Introduction to pharmacology

Pharmacology

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Introduction

• What is pharmacology?

• Why do we need to take pharmacology?

• Significance of pharmacology to Dentistry


History of Pharmacology

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

berries., poppy, lead, salt and crushed precious stones. Also included were products derived from animals, including lizard's blood, swine teeth, goose grease, ass hooves and the excreta from various animals. The effects of many of these drugs on patients of antiquity can only be imagined.



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 eraThe 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.

Although, traditional remedies still generally consisted of complex mixtures of distinct herbs and minerals, perhaps only one of which possessed any activity. Many poisonous mixtures were made.


History of Pharmacology 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,

morphine was isolated from the opium poppy (Papaver somniferum) and the anti-malarial compound quinine from the bark of the cinchona tree (Cinchona officinalis).


History of PharmacologyMateria MedicaThe 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.

• Each remedy has an identifiable nature or essence that is extracted from the natural product by chemical extraction.

• The administration of a remedy is based on testing the amount of drug needed to achieve an effect (dose-response).


History of Pharmacology 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 worldwide, and remains an important drug today. (Interestingly, it was not until 1971 that Sir John Vane discovered the mechanism of action of aspirin, a feat that earned him the 1981 Nobel Prize for Medicine.)



Paul Ehrlich described drug-receptor binding:

“Corpora non agunt nisi fixate”.P. Ehrlich (1908)

(“Agents do not act unless they are bound”)

In the United States, transformation was marked by the creation of the American Society for Pharmacology and Experimental Therapeutics (ASPET) in 1908. www.freelivedoctor.com

History of Pharmacology The modern eraThese, 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 theexperimental science of pharmacology, which is devoted to understanding the physiological action of these molecules.


History of Pharmacology 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 infectionsdiabeteshypertensiondepressionAIDS


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 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

– 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.

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).


ReceptorsMost drugs combine (bind) with specific receptorsto 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. Carriersb. Receptors

i. G protein-linked ii. Ligand gated channelsiii. Intracellular

c. Enzymes2. DNA


Endogenous compounds act on their Receptors

Neurotransmitter

Neuropeptides

Hormones

Ions


Receptor

1) PharmacologicalMediator (i.e. Insulin, Norepinephrine, estrogen)

2) Biophysical and BiophysicalSecond messenger system (i,.e. cAMP, PLC, PLA)

3) Molecular or StructuralSubunit composition (i.e. 5HT1A )

4) AnatomicalTissue (i.e muscle vs ganglionic nAChRs)Cellular (i.e. Membrane bound vs Intracellular)

Classification of Receptors


Types of ReceptorsMEMBRANE BOUND RECEPTORS• G-Protein-linked receptors

Serotonin, Muscarinic, Dopaminergic, Noradrenergic

• Enzyme receptorsTyrosine kinase

• Ligand-gated ion channel receptorsNicotinic, 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 Receptorswww.freelivedoctor.com

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 InteractionsChemical Bonds

Van der Waals Interactions

Hydrophobic Interactionswww.freelivedoctor.com

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

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Receptor Signaling Pathways

Second Messengers:1. Ions (Ca2+, Na+, K+, Cl-)2. cAMP, cGMP, IP3, Diacylglycerol3. DNA binding – Transcriptional regulation.4. Phosphorylated proteins and enzymes via tyrosine kinase

receptors.

Third Messengers:1. Enzymes (PKC, PKA)2. Ions (Ca2+, K+)



cAMP

cGMP

DAG and IP3

Arachidonic acid

NO and CO

Na+, Ca2+

, K+

, Cl-

EFFECTORS

Adenylate Cyclase (AC)

Guadenylyl Cyclase (GC)

Phospholipase C (PLC)

Phospholipase A (PLA2)

Nitric oxide Synthase

Ions

SECOND MESSENGER



R R R R


Drug-Receptor InteractionsTheory 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.www.freelivedoctor.com

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 = drugR = receptorDR = 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

k1

[D] + [R] [DR]

k2

k2 = KD = [D][R]

k1 [DR]

1 = KA = k1 = [DR]

KD k2 [D] [R]


Key Topics

• How are drugs described and referenced?

