A history of pharmacology Ancient Times A series of scattered facts exists that speak of the early history of humankind's efforts

to harness the healing properties of natural compounds. However, what we know for certain is that ancient peoples made extensive use of plant, animal and mineral sources for this purpose. The Ebers papyrus, written in Egypt in the 16th century B.C., lists the extensive pharmacopia of that civilization. Included in this are: beer, turpentine, myrrh, , juniper From ancient China comes evidence of that culture's extensive efforts to heal through the use of natural products. The Pen Tsao, or Great Herbal, comprised forty volumes describing several thousands of prescriptions. Interestingly, the eastern herb Artemisia annua L. (wormwood), used in China since antiquity to treat fevers, is the source of the modern drug qinghaosu, which shows great promise as a modern anti-malarial compound. Antiquity to the modern era The ancients considered disease a consequence of demonic possession, or the wrath of god. Thus, in ancient times, the treatment of illness with natural products was invariably accompanied by religious rituals deemed essential to the healing process. With time, the thoughts returned to the appreciation that the natural products themselves held the power to cure. For example, the purple foxglove, Digitalis purpurea, was one of twenty herbs used in a folk remedy to treat dropsy in 18th century England. From the leaves of this plant was isolated the cardiac glycoside digitalis, a drug still used today to treat heart failure. Over time, as a more sophisticated view of illness evolved, an increasingly scientific approach to the isolation of drugs from natural products was taken. In the early 19th century, Materia Medica The ancient discipline of Materia Medica was born, devoted to understanding the origin, preparation and therapeutic applications of medicinal compounds. It postulated that: Each disease has a unique cause for which there is a specific remedy.

In 1897, Felix Hoffman, a research chemist employed by the "Farbenfabrikin vorm. Freidr. Bayer and Co." synthesized acetylsalicylic acid. On February 1, 1899, Aspirin was registered as a trademark. On March 6th of the same year, this drug was registered with the Imperial Patent Office in Berlin. Aspirin quickly become popular The modern era These, and additional advances in the fields of chemistry and physiology, lead to the birth of modern pharmacology in the latter half of the 19th century. Thus, Materia Medica evolved into the

The 20th century has witnessed the discovery of a steady stream of important new drugs that have immeasurably improved the human condition. Not very long ago, vast numbers of humans perished prematurely or suffered an existence filled with pain due to the effects of infection or disorders that are now successfully treated. chemotherapy of cancer microbial infections diabetes hypertension depression AIDS Pharmacology Pharmacology is the study of how drugs exert their effects on living systems. Pharmacologists work to identify drug targets in order to learn how drugs work. Pharmacologists also study the ways in which drugs are modified within organisms. In most of the pharmacologic specialties, drugs are also used today as tools to gain insight into both normal and abnormal function. Divisions of Pharmacology Pharmacokinetics

Is what the body does to the drug. The magnitud of the pharmacological effect of a drug depends on its concentration at the site of action. Absorption Distribution Metabolism Elimination Pharmacodynamics

Is what the drug does to the body. Interaction of drugs with cellular proteins, such as receptors or enzymes, to control changes in physiological function of particular organs. Drug-Receptor Interactions

 Binding Dose-Response Effect Signal Transduction Mechanism of action, Pathways Pharmacogenetics

Area of pharmacology concerned with unusual responses to drugs caused by genetic differences between individuals. Responses that are not found in the general population, such as general toxic effects, allergies, or side effects, but due to an inherited trait that produces a diminished or enhanced response to a drug. Differences in Enzyme Activity Drugs Acetylation polymorphism Butylcholinesterase alterations Cytochrome P450 aberration

