CHAPTER 6 IN THE SYLLABUS: Principles of Pharmacology Dr. Robert L. Patrick Department of Neuroscience Brown University 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 NAMES USING 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 ED 50 This means that the lower the ED 50 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) = TD 50 / ED 50 True or False?: If Drug A has a higher TD 50 compared to Drug B, then Drug A must also have a higher therapeutic index.