CHAPTER 6 IN THE SYLLABUS:Principles of Pharmacology

Dr. Robert L. PatrickDepartment of Neuroscience

Brown UniversityRobert_Patrick@brown.edu

Biomed 370: January 12, 2005

PURPOSE OF TODAY’S LECTURE

• To provide a basic introduction to pharmacological principles

• To use these principles to help appreciate the approaches taken in the use of drugs to alter the activity of brain neurotransmitters

WHAT IS PHARMACOLOGY?

• Pharmacology is the science that deals with the mechanism of action, uses, and adverse effects of drugs

• The word ‘pharmacology’ comes from the Greek word for drug: pharmakon

DRUGS

• Most common description: A substance used as a medicine for the treatment of disease.

• In a larger context: A substance taken because of its biologically active properties. This would include substances such as caffeine, nicotine, alcohol, cannabis, heroin and cocaine.

Source of Drugs

• Natural: Plants, fungi, microrganisms

• Semi-synthetic (making a chemical derivative of a natural product)

• Synthetic

Source of Digitalis: Digitalis Purpurea (foxglove)

Source of atropine: Atropa belladonna (deadly nightshade)

DRUG NAMESUSING ANTIDEPRESSANTS AS

EXAMPLES

• GENERIC: FLUOXETINE

• PROPRIETARY: PROZAC

• GENERIC: AMITRIPTYLINE

• PROPRIETARY: ELAVIL

• Q: Which are easier to remember?

How Can Drugs Alter Brain Neurotransmitter Activity?

• By altering some aspect of the Life Cycle of the transmitter:

• Synthesis

• Storage

• Release

• Receptor Interaction

• Transmitter Inactivation

What Are The Common Drug Targets?

• Most common targets are body proteins:

• Receptors: Can alter transmitter signaling• Example: Using risperidone to block dopamine

receptors in schizophrenic patients

• Enzymes: Can alter transmitter synthesis• Example: Using L-DOPA, a substrate for DOPA

decarboxylase, to increase dopamine synthesis in the brains of patients with Parkinson’s Disease

Drug Targets (con’t)

• Transporters: Can alter transmitter inactivation

• Example: Using fluoxetine (Prozac) to inhibit serotonin reuptake in depressed patients

• Ion Channels: Can alter neuronal excitability

• Example: Using phenytoin to block sodium channels in epileptic patients

3 Types of Neurotransmitters

• Biogenic Amines: Acetylcholine, Dopamine,Norepinephrine, Epinephrine, Serotonin (can have either excitatory or inhibitory actions)

• Amino Acids: Glutamatic acid (excitatory) GABA and Glycine (inhibitory)

• Peptides: Enkephalins, Endorphins, Substance P (can be either excitatory or inhibitory)

Drug Action

• The degree of drug action at a target site will, in general, depend upon the drug concentration at that site

And What Determines Drug Concentration?

• Route of administration

• Absorption and distribution

• Binding

• Inactivation

• Excretion

Entry Into The Brain

• The brain can pose a problem for drug entry, due to the blood-brain barrier

• A drug can gain entry into the brain if:

• A. It is lipophilic, and can diffuse across membranes, or

• B. A specific transport system exists that can carry (transport) the drug across membranes

Drug Effects

• What does a curve look like when you plot drug effect on the y-axis and dosage administered on the x-axis?

• In words: You generate a dose-response curve!

• In pictures: The shape of the curve depends upon whether you plot dosage or log of the dosage on the x-axis

Points on the Curve

• The maximal effect is called the efficacy

• The amount of drug that produces 50% of the maximal effect is called the potency

• The potency is often expressed as the ED50

• This means that the lower the ED50 the greater the potency (important point to remember!)

Agonists and Antagonists

• Agonist: An agent producing a cellular effect (e.g., norepinephrine stimulating the heart or acetylcholine inhibiting the heart)

• Partial Agonist: Does not produce as great an efficacy as a full agonist (e.g., buprenorphine at opiate receptors)

• Antagonist: An agent which blocks the effect of the agonist (e.g., atropine preventing acetylcholine action at the heart)

THERAPEUTIC INDEX

• Therapeutic Index (TI) = TD50 / ED50

• True or False?: If Drug A has a higher TD50 compared to Drug B, then Drug A must also have a higher therapeutic index.