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A/Professor Ken Rodgers

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References
uRang and Dales
Pharmacology, 8th Edition,
Churchill Livingstone, Sydney by
Rang HP, Dale MM, Ritter JM,
Flower RJ, Henderson, G (2016)
u What is pharmacology? Section 1
Chapter 1.
u How drugs act: general principles
Section 1 Chapter 2.

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Lecture content
uThe birth of pharmacology as a science
uDefinitions
uHow drugs work
uDrug nomenclature
uTherapeutic drug market
uGuide to poisons regulations
uMechanisms of drug action
uDose-response relationships

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The emergence of pharmacology

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Alternative therapeutic options
u Modern medicine relies heavily on drug-based therapeutics.
u Other therapeutic procedures include surgery, diet, exercise,
psychological treatments, physiotherapy.
u Therapeutic systems that have a basis that lies outside the
domain of science are known as alternative or
complementary medicine. Approaches include blood letting,
emetics and purgatives and homeopathy (early 19th century)
guiding principles are: like cures like and activity can be
enhanced by dilution.
u Evidence-based health care is commonly practiced.

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Definitions 1
uWhat is pharmacology?
uThe study of the effects of drugs on the function of
living systems
uPaul Ehrlich drug action must be explicable in terms
of conventional interactions between drugs and
tissues
uThe study of chemical agents (drugs) that interact
with living systems through chemical processes,
especially by binding to regulatory molecules and
activating or inhibiting normal body processes

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Definitions 2
uWhat is a drug?
uA chemical substance of known structure,
other than a nutrient or an essential dietary
ingredient, which, when administered to a
living organsism, produces a biological effect.

uA chemical applied to a physiological system


that affects its function in a specific way

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Pharmacology the Discipline

Interface disciplines (brown boxes)


link pharmacology to other
mainstream biomedical disciplines
(green boxes)

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Definitions 2
uPharmacodynamics ?
uWhere a drug acts in the body (site of action)
uBiochemical, physiological and behavioural effects
of drugs (mode of action)

Where does the drug work?


How does the drug work?

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Definitions 3
u Pharmacokinetics?
u Way in which the drug concentration changes with time
u drug disposition (absorption, distribution, metabolism, excretion)
u quantitative pharmacokinetics (measure concentration of drug at
various times)
u Allows one to make intelligent decisions regarding dose and
frequency of drug administration

Its all about drug concentrations,


how drugs move around the body
and how they are excreted

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Definitions 4
uTherapeutics?
uUse of drugs used to cure, treat or prevent disease
and in the alleviation of pain and suffering
uChemotherapy?
uUse of drugs to kill or weaken invading cells or
organisms
uToxicology?
uStudy of poisons and the treatment of poisoning

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How Drugs Work
u The majority of drugs interact with specific molecules involved
in regulatory functions eg. a receptor, ion channel, pump or an
active site on an enzyme (DRUG TARGET)

u A small number of drugs interact with chemicals in the body but


are not bound to a tissue component
u Osmotic diuretics (mannitol) or osmotic laxatives (sorbitol) will bind to
water in the kidney
u Antacids will bind to acid in the stomach

targets

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Origins of Drugs
u1. Some drugs are synthesised within the body (eg.
hormones, autacoids, neurotransmitters) this
includes insulin, oestradiol, adrenaline, testosterone

u2. Most drugs are not synthesised within the body


uXenobiotics (Greek xenos 'stranger') eg. synthetic or
semisynthetic drugs
uPoisons

uToxins (poisons of biologic origin)

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Physical Nature of Drugs
uSolid
uaspirin, paracetamol
uLiquid
uEthanol

uGaseous
unitrous oxide
uThese factors often determine route of
administration
uSome liquid drugs are easily vaporised and
can be inhaled
uhalothane and amyl nitrate
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Drug Size
uVary from v. small eg lithium (MW
7 daltons) Rx bipolar depression, to
uV. Large eg tissue plasminogen
activator (TPA) (a protein of MW
59,050 daltons) Rx fibrinolytic
therapy
uBut most have masses of 100-1000
daltons, which alter the body's
function by interactions at the
molecular level

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Drug Nomenclature 1
O
N OH
H
H3 C
uChemical name - N-acetyl-p-aminophenol (identifies
chemical structure)
uGeneric name - Official name (lower case)
ueg. paracetamol (Australia, NZ & UK) but also
acetaminophen (USA)
uTrade name - proprietary/brand name (first letter
capitalised)
ueg. Panadol, Dymadon, Paralgin, Setamol,
Tylenol etc
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Drug Nomenclature 2
u Genericdrugs belonging to the same drug group (often)
have same suffix
u Phenothiazine antipsychotics -azine
u Eg. chlorpromazine, prochlorperazine, trifluoperazine
u Most antianxiety drugs (benzodiazepines) -azepam
u Eg. diazepam, temazepam, flunitrazepam, clonazepam
u Local Anaesthetics -caine
u Eg. lignocaine, amethocaine, cinchocaine, cocaine
u ACE inhibitors -pril
u Eg. enalapril, captopril, lisinopril, perindopril
u Most beta-receptor antagonists -olol
u Eg. propranolol, labetolol, metoprolol

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Spelling IS important!

