A/Prof. Ken Rodgers School of Life Sciences

Contents

The birth of pharmacology as a science

Definitions

How drugs work

Drug nomenclature

Therapeutic drug market

Guide to poisons regulations

Mechanisms of drug action

Dose-response relationships

References

Rang and Dale’s Pharmacology, 8th Edition, Churchill Livingstone, Sydney by Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson, G (2015)

1) What is pharmacology? – Section 1 Chapter 1.
2) How drugs act: general principles – Section 1 Chapter 2.

The Birth of Pharmacology as a Science

pharmacology-timeline

Alternative Therapeutic Principles

  • Modern medicine relies heavily on drug-based therapeutics.
  • Other therapeutic procedures include as surgery, diet, exercise, psychological treatments.
  • Therapeutic systems that have a basis that lies outside the domain of science are known as ‘alternative’ or ‘complementary’ medicine. Approaches include: allopathy (1735–1821) included blood letting, emetics and purgatives and homeopathy (early 19th century) guiding principles are: like cures like and activity can be enhanced by dilution.
  • Evidence-based health care

Definitions

What is a “drug”?

  • A chemical applied to a physiological system that affects its function in a specific way.
  • A 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.
  • 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.

What is “pharmacology”?

  • The study of the effects of drugs on the function of living systems.
  • Paul Ehrlich ‘drug action must be explicable in terms of conventional interactions between drugs and tissues’.
  • 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.

Interface disciplines (brown boxes) link pharmacology to other mainstream biomedical disciplines (green boxes)

Pharmacodynamics

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Pharmacodynamics definition

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  • Where a drug acts in the body (site of action)
  • Biochemical, physiological and behavioural effects of drugs (mode of action) → Where does the drug work? How does the drug work?
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Pharmacokinetics definition

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  • Way in which the drug concentration changes with time
  • Drug disposition (absorption, distribution, metabolism, excretion)
  • Quantitative pharmacokinetics (measure concentration of drug at various times)
  • Allows one to make intelligent decisions regarding dose and frequency of drug administration
    → It’s all about drug concentrations, how drugs move around the body and how they are excreted

Definitions

Therapeutics: Use of drugs used to cure, treat or prevent disease and in the alleviation of pain and suffering
Chemotherapy: Use of drugs to kill or weaken invading cells or organisms
Toxicology: Study of poisons and the treatment of poisoning

How Drugs Work

How drugs work

  • 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)
  • A small number of drugs interact with chemicals in the body but are not bound to a tissue component
    • Osmotic diuretics (mannitol) or osmotic laxatives (sorbitol) will bind to water in the kidney
    • Antacids will bind to acid in the stomach
      • Water and acid: targets

Origins of drugs

  1. Some drugs are synthesised within the body (eg. hormones, autacoids, neurotransmitters) this includes insulin, oestradiol, adrenaline, testosterone
  2. Most drugs are not synthesised within the body
  • Xenobiotics (Greek xenos ‘stranger’) eg. synthetic or semisynthetic drugs
  • Poisons
  • Toxins (poisons of biologic origin)

Physical nature of drugs

  • Solid
    • aspirin, paracetamol
  • Liquid
    • Ethanol
    • nitrous oxide
    • halothane and amyl nitrate
  • Gaseous
  • These factors often determine route of administration
  • Some liquid drugs are easily vaporised and can be inhaled
    • halothane and amyl nitrate

Drug sizes

  • Vary from v. small eg lithium (MW 7 daltons) Rx bipolar depression, to
  • V. Large eg tissue plasminogen activator (TPA) (a protein of MW 59,050 daltons) Rx fibrinolytic therapy
  • But most have masses of 100-1000 daltons, which alter the body’s function by interactions at the molecular level

Drug Nomenclature

Drug Nomenclature 1

  • Chemical name – N-acetyl-p-aminophenol (identifies chemical structure)
  • Generic name – Official name (lower case)
    eg. paracetamol (Australia, NZ & UK) but also acetaminophen (USA)
  • Trade name – proprietary/brand name (first letter capitalised)
    eg. Panadol®, Dymadon®, Paralgin®, Setamol®, Tylenol® etc

