Pharmacology DEFINITIONS: 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.

Pharmacology Divisions of Pharmacology Pharmacokinetics Pharmacodynamics Pharmacogenomics

Pharmacokinetics Is what the body does to the drug. The magnitude 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 – Acetylation polymorphism – Butylcholinesterase alterations – Cytochrome P450 aberration

Drugs Drugs can be defined as chemical agents that uniquely interact with specific target molecules in the body, thereby producing a biological effect. HOWARD UNIVERSITY Drugs can be stimulatory or inhibitory

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”. Receptor DRUG

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.G protein-linked ii.Ligand gated channels iii.Intracellular c.Enzymes 2.DNA

Endogenous compounds act on their Receptors Neurotransmitter Neuropeptides Hormones Ions

Receptor 1)Pharmacological Mediator (i.e. Insulin, Norepinephrine, estrogen) 2)Biophysical and Biochemical 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) Classification of Receptors

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 Hormone receptors Autocoid receptors Growth factors receptors Insulin receptors

G Protein–linked Receptors

Enzyme-like Receptors

Ligand-gated Ion-Channel Receptors

Nuclear Receptors

Drug-Receptor Interactions 1) Lipophilic 2) Hydrophilic 3) Ionic 4) Hydrogen bonds 5) Steric (stereospecificity) effects 6) Electronic effect 7) pK effects Physicochemical and steric interactions

Drug-Receptor Interactions Chemical Bonds Van der Waals Interactions Hydrophobic 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 DRUG DRUG + RECEPTOR DRUG + RECEPTOR EFFECTOR EFFECTOR INTERACTION COMPLEX SYSTEM STIMULUS BINDING ACTIVATION TRANSDUCTION AMPLIFICATION RESPONSE SIGNALLING PATHWAY

Receptor Signaling Pathways Second Messengers: 1.Ions (Ca 2+, 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 (Ca 2+, K + )

Receptor Signaling Pathways Adenylate Cyclase (AC) Guadenylyl Cyclase (GC) Phospholipase C (PLC) Phospholipase A (PLA 2 ) Nitric oxide Synthase Ions cAMP cGMP DAG and IP3 Arachidonic acid NO and CO Na +, Ca 2+, K +, Cl - EFFECTORS SECOND MESSENGER

Receptor Signaling Pathways RRR R

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 magnitude 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 k 1 = rate for association k 2 = rate for dissociation K D = Dissociation Constant K A = Affinity Constant k 2 [D] + [R]  [DR] k 1 k 1 = K D = [DR] k 2 [D][R] 1 =K A = k 2 = [D][R] K D k 1 [DR]