents

1. Penicillins

• Structure-function relationships-- the ß-lactam ring
• Role of penicillin binding proteins (PBP) and murein hydrolases
• Chemotherapeutic spectrum of penicillins
• Mechanisms of resistance — ß-lactamases
• Cross-resistance
• Acid- and ß-lactamase-resistant penicillins
• Adverse reactions — hypersensitivity

2. Cephalosporins

• Similarities to and differences from penicillins
• Changes in pharmacokinetics and chemotherapeutic spectrum of first- through fourth-generation cephalosporins

3. Other ß-lactams

a. Aztreonam

b. Imipenam, Meropenam

c. Clavulanic acid, Sulbactam

4. Other ICWS

a. Vancomycin

b. Bacitracin

c. Cycloserine

• Know sites of inhibition of cell wall synthesis
• Know clinical use

B. Membrane-active agents (Chapters 50*, 62*)

• Understand the mechanism of action of polymyxins and gramicidin, and how this differs from ICWS
• Know the clinical uses of these agents

C. Inhibitors of protein synthesis (IPS) (Chapters 44, 45)

• Understand targeting of bacterial protein synthesis
• Relate mechanism to therapeutic and adverse effects

1. Aminoglycosides

• Know mechanisms of action for aminoglycosides
• Know spectrum of activity and clinical uses
• Know pharmacokinetics — routes of administration, excretion
• Know the classic adverse effects of aminoglycosides
• Understand the dependency of therapeutic and toxic effects on pharmacokinetics
• Understand development of resistance to aminoglycosides
• Role in combination chemotherapy

2. Tetracyclines, macrolides, chloramphenicol, clindamycin, spectinomycin

• Know mechanisms of action for these IPS
• Know spectrum of activity and clinical uses
• Understand the dependency of therapeutic and toxic effects on pharmacokinetics
• Understand why the use of these IPS is relatively limited (i.e. specific indications for use)

D. Inhibitors of folate-dependent pathways (Chapter 46*)

• Understand the production and use of folate derivatives in bacterial systems

1. Sulfonamides

• Know the mechanism of action of sulfonamides
• Understand the concept of "antimetabolite"
• Appreciate the role of pharmacokinetics in the action and uses of sulfonamides
• Know the pharmacokinetic and pharmacodynamic differences among various sulfonamides
• Know the adverse effects of sulfonamides

2. Trimethoprim

• Know the mechanism of action of trimethoprim
• Understand the rationale of combined sulfonamide-trimethoprim chemotherapy
• Know the clinical uses and adverse effects associated with trimethoprim

E. DNA gyrase inhibitors (Chapter 46*)

• Understand the function of DNA gyrases, and the effects of their inhibition
• Know the clinical uses of quinolones and fluoroquinolones
• Know the adverse effects and potential drug-drug interaction for quinolones

F. Urinary tract antiseptics (Chapter 50*)

• Understand the role of pharmacokinetics in the treatment of urinary tract infections

G. Antimycobacterial agents (Chapter 47)

• Appreciate the consequences of the mycobacterial life cycle in regard to chemotherapy
• Know mechanisms of action for antimycobacterial drugs
• Know the distinction between "first-line" and "second-line" anti-TB drugs, and why this distinction is disappearing
• Know the pharmacogenetics of isoniazid metabolism
• Know the appropriate use of drug combinations in antimycobacterial chemotherapy

III. Antifungal Chemotherapy (Chapter 48):

• Understand why selective toxicity against fungal pathogens is more difficult to achieve than is antibacterial selectivity
• Know the mechanisms of action, pharmacokinetics, and clinical uses of the antifungal drugs
• Know the adverse effects of antifungal drugs

A. Antifungal azoles

B. Membrane-active agents

C. Antimetabolites

D. Griseofulvin

IV. Antiparasitic Chemotherapy:

A. Basic Principles of Antiparasitic Chemotherapy (Chapter 52)

B. Antiprotozoal Chemotherapy (Chapter 53)

1. Antimalarials

• Know the infectious cycles of the Plasmodia and which stages are susceptible to different antimalarials
• Understand the effect of drug resistance on the clinical use of antimalarials

2. Other antiprotozoal drugs

• Know the mechanism of action, clinical uses, and adverse effects associated with these drugs

C. Anthelminthic Agents (Chapter 54)

• Know mechanisms of action against intestinal and extra-intestinal parasites
• Know drugs used clinically in North America (limit to infections by Ascaris, pinworm, hookworm, tapeworm)

V. Antiviral Chemotherapy and Chemoprophylaxis (Chapter 49):

• Understand the viral life cycle and its' implications for chemotherapy
• Know the mechanisms of action for major antiviral drugs

VI. Anticancer Chemotherapy (Chapter 55):

• Know mechanisms of action for classes of anticancer drugs
• Understand the role of pharmacokinetics in anticancer chemotherapy
• Know the adverse effects of anticancer drugs, both the common effects and the "signature" toxicities of specific agents
• Understand the basis for selective toxicity of anticancer drugs, and how this relates directly to both therapeutic and adverse effects
• Understand the need for total kill of target cells
• Understand resistance and multi-drug resistance in anticancer chemotherapy
• Appreciate the importance of multi-drug and multi-modality therapy

VII. Drug List for the Chemotherapy Unit

A. Cell Wall Synthesis Inhibitors

1. Penicillins

2. Cephalosporins

3. Other beta-lactams

4. Other cell wall synthesis inhibitors

B. Agents Which Affect Cell Membranes

1. Polymyxins

C. Protein synthesis inhibitors

1. Aminoglycosides

2. Tetracyclines

3. Macrolides

4. Other protein synthesis inhibitors

D. Inhibitors of folate-dependent pathways

1. Sulfonamides

2. Dihydrofolate reductase inhibitors

E. DNA gyrase inhibitors

F. Urinary tract antiseptics

G. Antimycobacterial drugs

H. Antifungal Agents

I. Antiparasitic drugs

1. Antimalarials

2. Anti-protozoal drugs

3. Anthelminthic drugs

J. Antiviral Agents

K. Antitumor Agents

1. Agents which alter DNA

a. alkylating agents

2. Antimetabolites

a. folic acid antagonists

b. purine antagonists

c. pyrimidine antagonists

3. Plant alkaloids

a. vinca alkaloids

b. podophyllotoxins

c. other

4. Antibiotics

5. Hormonal agents

a. Hormones

b. Modulation of hormone release and action

6. Miscellaneous agents