Drug Nomenclature 1

  • Generic name
  • Chemical name
  • Trade name

Drug Nomenclature 2

  • Generic drugs belonging to the same drug group (often) have same suffix
  • Phenothiazine antipsychotics ‘-azine’
    • Eg. chlorpromazine, prochlorperazine, trifluoperazine …
  • Most antianxiety drugs (benzodiazepines) ‘-azepam’
    • Eg. diazepam, temazepam, flunitrazepam, clonazepam …
  • Local Anaesthetics ‘-caine’
    • Eg. lignocaine, amethocaine, cinchocaine, cocaine …
  • ACE inhibitors ‘-pril’
    • Eg. enalapril, captopril, lisinopril, perindopril …
  • Most beta-receptor antagonists ‘-olol’
    • Eg. propranolol, labetolol, metoprolol …

Spelling is important!

One spelling mistake can destroy your life… a husband sent this to his wife: “I’m having a wonderful time, wish you were her”

QUININE ≠ QUINIDINE

MECLOBEMIDE ≠ METOCLOPRAMIDE

TRIMIPRAMINE ≠ TRIMETHOPRIM

Therapeutic Drug Market

The Therapeutic Drug Market 1

  • ~700 active ingredients
  • Multiple combinations eg:
    • PANADEINE® = codeine + paracetamol
    • TYLENOL SINUS® = paracetamol + pseudoephedrine
  • Delivery forms eg:
    • ADALAT OROS® = slow release nifedipine tablets (once daily)
    • ADALAT® = nifedipine tablets (twice daily)
  • Over 30,000 different medicinal drug products on Australian market

The Therapeutic Drug Market 2

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

The Therapeutic Drug Market 2

Guide to Poison Regulations

Guide to Poison Regulations

guide to poison

Guide to Poisons Regulations

TGA

slim collagen

Mechanisms of Drug Action

Mechanisms of Drug Action 1

  • Structure-activity relationships
    • Why do most drugs vary widely in 3-dimensional shape?
    • Because most interact with specific sites – receptors (drug targets)
    • Receptors are macromolecular structures in or on the cell surface with which drugs interact to produce effects
      • Change in structure can change activity of drug
      • The type of chemical interaction with the receptor can influence the action of the drug
      • A high degree of specificity can result in fewer toxic side-effects

Nicotinic acetylcholine receptor

nicotinic

Mechanisms of drug action 3

Targets for drug action 1

  • Receptors
    • Sensing elements for chemical communication (hormone, neurotransmitter, neurohormones etc)
    • Example: D2 dopamine
      • Agonist: dopamine
      • Antagonist: chlorpromazine

Targets for drug action 2

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

Targets for drug action 3

  • Enzymes
    • Drugs may be competitive (eg neostigmine – AChE enzyme) or non-competitive (eg aspirin – COX enzyme) inhibitors of enzymes
  • Pumps
    • Drugs may inhibit the action of carrier molecules – eg proton pump inhibitors (eg. omeprazole)

Drug effects not mediated by receptors 1

  • Binding to DNA (cross-linking or degradation)
    • Some antitumor alkylating agents (eg. cisplatin) and cytotoxic antibiotics (eg bleomycin)
  • Counterfeit substrates
    • The antihypertensive agent alpha-methyldopa substitutes for a normal substrate in the synthesis of NAd resulting in a less active end-product

Drug effects not mediated by receptors 2

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

Dose-response Relationships

Dose-response relationships 1

Four basic characteristics

Dose-response relationships 2

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

Dose-response relationships 3

  • Slope
    • Relationship between change in dose and change in effect
    • Sometimes called the Hill slope or Hill coefficient (nH)
    • For some drugs a small change in dose can change a therapeutic effect into a toxic effect (steep slope)

Dose-response relationships 4

Dose-response relationships 5

  • Maximal Effect (Emax)
    • Maximal efficacy – plateau in the DR-curve (eg maximal efficacy of buprenorphine is lower than morphine)
    • Thus buprenorphine never reaches full maximal efficacy – partial agonist
    • Dependent on intrinsic activity of the drug
    • 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

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

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

Dose-response relationships 6

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