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PCTH 325

Introduction to Pharmacology*Self-directed Lecture*

Dr. Shabbitsjennifer.shabbits@ubc.ca

September 5, 20132

At the end of this lecture you should be able to:

1. Define the terms: pharmacology, drug, pharmacokinetics, pharmacodynamics, receptor

2. Describe the categories of drug effects

3. Explain the drug-receptor theory

4. Compare and contrast the four main families of drug receptors

5. Compare and contrast agonists and antagonists

Lecture 1 Learning Objectives

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What is Pharmacology?

Some Definitions

Pharmacology = the study of drugs what they do and how they do it

pharmakon = druglogos = the study of

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Webster’s Dictionary:“a substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease”

“Drug” has many definitions

“any substance that brings about a biological change or effect on the body”

More Broadly:

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Drugs come from many sources

Penicillin: antibiotic derived from mold

Vincristine: anticancer drug derived from periwinkle

St. John’s Wort: antidepressant derived from Hypericum perforatum

“Caffeine-loaded energy drinks have now crossed the line from beverages to drugs delivered as tasty syrups,” the Canadian Medical Association Journal says.

~Vancouver Sun, July 27, 2010

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The same drug can have many names

1. Chemical Name:Identifies the chemical elements and compounds that are found in the drug – most important to chemists, pharmacists and researchers who work with the drug at a chemical level.

2. Generic or Non-proprietary Name:The universally accepted name of a drug. It appears on all drug labels, resource guides and publications. Generic names often follow similar patterns for drugs of the same class or mechanism. (ex: lidocaine, procaine)

3. Brand or Trade or Proprietary Name:The copyrighted and trademarked name given by the drug company – restricts the use of the name. 8

The same drug can have many names

Chemical name: ()-2-(p-isobutylphenyl) propionic acid

Generic name: Ibuprofen

Brand names: Advil, Motrin

Chemical name: Ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidine)-1-piperidinecarboxylate

Generic name: Loratadine

Brand name: Claritin

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The history of pharmacology

Double, double toil and trouble;Fire burn and cauldron bubble.

Fillet of a fenny snake,In the cauldron boil and bake;Eye of newt, and toe of frog,

Wool of bat, and tongue of dog,Adder's fork, and blind-worm's sting,

Lizard's leg, and howlet's wing,For a charm of powerful trouble,Like a hell-broth boil and bubble.~ William Shakespeare’s ‘Macbeth’

Pharmacology• pre-3000 BC

• drugs = animals, herbs, potions & religion

• drugs seen as “magical” and used empirically 10

From then until now

* Advances in multidisciplinary fields have paved the way

- increased understanding of human physiology (normal & disease)

- developments in chemistry, biochemistry, microbiology, botany etc.

• It takes 7-10 years from bench to market $1,000,000,000 US dollars

* Pharmacologists involved in every step *

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Pharmacology has 2 arms

2. Pharmacokinetics: “what the body does to the drug”• the study of the movement of drugs in the body (how it reaches and leaves its site of action and at what concentration)

1.Pharmacodynamics: “what the drug does to the body”

• the study of the effect(s) of drugs on body processes

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The PK – PD relationship

Dosage Regimen

How much? How often? How long?

What form?

[DRUG] - Plasma Pharmacological Effect

Pharmacokinetics Pharmacodynamics

[DRUG] - Receptors at Target Site

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Simplification of drug action

Drug

Biological Alteration

Effect

Alterations in body control systems (chemical transmitters, hormones, enzymes, carrier molecules, DNA etc.)

Effects

Desirable (therapeutic)

Undesirable

RiskBenefit

Deleterious (toxicities)

Non-deleterious

(side effects)

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Categories of drug action

1. Replacement: the drug replaces a physiological process

Ex. insulin therapy for type 1 diabetes

3. Potentiation: the drug stimulates a physiological process

Ex. diuretics promote urine output

2. Interruption: the drug interferes with a physiological process

Ex. antihypertensive (blood pressure) medications relax blood vessels to lower blood pressure

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How do drugs elicit their effects?

Paul Ehrlich (1854-1915) ~ pioneered the scientific approach to drug discovery

“Corpora non agunt nisi fixata”

“A drug will not work unless it is bound”

(almost) All drug effects are the result of drug-receptor interactions

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What are receptors?

Receptors = macromolecules that mediate a biological change following ligand (drug) binding

• most receptors are proteins

Drug-receptor binding analogous to enzyme-substrate binding

multiple chemical interactions between drug and receptor

Drug + Receptor [Drug-Receptor Complex] Effect

(VDW forces, H-bonds, ionic interactions)

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Receptors

Most receptors have naturally occurring (endogenous) molecules that bind to them

Exogenous (foreign) molecules can be designed to bind to the same receptor rational drug design

Endorphins (endogenous)Morphine (exogenous)

Bind opiate receptorsin brain

Example ~

EUPHORIA18

Receptors

Exception ~ a few drugs work via non-receptor mechanisms, for example:

Antacids - purely chemical basis via acid neutralization in the stomach

Osmotic diuretics - promote urine excretion by altering water flow independent of receptors

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There are 4 main families of receptors

DRUGNa+

Na+

1. Ion Channels

• fastest effect (milliseconds)

• receptor itself is the ion channel

• drug binds receptor and causes channel to open

• drugs often = neurotransmitters (ex: acetylcholine, GABA – more on these later)

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There are 4 main families of receptors

2.G-Protein Coupled Receptors

• most common

• receptor coupled to G-protein that interacts with an effector protein . Generates a 2nd messenger (cAMP) when drug binds

• 2nd messenger mediates drug’s intracellular effect

• drugs often = adrenergic agents (ex: adrenaline)

DrugReceptor Effector

2nd Messenger

Effect

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There are 4 main families of receptors

3.Enzymatic Receptors

• drug binding causes receptor dimerization

• kinase or phosphatase enzymes activated

• phosphorylation or dephosphorylation of target molecules mediates the effect

• receptors are often ‘tyrosine kinases’ 22

There are 4 main families of receptors

4. Intracellular Receptors• slowest effect

• drug diffuses across cell membrane and binds to an intracellular receptor (in cytoplasm or nucleus)

• drugs must be lipid soluble in order to cross (ex: steroid hormones)

• drug usually affects transcription processes

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Drug-receptor binding is key to the effect

WHAT is the response? the NATURE of the drug

• agonists & antagonists

HOW BIG is the response?

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Agonists bind to receptors Response

AGONISTS have:1. AFFINITY for the receptor (they bind to it) 2. INTRINSIC ACTIVITY (binding elicits a response)

Both rate Agonists can be either

1. Endogenous (ex: adrenalin) 2. Exogenous (ex: dobutamine)

Effect

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Agonists come in 2 “strengths”

a FULL AGONIST produces a maximal effect

a PARTIAL AGONIST produces only a partial effect (*has full affinity but only partial intrinsic activity)

Effect

Effect

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Antagonists bind to receptors No response

ANTAGONISTS (aka receptor blockers or inhibitors)

1. have AFFINITY (bind the receptor)

2. LACK intrinsic activity (no response)

No Effect

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Drug-receptor binding is key to the effect

WHAT is the response? the NATURE of the drug

• agonists & antagonists

HOW BIG is the response? the AMOUNT of drug at the receptors → DOSE

Dose-response relationships can be quantified

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For next class please…

• Read the concept map assignment overview

• Check your email to ensure that you have received my welcome test message

• Bring a scientific calculator