ANE 510 Pharmacology I Instructor: Ron Dick, R.Ph., Ph.D. Office: 130 SNHS Telephone: 899-3365 E-Mail: rdick@mail.barry.edu Office Hours: Monday 9-12, Tuesday 1-3 or By Appointment

Introduction Course syllabus and rules Textbooks Required: Stoelting, R.K., Pharmacology and Physiology in Anesthetic Practice, 2006, 4th Ed. Kier and Dowd, The Chemistry of Drugs for Nurse Anesthetists, 2004, 1st Ed. Recommended: Brunton et al, Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 2006, 11th Ed. Evers, A.S. and Maze, M., Anesthetic Pharmacology: Physiologic Principles and Clinical Practice, 2004, 1st Ed. Course Information and Materials Blackboard

Basic Drug Chemistry Review Chirality (D and L pairs) Chiral refers to molecule with a center of three-dimensional asymmetry. > 50% of all drugs are chiral (enantiomeric pairs) Enantiomers (molecules having opposite shapes) are pairs of molecules existing in forms that are mirror images of each other (right-& left-hand) but that cannot be superimposed. Structure Activity Relationship (SAR) Understanding the relationship between drug structures and biological activities forms the basis of rational drug design. Computer-enhanced molecular modeling and information concerning three-dimensional receptor structure may combine to improve the effectiveness of rational drug design approaches. It is a racimic mixture it is a Mix of D and L forms. A lot of side affects of an inactive enatiomer. Drug industry are the profit organization. Standard cap on a drug is 17 years from the day it was discovered in the chemistry lab. The average time to bring a drug to market is 7 to 10 years to go through all of testing from the FDA. They have to produce all of their profits in the 17 years or they loose money, that is why meds are so expensive. About 1 in 300 drugs actually make it. SAR actually decides what drugs are produced and used.

Basic Pharmacology Review Drug Chemistry Three major types of chemical forces/bonds: Covalent--very strong Frequently "irreversible" under biological conditions Example - DNA-alkylating chemotherapy drugs Electrostatic:-- weaker than covalent More common then the covalent bonding in drug-receptor interactions Strong: interactions between permanently charged ionic molecules Weaker: hydrogen bonding Still weaker: induced-dipole interactions, e.g. van der Waals forces Hydrophobic interactions: generally weak probably significant in driving interactions: between lipophilic drugs and the lipid component of biological membranes between drugs and relatively nonpolar (not charged) receptor regions DNA alkylating drug is a drug that adds an Alkyl group on DNA, so it causes a mutation in DNA. So it actually stops formation of cancer cells by inhibiting. DNA to prevent rapid growth of Cancer.

Basic Pharmacology Review Drug Chemistry Henderson-Hasselbach equation pH = pKa + log [Ionized]/[Unionized] useful for determining how well an ionizable drug will cross biological membranes. most drugs are weak bases (RNH3+  RNH2 + H+) or weak acids (RCOO- + H+  RCOOH). lipid diffusion depends on adequate lipid solubility. drug ionization reduces a drug's ability to cross a lipid bilayer. Degree of Ionization determines how well a drug will cross the membrane.

Henderson-Hasselbach Only unionized crosses the membrane. At a particular ph there will be a certain ratio of Ionized to unionized.

Basic Pharmacology Review What is Pharmacology? What is a drug? Mimics endogenous ligand (usually) Where do drugs act? How much is enough or too much? How is a drug best given?

Drug Fate in the Body Elimination. A lot of metabolites of drugs have activities after the parent drug is elliminated.

Drug Disposition

Definitions Pharmacodynamics Pharmacokinetics The effects of a drug on the body. Relates the drug concentration to its effect. Pharmacokinetics Relationship between drug dose and tissue conc. Involves ADME processes

Definitions Agonist Antagonist A substance which interacts at a receptor to elicit a response. Antagonist A substance which blocks the response of an agonist at a receptor. Different types Competitive Non-competitive Negative Antagonists (inverse agonists) Partial Agonist/Antagonist

Neurotransmission Review Review of basic neurotransmission Cell body (soma) Dendrites Axon hillock Axon Nerve terminal Post Synaptic Receptors

Receptors Usually named for the agonist and antagonist which the interact with. Examples: Cholinergic receptors interact with acetylcholine Adrenergic receptors interact with norepinephrine GABA receptors interact with gamma amino butyric acid Receptor locations: Cell membrane (inside and outside) Cell cytoplasm Nuclear envelope

Receptor Types

Nature of Receptors Responsible for the transduction of biologic signals. Cellular components (usually) that interact with other molecules to elicit some effect. Effect may be some biologic response, or a biochemical change that eventually produces some effect. Not all drugs exert their effects via a receptor-mediated response.

Nature of Receptors Non-Receptor Mediated Examples Mannitol – an osmotic diuretic. Methyl cellulose - an osmotic laxative. Dextrans – when used IV, expand blood volume by pulling water from tissues into blood.

Nature of Receptors Many enzymes have been shown to be specific drug receptors (ex.- digitalis acts on Na+/K+ ATPase in heart muscles to increase force of contractions). Nucleic acids (ex.- DNA) can act as receptors to some compounds such as the antibiotic Actinomycin D. Other membrane components, such as fungal ergosterol, can bind agents (ex.- Amphotericin B).

Nature of Receptors Due to required fit at binding site, alterations in ligand structure will effect ligand affinity and/or intrinsic activity (SAR). Most drugs act on receptors, except: Some anesthetics, hypnotics, and sedatives Alcohols Osmotically-active drugs Acidifying/alkalinizing agents Antiseptics

Nature of Receptors Receptors can be blocked by receptor antagonists (affinity, but low-to-no intrinsic activity). For example, Atropine blocks muscarinic Ach receptors. Usually, nonspecific receptors (such as those for ethanol) require high drug concentrations for effect (millimolar to molar), whereas specific receptors require only low concentrations (nanomolar to millimolar).

Receptor Binding

Receptor Binding States

Gap Junctions

Receptor Agonists

Receptor Occupancy

Receptor Antagonists

Receptor Antagonists

Receptor Signaling

Drug/Receptor Binding D + R  DR The affinity of drug binding is referred to as the association constant, KA This is defined as: KA = kon/koff. The dissociation constant (KD), is the concentration at which 50% of the receptors are occupied, and is equal to 1/KA (or koff/kon).

Dose-Response Curve

Drug Potency

Receptor Sensitivity