• What are the relevant drug laws and regulations?

• What are the factors affecting how drugs are given?

• What are some of the key terms?

Drug Descriptions

• Names

• Sources

• Forms

• Reference Materials

• Components of Drug Profiles

Drug Names

• Chemical Name: 2-(diethylamino)-2’,6’-acetooxylid monohydrochloride monohydrate.

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Drug Names

• Generic Name: lidocaine hydrochloride

• Official Name: Lidocaine Hydrochloride, USP

• Brand (Trade) Name: Xylocaine®

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Drug References

• USP

• PDR

• Drug Inserts

• Nursing Drug References

• Pocket Field Guides

• Digital Guides– Jeff’s Pharmacology Reviewhttp://www.templejc.edu/ems/drugs/PharmIndex.html

Components of a Drug Profile

• Names• Classification

(including prototype)• Mechanism of Action• Kinetics• Indications• Contraindications

• Side Effects• Interactions• Routes of

Administration• Dosage• How Supplied• Special Considerations

Drug Laws

• Pure Food and Drug Act of 1906

• Harrison Narcotic Act of 1914

• Federal Food, Drug and Cosmetic Act of 1938– Durham-Humphrey Amendments

• Comprehensive Drug Abuse Prevention and Control Act of 1970

Controlled Substances

Schedule I High abuse potential with risk ofsevere dependence; no medical use.

Schedule II High abuse potential with risk ofsevere dependence. Some medicalindications

Schedule III Moderate abuse potential with riskof moderate to low physicaldependence and/or highpsychological dependence.

Schedule IV Low abuse potential with limitedrisk of dependence.

Schedule V Lowest abuse potential with limiteddependence risks.

State and Local Laws

• ‘Scope of Practice’ Laws

• Responsibility vs Authority of Medical Direction

Drug Standardization

• Assays

• Bioequivalence

• Bioassay

• USP is the official standard

Research and Development

• Key points from FDA handout– Purpose?– What are controls? – What are the phases? – What is an IND? An NDA?– Why is skepticism important?

Handout Source: http://www.fda.gov/fdac/special/newdrug/testing.html

Six Rights of Medication Administration

• Right Medication

• Right Dose

• Right Time

• Right Route

• Right Patient

• Right Documentation

Pregnancy Considerations

• Increased maternal HR, CO and blood volume– May affect absorption, distribution,

effectiveness

• Drugs may cross placenta

• Drugs may cross into breast milk

• Tertatogens

Pregnancy Categories

• A: controlled studies in pregnancy (<1 %).• B: animal studies show no risk; Inadequate

human data.• C: animal studies show risk, inadequate

human data.• D: human data show risk, benefit may

outweigh risk.• X: animal or human data positive for risk.

Use unwarranted.

Pediatric Considerations

Oral absorption

• Thinner skin ( topical absorption) Plasma protein concentration

Free protein-bound drug availability

Extracellular fluid in neonate

• Altered metabolic rates Elimination/metabolism

• BSA/weight based dosing important!

Geriatric Considerations

Oral absorption Plasma protein concentration Muscle mass, body fat Liver/renal function

• Multiple drugs

• Multiple diseases

Some Terminology

• Receptor affinity• Efficacy• 1° vs. 2nd messengers• Up vs. down receptor

regulation• Agonist vs. antagonist• -lytic vs. -mimetic

• Inhibition (antagonism)– Competitive vs.

noncompetitive vs. irreversible

• Allergic reaction• Idiosyncrasy• Tolerance

More Terminology

• Cross tolerance• Tachyphylaxis• Cumulative effect• Dependence• Drug interactions• Summation (1+1=2)

– Additive effect

• Synergism (1+1=3)• Potentiation• Interference

Basics of Drug Classification

• Knowledge grouping

• Prototype drug

• Predictive value

Drug Classification

• By chemistry– electrolytes

• By mechanism– Beta blockers– benzodiazepines

• By disease– antihypertensives– Antiemetics

Introduction to pharmacology

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