Intro to General Prinnciples and Pharmacodynamics I

General Principles of Drug Therapy

Integrated Scientific and Clinical Pharmacology

Definitions, Nomenclature and Pharmacodynamics I Marc Imhotep Cray, M.D. BMS / CK-CS Teacher

General Principles of Drug Therapy

Definition- pharmacology Derived from Greek words pharmakon, meaning drug or poison, and logos, meaning rational discussion or study rational discussion or study of drugs and their interactions with body body of knowledge concerned with action of chemicals on biologic systems Also see Integrated Basic and Clinical Pharmacology Course Syllabus and Digital Guidebook pgs. 9-13 2

General Principles of Drug Therapy

Definition- pharmacology (2) Study of drug action at both molecular and whole-organism levels ď Ž At molecular level, biologic effect of a drug ď Ž At whole-organism level, therapeutic effects of a drug and unwanted (i.e., adverse or side) effects

3

General Principles of Drug Therapy

Scope of Pharmacology “So what is pharmacology?� The question is only partially answered by the term’s derivation.

Pharmacology (MedPharm) is: a branch of biology, as it is concerned with living organisms it borrows heavily from physiology and biochemistry for substantive matter and experimental techniques MedPharm is related to chemistry, because it deals with chemical agents MedPharm is an essential part of medicine the cornerstone of modern therapeutics is the use drugs 4

General Principles of Drug Therapy

Scope of Pharmacology (cont.)

Pharmacology uses: mathematics to express its principles in quantitative terms behavioral sciences, such as psychology, to understand actions of drugs that lead to changes in mood or emotion (eg. psychoactive drugs)

5

General Principles of Drug Therapy

Definition- pharmacology (3) “Pharmacology is the unified study of the properties of chemicals and living organisms and all aspects of their interactions; it is an integrative rather than an autonomous science, drawing on the techniques and knowledge of many allied scientific disciplines.�

Levine's Pharmacology: Drug Actions and Reactions 7th ed. Walsh C and Schwartz-Bloom RD (Eds.) New York, Taylor Francis, 2005. Pg. 18

6

General Principles of Drug Therapy

“What Is Pharmacology?”

A Summary Statement …“Medical pharmacology is a bridge between basic science and clinical medicine. It makes use of all the disciplines that comprise the scientific foundation of clinical medicine; from anatomy, physiology, pathophysiology, pathology and immunology to biochemistry, molecular and cell biology, epidemiology, genetics and genomics. Hence…it is particularly useful for preclinical student to view and engage the subject as a major horizontal and vertical integrator, as it pulls together all the different strands of the basic medical science years and simultaneously introduces one to the cornerstone of modern clinical therapeutics, ie .drugs”…

From: Cray MI. (2015) Integrated Scientific and Clinical Pharmacology: A Course Syllabus and Digital Guidebook for Medical Students.. Pg.4 7

General Principles of Drug Therapy

“The broad science of pharmacology.� four main categories (subdivisions) 1. pharmacodynamics, 2. toxicology, 3. pharmacotherapeutics 4. pharmacy Clinical pharmacology =The principles behind the prescribing process as opposed to Pharmacotherapeutics =The process of medical treatment 8

General Principles of Drug Therapy

Pharmacology categories defined: Pharmacodynamics the study of the actions and effects of chemicals at all levels of organization of living material and of the handling of chemicals by the organism.

Toxicology is the study of the toxic or harmful effects of chemicals as well as of the mechanisms and conditions of occurrence of these harmful effects.

Pharmacotherapeutics the application of drugs in the prevention, treatment or diagnosis of disease and their use in purposeful alteration of normal functions...

Pharmacy concerned with the preparing, compounding and dispensing of chemical agents for therapeutic use.

