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Introduction to Pharmacology

  • Ancient civilisations around the world have used plant extracts as medicines
  • Many of these are merely placebos.
  • Some of them are truly effective:
    • Willow bark (aspirin)
    • Opium (morphine)
  • In many cultures the administration of remedies was accompanied by magic or religious rituals (heightened placebo)
  • An appreciation that natural products themselves had the power to cure began to emerge.
  • Many poisonous mixtures were made.
  • Toxicology is within pharmacology (for poisons).
  • Doses of pharmaceuticals affect quality
    • Too low dose = no effect
    • To high dose = poison.
  • 16th and 17th centuries: physiology, chemistry and physics were developed greatly
  • Physiologists documented the way in which the body functioned and chemists began to develop the technologies which permitted extractions, purification and the synthesis of chemical substances from plants (active ingredients)
  • These trends began to merge as the discipline of…
  • Pharmacology: the study of the actions of drugs or chemical substances on physiological processes
  • A young discipline.
  • Drug: An agent that interacts with specific target molecules in the body and produces a physiological effect
    • Tea, panadol, caffeine, alcohol, antibiotics, medication, illegal drugs, everyday stuff
  • Atropa belladonna
    • Deadly nightshade is native to Europe, North Africa and West Asia.
    • Is considered a toxic plant.
    • Symptoms:
      • Dilated pupils
      • Tachycardia (increased heart rate)
      • Hallucinations
      • Blurred vision
      • Loss of balance
      • Confusion
      • Paralysis
    • Contains atropine, the prototype for all anticholinergic drugs and is a competitive inhibitor of Ach (acetylcholine)
    • Clinical uses: antidote to poisoning by anticholinesterases
    • Chemical warfare agent
    • Organophosphatases
  • Digitalis Purpurea
    • Purple foxglove is native to most of Europe
    • From the leaves of this plant the cardiac glycosides digitoxin and digoxin were isolated. These drugs are still used to treat heart failure. (Their effectiveness is under review).
    • The leaves, flowers and seeds of Digitalis are all poisonous and can be fatal if eaten.
    • At the right dosage, the digitalis toxin can cause the heart to beat more strongly preventing heart failure.
    • Wrong dose can cause cardiac arrest:
    • Symptoms of Digitalis poisoning include a low pulse rate, nausea, vomiting, cardiac arrest and finally death
  • Willow bark
    • Willow bark has been used throughout the centuries in China and Europe to reduce fever and inflammation.
    • Salicin is the active principal constituent.
    • This led to the synthesis of salicylic acid and acetyl salicylic acid (Aspirin)
    • New uses for aspirin continue to be found:
      • Cardioprotective: anti-coagulant
  • Pharmacodynamics: the mechanism by which drugs exert their effect on the body in order for a therapeutic action to occur [what the drug does to the body, and how]
    • Includes:
      • Drug-receptor interactions
      • General principal of drug action
      • Dose response
  • Pharmacokinetics: is what the body does to the drug [absorption, distribution, elimination, metabolism]

Pharmacodynamics

  • Two main types of drugs:
    • Drugs with activity at high concentrations
      • Little structural specificity
      • Cause general change (e.g. general anaesthetics)
      • Can cause many quite different chemical changes
      • Low potency
      • Increased side effects (due to high dosage)
  • Drugs acting at low concentrations
    • Structural specificity
    • Act by chemical rather than physical interaction
    • Bind to receptor and produce a response
    • High potency
    • Less side effects (in general), due to a lower dosage.