uquinine
quinidine
umeclobemide metoclopramide
utrimipramine trimethoprim

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The Therapeutic Drug Market 1
u~700 active ingredients
uMultiple combinations eg:
u PANADEINE = codeine + paracetamol
u TYLENOL SINUS = paracetamol +
pseudoephedrine
uDelivery forms eg:
u ADALAT OROS = slow release nifedipine
tablets (once daily)
u ADALAT = nifedipine tablets (twice daily)

uOver 30,000 different medicinal drug


products on Australian market

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The Therapeutic Drug Market 2
u The availability of potentially dangerous drugs and chemicals
needs to be restricted to enable their safe and effective use.
u Scheduling is the legal process used to achieve this
(Therapeutic Goods Act 1989).
u Medicinal drugs (therapeutic goods) includes:
u Prescriptionand non-prescription products from synthetic and biological
sources, herbal products, vitamin and mineral supplements, sunscreens
and homeopathic products
u Unscheduled drugs can be sold through other retail outlets such
as supermarkets (eg, paracetamol)

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The Therapeutic Drug Market 2

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Guide to Poisons Regulations

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Guide to Poisons Regulations

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TGA

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Mechanisms of drug action 1
uStructure-activity
relationships
uWhy do most drugs vary
widely in 3-dimensional
shape?
uBecause most interact
with specific sites
receptors (drug targets)

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Mechanisms of drug action 1
uStructure-activity relationships
uWhy do most drugs vary widely in 3-dimensional
shape?
uBecause most interact with specific sites - receptors

uReceptors are macromolecular structures in or on the


cell surface with which drugs interact to produce
effects
uChange in structure can change activity of drug
uThe type of chemical interaction with the receptor can
influence the action of the drug
uA high degree of specificity can result in fewer toxic side-
effects
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Mechanisms of drug action 2
uWhat sort of shape?
uDrug must be complementary in shape to receptor
(lock and key model)

Receptor Activate receptor?


Drug


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Nicotinic acetylcholine receptor

ACh
Side view Top view

6 nm
Pore
~0.7 nm diameter

Out

Membrane 3 nm

In

2 nm

ACh

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Mechanisms of drug action 3
Real example
Acetylcholine
7 Angstroms

CH3
Cavity H3 C O CH3
N C
H2 C Possible
Cavity O electron donor
O H group
Glutamate C N
O Possible
N H-bond
site
Histidine
Anionic
group
Nicotinic acetylcholine receptor

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Targets for drug action 1

uReceptors
uSensingelements for chemical communication
(hormone, neurotransmitter, neurohormones
etc)
uExample: D2 dopamine
uAgonist:dopamine
uAntagonist: chlorpromazine

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Targets for drug action 2

uIon channels
uMay be blocked by a drug or the gating operation
may be modulated
uLocal anaesthetics (eg. procaine) physically block
the voltage-gated sodium channel
uBenzodiazepines (eg diazepam) bind to a region of
the GABA-receptor/chloride channel complex
uMost facilitate the opening of the channel by GABA

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Targets for drug action 3

uEnzymes
uDrugs may be competitive (eg neostigmine -
AChE enzyme) or non-competitive (eg aspirin -
COX enzyme) inhibitors of enzymes
uPumps
uDrugs may inhibit the action of carrier molecules
eg proton pump inhibitors (eg. omeprazole)

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Other drug effects

u Binding to DNA (cross-linking or


degradation)
u some antitumor alkylating agents (eg. cisplatin)
and cytotoxic antibiotics (eg bleomycin)
u Counterfeit substrates
u The antihypertensive agent alpha-methyldopa
substitutes for a normal substrate in the synthesis
of noradrenaline resulting in a less active end-
product

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Other drug effects

u Chemical effects
u Protamine - antagonist of the anticoagulant heparin is due
to interaction of highly +ve charged protamine molecule with
highly -ve charged heparin molecule
u Physiological effects
u Antacids - eg. AlOH3 (acts as a physiological buffer)
u Cathartics (purgatives)
u Ingestion of non-absorbable material (eg lactulose or
MgSO4) increases water content of faeces and promotes
defaecation

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Drug targets: receptors

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Drug targets: enzymes

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Drug targets: transporters

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Dose-response relationships 1
uFour basic characteristics
Maximal
Efficacy
(Emax)
% Maximal Effect

Slope
Variability

Potency

Log Dose
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Dose-response relationships 2
uPotency
uInherent ability of drug to combine with receptors -
depends on drug affinity
uImportant for dosage but unimportant for clinical
purposes as long as it can be administered
conveniently
uNo justification that the more potent of two drugs is
clinically superior (toxicity is also important)

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Dose-response relationships 3
uSlope
uRelationship between change in dose and change
in effect
uSometimes called the Hill slope or Hill coefficient
(nH)
uFor some drugs a small change in dose can change
a therapeutic effect into a toxic effect (steep slope)

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Dose-response relationships 4

Slope is important

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Dose-response relationships 5
uMaximal Effect (Emax)
uMaximal efficacy - plateau in the DR-curve (eg
maximal efficacy of buprenorphine is lower than
morphine)
uThus buprenorphine never reaches full maximal
efficacy partial agonist
uDependent on intrinsic activity of the drug
uPotency vs. efficacy - whereas potency refers to the
concentration of drug required to produce a
particular effect, efficacy refers to the maximal
possible effect that can be produced by the drug

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Drugs X and Z have the same efficacy
Drugs X and Z differ in potency
Same Emax

ED50 ED50

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Drugs X and Y differ in efficacy
Drug Y = partial agonist
Emax

Emax

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Dose-response relationships 6
u DR-curves are plotted on a log10 x-axis (dose/conc.) against %
of maximal response (y-axis)
u This gives a sigmoidal (S-shaped) curve defined by:
u Linear portion (30-70% effect)
u Median effective dose (ED50) or concentration (EC50)
u Slope of the linear portion of the curve (nH)
u ED50 or EC50 = dose or conc. of drug required to produce an
effect of specified intensity in 50% of subjects
u Curves are fitted using non-linear regression employing a
Logistic equation 100
y = 100
# x &nH
1+ % (
$ EC50 '
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