Introduction to pharmacology
Transcript of Introduction to pharmacology
Pharmacology
www.freelivedoctor.com
Introduction
• What is pharmacology?
• Why do we need to take pharmacology?
• Significance of pharmacology to Dentistry
www.freelivedoctor.com
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.
www.freelivedoctor.com
History of Pharmacology
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.
www.freelivedoctor.com
History of Pharmacology
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.
www.freelivedoctor.com
History of Pharmacology
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.
www.freelivedoctor.com
History of Pharmacology
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.
www.freelivedoctor.com
History of Pharmacology
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.
www.freelivedoctor.com
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.
www.freelivedoctor.com
History of Pharmacology
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).
www.freelivedoctor.com
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).
www.freelivedoctor.com
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.)
www.freelivedoctor.com
History of Pharmacology
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.
www.freelivedoctor.com
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
www.freelivedoctor.com
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.
www.freelivedoctor.com
Pharmacology
Divisions of Pharmacology
• Pharmacokinetics
• Pharmacodynamics
• Pharmacogenomics
www.freelivedoctor.com
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
www.freelivedoctor.com
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
www.freelivedoctor.com
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
www.freelivedoctor.com
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
www.freelivedoctor.com
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
www.freelivedoctor.com
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).
www.freelivedoctor.com
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
www.freelivedoctor.com
Endogenous compounds act on their Receptors
Neurotransmitter
Neuropeptides
Hormones
Ions
www.freelivedoctor.com
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
www.freelivedoctor.com
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
www.freelivedoctor.com
G Protein–linked Receptors
www.freelivedoctor.com
Enzyme-like Receptors
www.freelivedoctor.com
Ligand-gated Ion-Channel Receptors
www.freelivedoctor.com
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
www.freelivedoctor.com
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
www.freelivedoctor.comz
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+)
www.freelivedoctor.com
Receptor Signaling Pathways
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
www.freelivedoctor.com
Receptor Signaling Pathways
R R R R
www.freelivedoctor.com
Receptor Signaling Pathways
www.freelivedoctor.com
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]
www.freelivedoctor.com
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.
NotNotParticularlyParticularlyUseful!Useful!
NotNotParticularlyParticularlyUseful!Useful!
Drug Names
• Generic Name: lidocaine hydrochloride
• Official Name: Lidocaine Hydrochloride, USP
• Brand (Trade) Name: Xylocaine®
MuchMuchMoreMoreUsefulUseful
MuchMuchMoreMoreUsefulUseful
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