Agonists and antagonists

  • Agonists
    • Mimic endogenous ligands (substances found in the body).
    • They bind to a receptor and cause a secondary effect, which is a physiological response (affixing).
    • Needs
      • affinity for receptor
      • production of a response
    • Like turning a key in a lock to open a door
  • Antagonist
    • Binds to a receptor and prevents the action of an agonist
    • Can be endogenous or exogenous
    • Needs
      • Affinity for receptor
      • Doesn’t produce a response (just blocks the receptor)
    • Like jamming a stick in a lock to prevent a key from going in (prevents action of agonists)

Receptors

  • A receptor is the site at which a ligand (agonist or antagonist) can attach
  • The majority of drug receptors are proteins
  • Ligands may be neurotransmitters, hormones, or local factors
  • Activation of receptors by an agonist produces a response (effect)
  • They show:
    • Affinity (for ligands)
    • Selectivity (drug/ligand acts preferentially with only one receptor)
  • Types of receptor (in textbook)
    • Ligand-gated ion channels
      • Fastest
      • Nicotinic, gamma, and another one
      • Ionotrophic receptors
    • G protein-coupled receptors
      • Most common
      • Slow neurotransmitters: acetylcholine etc
    • Kinase-linked receptors
      • Insulin, cytokines etc
      • Respond to protein mediator
    • Nuclear receptors
      • Regulate genetic transcription
      • Steroid, thyroid and retinoic acid
  • Receptor action pathways:
    • Agonists
      • Direct (most common)
        • Ion channel opening/closing
      • Transduction mechanisms
        • Enzyme activation/inhibition
        • Ion channel modulation
        • DNA transcription
    • Antagonists
      • No effect.
      • Endogenous mediators blocked
  • Receptor sub-types
    • Receptors within a given family generally occur in several subtypes
    • Cholinergic: muscarinic; nicotinic
    • Adrenergic receptor sub-types include beta-2 (lungs – bronchodilation), beta-1 (heart – increased heart rate=tachycardia) and alpha-1 (blood vessels – vasoconstriction)
    • (Different organs have different types)
    • Development of drugs which interact ONLY with specific receptor sub-types has revolutionised pharmacology
    • Side effects = drug interferes with >1 type of receptor
    • E.g. don’t treat asthma with noradrenaline (beta-1 and beta-2 will make it worse!)
  • Side effects
    • Occur because receptors for a drug occur in several tissues, not just the target tissue
    • Because of non-specificity of drugs (act on several receptors)
    • Higher dose = more side effects
    • (Hence high potency is better)
    • Any drug at high dosage has side effects

Drug Regulations

  • Until the 1930s drugs did not need to be tested for safety or effectiveness
  • 1937 – drugs had to be tested for safety before they reach the market (you have to make sure it is safe… NOT that it works)
    • Due to “elixir of sulfonamide tragedy” – dissolved in ethylene glycol. 107 children died.
    • Clinical trials were not required
    • Led to animal testing
  • Thalidomide
    • Introduced as a safe sedative/hypnotic in the 1950s
    • Many pregnant women took it for morning sickness/nausea
    • Tested on male rats only; no teratogen testing
    • Turns out it was safe for male rats, but not for pregnant women
    • Was found to be a teratogen which causes birth defects
    • All drugs capable of crossing the placenta are capable of affecting the foetus
    • Effects: truncated limbs etc
    • Minimise taking drugs when pregnant
    • Drugs are most dangerous in the first trimester, when women might not know they’re pregnant
    • Animal/human correlation is not always strong.
  • Modern drug testing:
    • Nowadays, you have to test on males and females and on several species.
    • You have to show that the drug is EFFECTIVE (more effective than everything else out there) and SAFE
    • Done in phases:
      • Computer models
      • Animals
      • Phase 1 testing (healthy people)
      • Phase 2 testing (People trying it… volunteers)
      • Phase 3 testing (a larger sample size)
      • BUT: each of these phases is short term, so we can’t see long-term effects.
      • Thus, even now, we see drugs being taken off shelves after long-term effects are realised.