For additional related key terms see: MedPharm Glossary

9

General Principles of Drug Therapy

Two major divisions of medical pharmacology: pharmacodynamics (PD) & pharmacokinetics (PK)

Pharmacodynamics study of 1) molecular, biochemical and physiologic effects of drugs on cellular systems 2) Drug-receptor interactions 3) drug mechanisms of action= therapeutic and toxic  Operationally, what drug does to body  Processes that determine variability in drug actions despite equivalent drug delivery to effector sites  Drug Concentration-Effect relationship Dose-Response phenomena

10

General Principles of Drug Therapy

Two major divisions of med pharm (2) Pharmacokinetics study of ADME Absorption drug in Distribution Metabolism drug out = Elimination Excretion Movement of drug molecules through various physiologic compartments drug deposition Operationally, what body does to drug Processes that determine drug delivery to (in) and removal from (out) molecular targets Drug Concentration-Time relationship 11

General Principles of Drug Therapy

Drug deposition Locus of action “receptors�

Bound

Free

Tissue reservoirs Bound

Free

Systemic circulation

Absorption

Free drug

Bound drug

Excretion

Metabolites

Biotransformation

The summation of these processes will determine plasma drug concentrations (Cp) at any point in time

12

General Principles of Drug Therapy

Third emerging division of medical pharmacology

Pharmacogenomics study of how genetic makeup affects PD and PK affects drug selection and application to individual patients “Pharmacogenomics may hold the opportunity of allowing practitioners to integrate a molecular understanding of the basis of disease with an individual's genomic makeup to prescribe personalized, highly effective, and safe therapies.�

From: Roden DM. (2012) Ch. 5 Principles of Clinical Pharmacology. In: Longo DL, Fauci AS, et al. Harrison's Principles of Internal Medicine,18th Ed., McGraw-Hill 2012, Pg. 33 Learn more: Ritter JM, Lewis LD, Mant TG, Ferro A. Ch.14 Pharmacogenetics. In: A Textbook of Clinical Pharmacology and Therapeutics 5th-ed. Hodder Arnold, 2008; Pgs. 79-85.

13

General Principles of Drug Therapy

Relationship between PK and PD Pharmacokinetics

Dose of drug

Pharmacodynamics

Drug concentration in target organ over time

Absorption Distribution Biotransformation Excretion

Mechanism and magnitude of drug effect

Receptor binding Signal transduction Physiological effect

Redrawn after Brenner GM and Stevens CW. Pharmacology 4th ed. (Sanders, 2014)

14

General Principles of Drug Therapy

Definition-Drug No precise uniformly accepted definition ď Ž

commonly accepted -drug is any exogenous non-nutritive substance that affects bodily function

In medicine drug is a chemical agent used in prevention, diagnosis, treatment or cure of disease (or affect fertility)

15

General Principles of Drug Therapy

Drug- cardinal features:  modify communication system within organism [humans and (or) animals]

modification should not interfere with fidelity of biochemical and physiologic signal  should not activate unwanted compensatory response  should selectively target specific cellular components that Fx in normal signaling process 

16

General Principles of Drug Therapy

Properties of an ideal drug  Safety Fewer side effects or lower toxicity  Effectiveness Better therapeutic effects  Selectivity Target to desired sites or molecules NB Due to the multiple variations in patient profiles and drug variables and the interaction between the two, the ideal drug “Does not exist”

17

General Principles of Drug Therapy

Clinical Pharmacology A complex interaction between patient and drug Patient profile  The patient is a unique individual, Patient profile with many distinguishing features that need Age to be taken into account during prescribing Weight

Drug profile  The drug, likewise, is unique, with its own distinguishing features  Good prescribing involves tailoring drug and dosing regimen to unique patient  Clinical pharmacology provides basis of this pharmacotherapeutic principle

Sex Race Allergies Smoking history Alcohol history Diseases Pregnant/lactating Current therapy Intelligence

Drug profile Name (generic) Class Action Pharmacokinetics Indications Contraindications/ precautions Interactions Side effects Dosing regimen Monitoring Overdose 18

General Principles of Drug Therapy

Drug Nomenclature Several names refer to the same drug:

  

Chemical Name



Based on a drug's chemical and molecular constituents and structure

Generic Name (Nonproprietary, Approved)



Assigned by manufacturer after approval by regulatory body in country of origin (e.g., United States Adopted Names Council)

