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CHAPTER 6 IN THE SYLLABUS: Principles of Pharmacology Dr. Robert L. Patrick Department of Neuroscience Brown University [email protected] 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 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.