II. Mechanism: Cellular Level
- Drugs act at receptors (Proteins or Glycoproteins) present on cell surfaces, organelles and in cytoplasm
- Drug response is related to a drug's affinity for receptor sites and the drugs efficacy
- Drugs must bind enough receptor sites to overcome a lower threshold to exert their effect
- Receptor sites are limited and there is a threshold at which no additional receptors are available for drug binding
- Drug response is proportional to number of receptors bound
- Not all receptors need to be bound for maximal effect
- Endogenous Ligands
- Endogenous chemicals that exert their physiologic cellular effects by binding receptor sites
- Drugs trigger various actions on binding to receptor sites
- Ion channel state change (open or closed)
- Second messenger activation (e.g. cAMP, Calcium, Inositol), triggering a cascade of further reactions
- Cell function is promoted or inhibited (e.g. specific Protein synthesis inhibition, increased specific DNA Transcription)
- Drug Affinity
- Affinity is the drug's binding strength to their receptor sites
- Drugs reach an equilibrium of receptor bound and unbound drug
- Higher affinity drugs have a higher ratio of receptor bound drug (more receptor bound drug than unbound drug)
- Lower affinity drugs have a lower ratio of receptor bound drug
- Dissociation Constant (Kd)
- Drug concentration (in moles) to reach 50% of receptor sites bound
- Kd reflects Drug Affinity, in that high affinity drugs will require lower drug concentrations (lower Kd)
- Agonists
- Agonist drugs bind cell receptors, triggering an effect on a cellular function
- Strong Agonists have maximal effects even at low concentration
- Weak Agonists require higher concentrations, and partial Agonists do not reach maximal activity even at 100% receptor binding
- Antagonists
- Antagonists block Agonist activity
- Competitive Antagonists
- Reversibly bind Agonist receptor sites, preventing Agonist binding
- Agonists, at higher concentration (higher Kd), may displace the Antagonists and reach target activity
- Examples: Naloxone at Opioid receptors, Flumazenil at Benzodiazepine receptors
- Noncompetitive Antagonists
- Irreversible Antagonists
- Permanently bind Agonist receptor sites, preventing future Agonist binding
- Agonists, reagardless of dose, can not overcome irreversible Antagonist inhibition (as with Noncompetitive Antagonists)
- Physiologic Antagonists
- Two different Agonists have opposing activity, each countering the other's function
- Neutralization
- Drugs that bind each other, inactivated both drugs
III. Mechanism: Individual and Population Effects
- Efficacy
- Maximal effect a drug is able to achieve
- Used to compare effect across Drug Classes (e.g. Analgesic effect of Ibuprofen or Acetaminophen versus Opioids)
- Drug effects may be plotted against dose (graded dose response curve) to identify an optimal drug dose
- Potency
- Drug dose required to achieve 50% of maximal effect
- Used to compare agents within a Drug Class (e.g. Morphine Equivalent)
- Toxicity and Safety
- Effective Concentration 50% (EC50)
- Drug concentration needed to reach target effect in 50% of a population reaching that drug level
- Lethal Dose 50% (LD50)
- Drug concentration high enough to kill 50% of a population reaching that drug level
- Therapeutic Index (LD50/ED50)
- Reflects drug safety in a ratio of lethal dose to therapeutic dose
- Margin of Safety
- Margin of safety reflects the margin between therapeutic doses and lethal doses
- Effective Concentration 50% (EC50)
IV. Resources
- Receptor Agonist (Wikipedia)
- Receptor Antagonist (Wikipedia)
V. References
- Olson (2020) Pharmacology, Medmaster, Miami, p. 1-12
Images: Related links to external sites (from Bing)
Related Studies
| Definition (MSH) | Used with chemicals, drugs, and endogenous substances to indicate substances or agents which counteract their biological effects by any mechanism. |
| Definition (CSP) | antagonist is any agent which blocks, inhibits, or attenuates the pharmacological action of another agent; can be indexed with other agent or receptor terms to cover specific antagonist types when a specific precoordinated term is not available. |
| Concepts | Chemical Viewed Functionally (T120) |
| MSH | Q000037 |
| English | ANTAG, AI, antagonists & inhibitors, inhibitor/antagonist |
Ontology: Lethal Dose 50 (C0023378)
| Definition (NCI) | The dose of a chemical or biologic preparation (e.g., a bacterial exotoxin or a suspension of bacteria) that is likely to cause death in 50% of the animals being tested; it varies in relation to the type of animal and the route of administration; (the absolute lethal dose is LD100, and minimal lethal dose is LD05). |
| Definition (MSH) | The dose amount of poisonous or toxic substance or dose of ionizing radiation required to kill 50% of the tested population. |
| Concepts | Quantitative Concept (T081) |