Drugs can be defined as chemical agents that uniquely interact with specific target molecules in the body, thereby producing a biological effect. Drugs Drugs, as well as hormones, neurotransmitter, autocoids and toxins can make possible the transfer of information to cells by interaction with specific receptive molecules called receptors. Drugs Drugs interact with biological systems in ways that mimic, resemble or otherwise affect the natural chemicals of the body. Drugs can produce effects by virtue of their acidic or basic properties (e.g. antacids, protamine), surfactant properties (amphotericin), ability to denature proteins (astringents), osmotic properties (laxatives, diuretics), or physicochemical interactions with membrane lipids (general and local anesthetics). Receptors

Most drugs combine (bind) with specific receptors

to produce a particular response. This association or binding takes place by precise physicochemical and steric interactions between specific groups of the drug and the receptor. 1. Proteins a. Carriers b. Receptors i. ii. iii. G protein-linked Ligand gated channels Intracellular

c. Enzymes 2. DNA Endogenous compounds act on their Receptors Receptor

1) Pharmacological Mediator (i.e. Insulin, Norepinephrine, estrogen) 2) Biophysical and Biophysical Second messenger system (i,.e. cAMP, PLC, PLA) 3) Molecular or Structural Subunit composition (i.e. 5HT1A ) 4) Anatomical Tissue (i.e muscle vs ganglionic nAChRs) Cellular (i.e. Membrane bound vs Intracellular) Types of Receptors

MEMBRANE BOUND RECEPTORS G-Protein-linked receptors

Serotonin, Muscarinic, Dopaminergic, Noradrenergic Enzyme receptors

Tyrosine kinase Ligand-gated ion channel receptors

Nicotinic, GABA, glutamate INTRACELLULAR AND NUCLEAR RECEPTORS 1) 2) 3) 4) 5) 6) 7) Hormone receptors Autocoid receptors Growth factors receptors Insulin receptors G Proteinlinked Receptors Enzyme-like Receptors Ligand-gated Ion-Channel Receptors Nuclear Receptors Drug-Receptor Interactions Lipophilic Hydrophilic Ionic Hydrogen bonds Steric (stereospecificity) effects Electronic effect pK effects Drug-Receptor Interactions Drug-Receptor Interactions Drug-receptor interactions serve as signals to trigger a cascade of events. This cascade or signaling pathway, is a collection of many cellular responses which serve to amplify the signal and produce a final effect. Effectors are thus the molecules that translate the drug-receptor interaction into changes in cellular activity. EFFECT EFFECTOR EFFECTOR SYSTEM RESPONSE

+ DRUG

DRUG + RECEPTOR DRUG + RECEPTOR INTERACTION COMPLEX ACTIVATION

STIMULUS

BINDING

TRANSDUCTION AMPLIFICATION

Receptor Signaling Pathways

Second Messengers: 1. Ions (Ca2+, Na+, K+, Cl-) 2. cAMP, cGMP, IP3, Diacylglycerol 3. DNA binding Transcriptional regulation. 4. Phosphorylated proteins and enzymes via tyrosine kinase receptors. Third Messengers: 1. Enzymes (PKC, PKA) 2. Ions (Ca2+, K+) Receptor Signaling Pathways

Adenylate Cyclase (AC) Guadenylyl Cyclase (GC) Phospholipase C (PLC) Phospholipase A (PLA2) Nitric oxide Synthase Ions Receptor Signaling Pathways Receptor Signaling Pathways Drug-Receptor Interactions

Theory and assumptions of drug-receptor interactions. Drug Receptor interaction follows simple mass-action relationships, i.e. only one drug molecule occupies each receptor and binding is reversible (We know now there are some exceptions). For a given drug the magnitud of the response is proportional to the fraction of total receptor sites occupied by drug molecules. Combination or binding to receptor causes some event which leads to a response. Response to a drug is graded or dose-dependent. Law of Mass Action

When a drug (D) combines with a receptor (R), it does so at a rate which is dependent on the concentration of the drug and the concentration of the receptor.

D = drug R = receptor DR = drug-receptor complex k1 = rate for association k2 = rate for dissociation KD = Dissociation Constant KA = Affinity Constant Read the Appendix at the back of lecture 1B