Trade, Brand, or Proprietary Name



Assigned by manufacturer, copyrighted and therefore can be used commercially only by originating pharmaceutical company 19

General Principles of Drug Therapy

Drug Nomenclature (2) Clinical Connection: Drugs can have many different names: For example, a prototypical calcium channel blocker of dihydropyridine class has  Chemical name 3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4dihydropyridine-3,5-dicarboxylate

 Generic name nifedipine, and is available in U.S.under several  Trade names including Adalat, Nifedical, and Procardia 20

General Principles of Drug Therapy

How drugs work Drug effects are produced by altering normal functions of cells and tissues via one of four general mechanisms: 1. Interaction with receptors 2. Nonspecific chemical or physical interactions Ligand-activated ion channels  e.g., antacids G-protein–coupled receptors 3. Antimetabolite action  Gαs-coupled receptors  e.g., ChemoTx agents  Gαi (Ginhibitory)-coupled receptors 4. Alteration of the activity of enzymes  Gq (and G11)-coupled receptors  increasing or decreasing Intracellular nuclear receptors Receptor-activated tyrosine kinases Note:  Drugs do not produce new function  No drug has a single action, but have both therapeutic and adverse actions or have multiple therapeutic effects  Drug vs poison dose related

21

General Principles of Drug Therapy

Receptors*

 Specialized proteins that are binding sites for neurotransmitters and hormones  Postsynaptic cell membranes (neurotransmitters)  Cell nucleus (steroid hormones)  Linked to one of many signal transduction mechanisms “Receptor” (According to Rang & Dale Pharmacology): A target or binding protein for a small molecule (ligand), which acts as an agonist or antagonist.

Rang HP etal. Rang & Dale's Pharmacology, Churchill Livingstone; 7th edition 2011

*“not to be confuse with other drug targets such as enzymes etc.”

22

General Principles of Drug Therapy

Ligand-Receptor Interactions  Complementary conformations in 3 dimensions  Similar to enzyme-substrate interactions

 Physiologic interactions are weak attractions  H-bonding, van der Waal’s forces

 Drug mechanisms – Agonists - bind and activate receptors – Antagonists - bind but DO NOT activate receptors "Receptor" according to IUPHAR (International Union of Basic and Clinical Pharmacology): A cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells. Combination of a hormone, neurotransmitter, drug, or intracellular messenger with its receptor(s) initiates a change in cell function.

23

General Principles of Drug Therapy

Steps in Signal Transduction Process  There are three general classes of signal transducing receptors:  G-proteins are one and are referred to as serpentine receptors

Binding of the neurotransmitter, hormone or drug to receptor> signaling of G-protein> enzyme activation> production of a secondmessenger> protein kinase activation > phosphorylation of specific proteins (effect)> termination See: GPCRs-Signal Transduction Toolkit (& Other Receptor Mechanisms)

24

General Principles of Drug Therapy

GPCR structure & function (simplified) G-Protein Coupled Receptor

Mechanism of cAMP dependent signaling

Binding of neurotransmitter, hormone or drug to receptor> signaling of Gprotein> enzyme activation> production of a second-messenger> protein kinase activation >phosphorylation of specific proteins (effect)>termination

The neurohormone epinephrine and its receptor (pink) is used in this example: The activated receptor releases the Gs alpha protein (tan) from the beta and gamma subunits (blue and green) in the heterotrimeric G-protein complex. The activated Gs alpha protein in turn activates adenylyl cyclase (purple) that converts ATP into the second messenger cAMP 25

General Principles of Drug Therapy

Neal, MJ Medical Pharmacology at a Glance.

26

General Principles of Drug Therapy

27

General Principles of Drug Therapy

Further study:  eNotes: GP- General Principles of Drug Action  Drug-Receptor Interactions, Morris ZS, Golan DE and (or) Brody’s Human Pharmacology: Ch.1 Pharmacodynamics- Receptors and ConcentrationResponse Relationships  Enzyme kinetics Notes  MedPharm Wiki| PK and PD, Pgs. 73-88  Integrated Scientific & Clinical Pharmacology Course Website

28