| MSH | D007928 |
| SnomedCT | 409645006 |
| English | Dose 50, Lethal, LD50, Lethal Dose 50, LD 50, LC-50, LC50, median lethal dose, ld50, lethal dose 50, median lethal dose (LD50), Median Lethal Dose, LD 50-Lethal dose 50, Lethal dose 50 (observable entity), Lethal dose 50, LD-50, Lethal Dose - 50% |
| Swedish | Letal dos 50 |
| Czech | letální dávka 50, střední smrtelná dávka, LD50, střední letální dávka |
| Finnish | LD50 |
| French | DL50, Dose létale à 50 %, DL 50, Dose létale 50 |
| Russian | LETAL'NAIA DOZA 50, ЛЕТАЛЬНАЯ ДОЗА 50 |
| Italian | LD50, Dose Letale 50 |
| German | LD 50, LD50, Letaldosis 50 |
| Polish | Dawka śmiertelna 50, Dawka letalna 50, LD50 |
| Japanese | 50パーセント致死量, 薬物50%致死量, 半致死量, 致死量50% |
| Norwegian | Dødelig dose 50, LD50, Letal dose 50 |
| Spanish | Dosis Letal 50, dosis letal 50 (entidad observable), dosis letal 50, DL50, Dosificación Letal Mediana |
| Portuguese | Dose Letal 50, LD50, Dose Letal Mediana |
| Dutch | DL50, Dosis letalis media, LD50 |
Ontology: Pharmacology (C0031330)
| Definition (NCI_NCI-GLOSS) | The study of the origin, chemistry, and uses of drugs and their effects on the body. |
| Definition (NCI_CDISC) | Science that deals with the characteristics, effects, and uses of drugs and their interactions with living organisms. |
| Definition (NCI) | The study of pharmacologic agents. This includes the preparation, compounding, and dispensing of drugs, as well as the characteristics and properties of drugs, their effects on the body, and how they are metabolized and eliminated from the body. |
| Definition (MSH) | The study of the origin, nature, properties, and actions of drugs and their effects on living organisms. |
| Definition (PSY) | The study of the chemistry, actions, and effects of drugs on living organisms or tissues. Used for intended effects of drugs; for adverse or undesired effects of drugs, use SIDE EFFECTS (DRUG). For the use of drugs in a treatment capacity, use DRUG THERAPY. |
| Definition (CSP) | biological effects of drugs in living organisms or tissues; use this term mainly for intended, desired effects; for harmful or undesired effects, see DRUG ADVERSE EFFECT or TOXICOLOGY. |
| Concepts | Biomedical Occupation or Discipline (T091) |
| MSH | D010600 |
| English | Pharmacology, PHARMACOL, Pharmacologic, Pharmacological, pharmacology (field), pharmacology, Pharmacologies, P |
| Swedish | Farmakologi |
| Czech | farmakologie |
| Finnish | Farmakologia |
| Russian | FARMAKOLOGIIA, ФАРМАКОЛОГИЯ |
| Croatian | FARMAKOLOGIJA |
| Polish | Farmakologia |
| Norwegian | Farmakologi |
| French | Pharmacologie |
| German | Arzneimittelkunde, Pharmakologie |
| Italian | Farmacologia |
| Dutch | Farmacologie |
| Portuguese | Farmacologia |
| Spanish | Farmacología |
Ontology: agonists (C0243192)
| Definition (MSH) | Used with chemicals, drugs, and endogenous substances to indicate substances or agents that have affinity for a receptor and intrinsic activity at that receptor. (From Textbook of Pharmacology, 1991, p.16) |
| Concepts | Pharmacologic Substance (T121) |
| MSH | Q000819 |
| English | AGON, AG, agonists |
Ontology: Competitive inhibition (C0301626)
| Concepts | Molecular Function (T044) |
| SnomedCT | 87719002 |
| English | Competitive inhibition, function, Competitive inhibition, Competitive inhibition, function (observable entity), Competitive inhibition (function) |
| Spanish | inhibición competitiva (entidad observable), inhibición competitiva (función), inhibición competitiva, inhibición selectiva |
Ontology: Noncompetitive inhibition (C0301627)
| Concepts | Molecular Function (T044) |
| SnomedCT | 63582009 |
| English | Noncompetitive inhibition, function, noncompetitive inhibition, Noncompetitive inhibition, Noncompetitive inhibition, function (observable entity), Noncompetitive inhibition (function) |
| Spanish | inhibición no competitiva (entidad observable), inhibición no competitiva (función), inhibición no competitiva |
Ontology: receptor sensitivity (C0597362)
| Definition (CSP) | parameter which is increased by agonists and decreased by antagonists, usually measured as the effective dose of ligand for binding or physiological endpoint. |
| Concepts | Functional Concept (T169) |
| English | receptor sensitivity |
Ontology: effective drug concentration (C0678791)
| Concepts | Quantitative Concept (T081) |
| English | effective drug concentration |
Ontology: drug potency (C0678792)
| Concepts | Biologic Function (T038) |
| English | drug potency, drugs potency |
Ontology: therapeutic index (C0678793)
| Definition (NCI) | The difference between the concentration at which clinical benefit (cancer cell killing) is seen and that at which toxicity to normal tissues occurs. The larger the therapeutic index the safer a drug is. |
| Concepts | Quantitative Concept (T081) |
| English | index therapeutic, therapeutic index, Therapeutic Index |