Drug-receptor interaction

  • Classical law of Pharmacology:
    • Assume that the effect of a drug is proportional to the fraction of receptors occupied
    • Assume that the maximal effects occur when all the receptors are occupied
  • Note: These assumptions are not always true
    • Some drugs are so effective that they don’t need to occupy all receptors to give a maximal effect
    • Receptors that are not needed are called “spare” receptors
  • Drug (D) + Receptor (R) <--> DR -> Effect
    • First arrow: reversible drug-receptor complex (at equilibrium, the forward rate equals the backward rate)
    • Second arrow: Only true if the drug is an agonist
  • Factors involved are:
    • Binding of drug to receptor (AFFINITY)
    • Response due to binding (EFFICACY)
  • Efficacy is the “measure of effectiveness of a drug in producing a maximum response”.
  • Dose-response
    • Theorem: the dose at which the drug has 50% of its max effect is equal to K_D
    • Proof: See http://www.chm.davidson.edu/erstevens/dose-response/dose.html
    • ED_50 is the effective dose at which 50% of the maximum effect is observed (used for humans and animals). EC_50 is the effective concentration at which the maximum effect is observed (used for cells/organs)
      • K_D is a binding constant and refers to receptor binding sites
      • Assumed: the effect is proportional to receptor occupancy and maximal effect occurs when all receptors are occupied (the classical law of Pharmacology)
      • Then (AND ONLY THEN) does K_D become the ED_50 (i.e. the dose that produces a 50% effect)
    • Log Dose-response curve
      • Taking the log of the dose axis (to get log dose) makes about 75% of the range into an approximately linear curve.
      • This makes it easier (and more accurate) to get the ED_50.
    • We use ED_50 because ED_100 approaches a limit, where the curve plateaus and ∆(dose) has a very small ∆(maximal effect) in the limit.
      • ED_50 is used to compare potencies of different drugs (i.e. to compare the efficacy of drugs)
        • Lower ED_50 means greater potency
  • Potency vs Efficacy
    • Potency:
      • A measure of the drug dosage needed to produce a particular therapeutic effect
      • It is determined by the strength of binding of a drug to a receptor or the receptor affinity for the drug AND the efficacy of the drug
      • Potency = f(efficacy, affinity)
    • Efficacy:
      • Is a measure of the effectiveness of a drug in producing a maximum response
      • Full agonists have high efficacy.
      • Antagonists have no efficacy
    • Antagonists w.r.t. Potency and Efficacy:
      • Can have potency
      • NEVER have efficacy (can never produce a response)
      • Note that agonists have both.
  • Dose-response measurement
    • Measurement of the response can be done, for example, in an organ bath, or in whole animals (e.g. recording blood pressure or some other variable)
    • Addition of a known dose of drug leads to a measurable response.
    • Thus a dose-response relationship can be built up
    • Within a given dose range, the higher the dose, the higher the response (allow for wash-out, to clear receptors, and recovery, so that the organ can perform again)
    • E.g. piece of a guinea pig gut in a bath. Add a drug that causes contractions. Force transducer measures sizes of contractions. Plot contraction strength versus time. Contraction will depend upon the dosage given. Know when you gave each dosage, and measure the heights of peaks to create a dose-response graph.
    • You will get a sigmoidal (log)dose-response curve.
    • 2 doses in a row with no change in response = maximum (beyond this, response will decrease).
    • Note: too high dose: curve goes down
      • Receptors desensitise
      • Nonspecific effects
      • Hence only measure 2 equal responses to determine maximum
    • Use maximum to plot response as a percentage of maximum response.
    • All (log)dose-response curves are sigmoidal. The measurement includes all effects downstream of the particular drug-receptor interaction are measured.
    • We’re measuring the effect of an agonist on a response (e.g. BP, contraction/relaxation of muscle).
    • Not all the drug is absorbed by the receptor. Some of it is lost.
    • Hence we don’t know how much of it is bound to the receptors… we only know the dose.
    • Drug concentration at the receptor site is not known e.g. Ach may be metabolised by AchE
    • Hence we cannot use dose-response curves to calculate the affinity of a drug to a particular receptor.