Pharmacology

1. 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.

2. Pharmacology Divisions of Pharmacology • Pharmacokinetics • Pharmacodynamics • Pharmacogenomics

3. 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

4. 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

5. 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

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

7. DRUG Receptor 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”.

8. 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).

9. 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. • Proteins • Carriers • Receptors • G protein-linked • Ligand gated channels • Intracellular • Enzymes • DNA

10. Endogenous compounds act on their Receptors Neurotransmitter Neuropeptides Hormones Ions

11. Receptor Classification of Receptors • Pharmacological Mediator (i.e. Insulin, Norepinephrine, estrogen) • Biophysical and Biochemical Second messenger system (i,.e. cAMP, PLC, PLA) • Molecular or Structural Subunit composition (i.e. 5HT1A ) • Anatomical Tissue (i.e muscle vsganglionicnAChRs) Cellular (i.e. Membrane bound vs Intracellular)

12. 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

13. G Protein–linked Receptors

14. Enzyme-like Receptors

15. Ligand-gated Ion-Channel Receptors

16. Nuclear Receptors

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

18. Drug-Receptor Interactions Chemical Bonds Van der Waals Interactions Hydrophobic Interactions

19. 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

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

22. Receptor Signaling Pathways EFFECTORS SECOND MESSENGER Adenylate Cyclase (AC) Guadenylyl Cyclase (GC) Phospholipase C (PLC) Phospholipase A (PLA2) Nitric oxide Synthase Ions cAMP cGMP DAG and IP3 Arachidonic acid NO and CO Na+,Ca2+,K+, Cl-

23. Receptor Signaling Pathways R R R R

24. Receptor Signaling Pathways

25. 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.

26. 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 • k2 • [D] + [R]  [DR] • k1 • k1= KD = [DR] • k2 [D][R] • 1 = KA = k2= [D][R] • KDk1 [DR]