A/Professor Ken Rodgers

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 References

u Rang and Dale’s

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
u The birth of pharmacology as a science
u Definitions
u How drugs work
u Drug nomenclature
u Therapeutic drug market
u Guide to poisons regulations
u Mechanisms of drug action
u Dose-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 options include procedures such
as surgery, diet modification, exercise,
psychological treatments and physiotherapy.
u Therapeutic systems that have a basis that lie
outside the domain of science are known as
‘alternative’ or ‘complementary’ medicine..
u Evidence-based health care is commonly practiced
in Australia.

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 Definitions 1
u What is “pharmacology?
u The study of the effects of drugs on the function of
living systems
u Paul Ehrlich ‘drug action must be explicable in
terms of conventional interactions between drugs
and tissues’
u The 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
u Pharmacodynamics ?
u Where a drug acts in the body (site of action)
u Biochemical, 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
u Therapeutics?
u Use of drugs used to cure, treat or prevent disease
and in the alleviation of pain and suffering
u Chemotherapy?
u Use of drugs to kill or weaken invading cells or
organisms
u Toxicology?
u Study 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
u 1. Some drugs are synthesised within the body (eg.
hormones, autacoids, neurotransmitters) this
includes insulin, oestradiol, adrenaline, testosterone

u 2. Most drugs are not synthesised within the body

u Xenobiotics (Greek xenos 'stranger') eg. synthetic or
semisynthetic drugs
u Poisons

u Toxins (poisons of biologic origin)

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 Physical Nature of Drugs
u Solid
u aspirin, paracetamol
u Liquid
u Ethanol

u Gaseous
u nitrous oxide
u These factors often determine route of
administration
u Some liquid drugs are easily vaporised and
can be inhaled
u halothane and amyl nitrate
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 Drug Size
u Vary from v. small eg lithium (MW
7 daltons) Rx bipolar depression, to
u V. Large eg tissue plasminogen
activator (TPA) (a protein of MW
59,050 daltons) Rx fibrinolytic
therapy
u But 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
u Chemical name - N-acetyl-p-aminophenol (identifies
chemical structure)
u Generic name - Official name (lower case)
u eg. paracetamol (Australia, NZ & UK) but also
acetaminophen (USA)
u Trade name - proprietary/brand name (first letter
capitalised)
u eg. Panadol®, Dymadon®, Paralgin®, Setamol®,
Tylenol® etc
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 Drug Nomenclature 1

u Chemical name -

u Generic name -

u Trade name -

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 Drug Nomenclature 2
u Generic drugs 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!

u quinine
≠ quinidine
u meclobemide ≠ metoclopramide
u trimipramine ≠ trimethoprim

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 The Therapeutic Drug Market 1
u ~700 active ingredients
u Multiple combinations eg:
u PANADEINE® = codeine + paracetamol
u TYLENOL SINUS® = paracetamol +
pseudoephedrine
u Delivery forms eg:
u ADALAT OROS® = slow release nifedipine
tablets (once daily)
u ADALAT® = nifedipine tablets (twice daily)
u Over 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 Prescription and 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
u Structure-activity
relationships
u Why do most drugs vary
widely in 3-dimensional
shape?
u Because most interact
with specific sites –
receptors (drug targets)

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 Mechanisms of drug action 1
u Structure-activity relationships
u Why do most drugs vary widely in 3-dimensional
shape?
u Because most interact with specific sites - receptors

u Receptors are macromolecular structures in or on the

cell surface with which drugs interact to produce
effects
u Change in structure can change activity of drug
u The type of chemical interaction with the receptor can
influence the action of the drug
u A high degree of specificity can result in fewer toxic side-
effects
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 Mechanisms of drug action 2
u What sort of shape?
u Drug 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

u Receptors
u Sensingelements for chemical communication
(hormone, neurotransmitter, neurohormones
etc)
u Example: D2 dopamine
u Agonist:dopamine
u Antagonist: chlorpromazine

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 Targets for drug action 2

u Ion channels
u May be blocked by a drug or the gating operation
may be modulated
u Local anaesthetics (eg. procaine) physically block
the voltage-gated sodium channel
u Benzodiazepines (eg diazepam) bind to a region of
the GABA-receptor/chloride channel complex
u Most facilitate the opening of the channel by GABA

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 Targets for drug action 3

u Enzymes
u Drugs may be competitive (eg neostigmine -
AChE enzyme) or non-competitive (eg aspirin -
COX enzyme) inhibitors of enzymes
u Pumps
u Drugs 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
u Four basic characteristics
Maximal
Efficacy
(Emax)
% Maximal Effect

Slope
Variability

Potency
Log Dose
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 Dose-response relationships 2
u Potency
u Inherent ability of drug to combine with receptors -
depends on drug affinity
u Important for dosage but unimportant for clinical
purposes as long as it can be administered
conveniently
u No justification that the more potent of two drugs is
clinically superior (toxicity is also important)

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 Dose-response relationships 3
u Slope
u Relationship between change in dose and change
in effect
u Sometimes called the Hill slope or Hill coefficient
(nH)
u For 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
u Maximal Effect (Emax)
u Maximal efficacy - plateau in the DR-curve (eg
maximal efficacy of buprenorphine is lower than
morphine)
u Thus buprenorphine never reaches full maximal
efficacy – partial agonist
u Dependent on intrinsic activity of the drug
u Potency 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). See tutorial on UTS online.

u This gives a sigmoidal (‘S’-shaped) curve defined by:

u Linear portion (~ 30-70% effect)
u Median effective dose (ED50) or concentration (EC50) can be estimated
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. Note: response can be graded or quantal.

u Curves are fitted using non-linear regression employing a Logistic equation but
data can be made linear using a few methods to transform the data.
100
y = 100 −
# x &nH
1+ % (
$ EC50 '
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