Principles of Pharmacology Flashcards

Principles of Pharmacology: Concentration-Response Curve

Learning Outcomes

• Draw typical "concentration vs response" and "log concentration vs response" curves with labeled axes.
• List common responses to drugs and explain how they are measured.
• Distinguish between in vitro, in vivo, and ex vivo measurements.
• Explain the term "EC50" and how it is measured.
• Distinguish between the terms "potency", "potency ratio", and "relative potency".
• Explain the term "Therapeutic Index" and how it is measured.

Introduction

• "All substances are poisons: There is none which is not a poison. The right dose differentiates a poison and a remedy." - Paracelsus (1493-1541)

The Concentration-Response Relationship

• Drug effects are quantified by studying the relationship between drug concentration (or dose) and the response produced by the drug.
• This relationship is described by concentration-response curves.
  • Drug concentration vs. response: rectangular hyperbola.
  • Log drug concentration vs. response: symmetrical sigmoid.

Types of Pharmacological Experiments

• In vitro: Drug effects are studied on a piece of tissue dissected from an animal (or human) and kept alive outside the body.
  • Most common type of experiment, including experiments on cells grown in tissue culture.
  • Responses measured: changes in muscle tension, enzyme activity, or hormone/neurotransmitter secretion.
  • Example: Effects of nicotine (NIC) on noradrenaline release from human cerebral cortex slices.
• In vivo: Drug effects are studied in the living animal (or human).
  • Includes clinical trials, tightly regulated.
  • Responses measured: increase in blood pressure, reduction in pain threshold, reduction in allergen-induced bronchoconstriction.
• Ex vivo: A tissue or organ is removed from an animal treated with a drug, and the drug's effects on organ function are tested in vitro.
  • Tightly regulated.
  • Examples: Experiments to see whether long-term drug treatment induces liver damage or alters brain biochemistry.

Concentration Units

• For in vitro experiments, concentrations are expressed in Moles per litre i.e. Molar (M).
  • 1 Mole of a drug contains 6.02 \times 10^{23} drug molecules which weighs the molecular mass, in grams.
  • A 1 Molar solution contains 1 Mole of a drug dissolved in 1 litre of solvent.
  • A 1 Molar solution of drug “X” will contain the same number of drug molecules as a 1 Molar solution of drug “Y”.

Drug Concentrations

• Most clinically useful drugs act at concentrations in the range 1 \times 10^{-6}M to 1 \times 10^{-12}M.
• Pharmacologists use prefixes: milli (m) for 10^{-3}, micro ((\mu)m) for 10^{-6}, and nano (n) for 10^{-9}.
• A 1 micromolar ((\mu)M) solution is the same as a 1 \times 10^{-6} M solution.

Scientific Notation Examples

• 0.1 nM = 0.1 \times 10^{-9} M = 1.0 \times 10^{-10} M
• 0.5 mM = 0.5 \times 10^{-3} M = 5.0 \times 10^{-4} M
• 10 mM = 10 \times 10^{-3} M = 1.0 \times 10^{-2} M
• 30 nM = 30 \times 10^{-9} M = 3.0 \times 10^{-8} M

Constructing a Concentration-Response Curve

• Simplified organ bath apparatus is used.
• Cumulative concentration-response curve: Drug is not washed out between different concentrations.

Doses In Vivo

• Molar concentrations cannot be used for in vivo experiments because the volume of the solvent (e.g., blood) is not known.
• Drug doses are expressed as weight of drug per weight of animal, e.g., 1 mg per kg (1 mgkg^{-1}).
• This allows an approximate extrapolation of the dose from a 20 gram mouse to a 70 kg human.

Maximum Effect (Emax)

• Indicates the maximum response (effect) the drug can produce.
• Increasing the concentration of the drug produces no greater effect.

EC50

• Tells us the position of the curve on the concentration axis.
• Defined as "the Molar concentration of a drug that produces 50% of the maximum response for that drug".
• Sometimes other percentage values are used, e.g., EC90 or EC20.

Potency

• A commonly used term to describe the concentration at which a drug is effective.
• A potent drug is effective in very small amounts.
• Can be quantified using the EC50.
• The lower the EC50, the more potent the drug.
• Comparing EC50 values for two drugs with the same action allows us to calculate their relative potencies, described by the potency ratio (M).
• Often we will be comparing a new drug (the ‘test’ drug) with a drug that is already available (the ‘standard’ drug).
• M = \frac{EC50(test)}{EC50(standard)} or \log M = \log EC50(test) - \log EC50(standard)

Potency Ratio

• If drug ‘A’ is our standard drug, then M = 20. What if ‘B’ were the standard?
• Note that a value of M less than 1.0 means that the test drug is more potent than the standard

Therapeutic Index

• The ratio between the toxic dose of a drug and the dose producing the desired therapeutic effect.
• The higher the therapeutic index, the less chance of the drug producing toxic side-effects in therapeutic use.
• An important concept, but actually very difficult to quantify.
• Sometimes defined as: Therapeutic index = \frac{LD50}{ED50}
  • LD50 = lethal dose in 50% of the population
  • ED50 = Effective dose in 50% of the population
• No longer used for several reasons:
  • It is a meaningless definition from a clinical perspective. Death is a rather extreme side effect!
  • Ethically, it is no longer defensible to obtain LD50 values in animals.
• In humans, therapeutic index can be calculated as \frac{TD50}{ED50}
  • Where TD50 is the “toxic” dose in 50% of the population, where look for the dose that produces some sign of toxicity e.g. causes nausea
• But even then, we must treat it with caution because:
  • There is a wide person-to-person variation in both toxic and beneficial effects of drugs.
  • A drug can have different ED50 values depending on the condition being treated; e.g., the effective dose of ibuprofen for treating headache is lower than that for treating arthritis.
• So, the concept of the therapeutic index is an important one, but it is not easy to derive a single value for any given drug.