Molecular Pharmacology and Local Hormones

Molecular Pharmacology

• Molecular pharmacology explores drug interactions at the molecular level, leading to the development of new medications.
• Key aspects include: binding affinity, intrinsic activity, efficacy, potency, signal transduction, drug metabolism, pharmacogenetics, pharmacokinetics, and pharmacodynamics.
• Drugs binding to receptors initiate signal transduction by activating second messengers, which activate kinases that affect the genome and proteins involved in biological function.

Local Hormones

• Local hormones, like thyroxine and insulin, are chemical messengers that facilitate communication between cells.
• To be classified as a local hormone, a substance should be released from local cells in sufficient amounts to produce a biological action on target cells within an appropriate timeframe.
• Applying an authentic sample of the mediator should reproduce the original biological effect, and interference with its synthesis, release, or action should ablate or modulate the original biological response.

Histamine

• Dale and his colleagues discovered that a local anaphylactic reaction, a type I hypersensitivity reaction, is caused by antigen-antibody reactions in sensitized tissue.
• Histamine was found to mimic this effect both in vitro and in vivo, confirming its role as a mediator in anaphylaxis.

Synthesis and Storage of Histamine

• Histamine is a basic amine synthesized from histidine by histidine decarboxylase.
• It is found in most tissues but is present in high concentrations in tissues exposed to the external environment (lungs, skin, and gastrointestinal tract).
• Histamine affects the ileum, though less prominently in humans than in guinea pigs.
• It reduces airflow in the first phase of bronchial asthma, but H1 antagonists are not effective in treating the human disease.
• H4 receptors may play a more significant role in mediating these resistant histamine effects.

Cardiovascular Effects of Histamine

• Histamine dilates blood vessels and increases the permeability of postcapillary venules by activating H1 receptors.
• This effect is partly endothelium-dependent in some vascular beds.
• It increases heart rate and output, primarily by activating cardiac H2 receptors.

Gastric Secretion and Histamine

• Histamine stimulates gastric acid secretion by acting on H2 receptors.
• This is the most significant action of histamine, as it is involved in the pathogenesis of peptic ulcers.

Effects of Histamine on the Skin

• Intradermal injection of histamine causes skin reddening and a weal with a surrounding flare, mimicking the triple response to skin scratching.
• Reddening results from vasodilation of small arterioles and precapillary sphincters, while the weal reflects increased permeability of postcapillary venules.
• These effects are primarily mediated by H1 receptor activation.
• The flare is an axon reflex, where sensory nerve fiber stimulation triggers antidromic impulses, releasing vasodilators like calcitonin gene-related peptide.
• Histamine causes intense itching when injected into the skin or applied to a blister base, stimulating sensory nerve endings through an H1-dependent mechanism.
• H1 antagonists are used to control itch caused by allergic reactions and insect bites.

Role of Histamine in Inflammation

• Even though histamine release can replicate many inflammatory signs and symptoms, H1 antagonists are not very effective in treating the acute inflammatory response itself.
• This is because other mediators are more important in acute inflammation.
• Histamine is, however, crucial in type I hypersensitivity reactions like allergic rhinitis and urticaria.
• Histamine also affects B and T cells, modulating the acquired immune response.

Future Research on Histamine and Inflammation

• The emerging field of H4 receptor pharmacology holds promise for deepening our understanding of histamine's role in inflammation.

Eicosanoids: General Remarks

• Eicosanoids are mediators synthesized from specific fatty acid precursors.
• They play a role in regulating many physiological processes, are major mediators and modulators of the inflammatory response, and are significant targets for drug action.
• The study of eicosanoids began in the 1930s, when a lipid substance in semen, originating from the prostate gland, was shown to contract uterine smooth muscle.
• This substance, named prostaglandin, was later found to be a family of compounds synthesized by virtually all cells from 20-carbon unsaturated fatty acid precursors.

Structure and Biosynthesis of Eicosanoids

• The main eicosanoid precursor is arachidonic acid (5,8,11,14-eicosatetraenoic acid), a 20-carbon unsaturated fatty acid with four double bonds.
• The primary groups of eicosanoids include prostaglandins, thromboxanes, leukotrienes, lipoxins, and resolvins.
• Prostanoids encompass only prostaglandins and thromboxanes.

Arachidonic Acid Release and Eicosanoid Synthesis

• Arachidonic acid is usually a component of phospholipids in most cell types, with low levels of free acid.
• Eicosanoids are not stored in cells but are synthesized and released immediately.
• The initial and rate-limiting step in eicosanoid synthesis is the release of arachidonate, typically catalyzed by phospholipase A2.
• An alternative multi-step process involving phospholipases C or D in conjunction with diacylglycerol lipase can also occur.
• Several types of PLA2 exist, with cytosolic PLA2 (cPLA2) being particularly important due to its regulation.
• cPLA2 generates not only arachidonic acid but also lysoglyceryl-phosphorylcholine (lyso-PAF), the precursor of platelet-activating factor (PAF).

Activation of Cytosolic PLA2

• Cytosolic PLA2 is activated by phosphorylation, which can be triggered by signal transduction systems activated by various stimuli, including:
  • Thrombin action on platelets
  • C5a on neutrophils
  • Bradykinin on fibroblasts
  • Antigen-antibody reactions on mast cells
• General cell damage also activates cPLA2.

Metabolism of Free Arachidonic Acid

• Free arachidonic acid is metabolized separately or jointly by several pathways, including:
  • Fatty acid cyclo-oxygenase (COX)
  • Lipoxygenases

Prostanoids: COX Enzymes

• Two main COX isoforms exist, COX-1 and COX-2, which are highly homologous but regulated differently in a tissue-specific manner.
• COX-1 is present in most cells as a constitutive enzyme, producing prostanoids that primarily act as homeostatic regulators.
• COX-2 is not normally present in most tissues (except for the CNS and renal tissue) but is strongly induced by inflammatory stimuli, making it a more relevant target for anti-inflammatory drugs.

Prostanoid Synthesis Pathway

• Both COX enzymes catalyze the incorporation of two oxygen molecules into two unsaturated double bonds in each arachidonate molecule, forming unstable endoperoxides: prostaglandin (PG)G2 and PGH2.
• PGG2 and PGH2 are quickly transformed in a tissue-specific manner by endoperoxide isomerase or synthase enzymes into key bioactive products: PGE2, PGI2 (prostacyclin), PGD2, PGF2α, and thromboxane (TX)A2.
• The mix of eicosanoids produced varies between cell types based on the specific endoperoxide isomerases or synthases present.

Yin-Yang Effect of Prostanoids in Inflammation

• Prostanoids exert opposing effects in inflammation, stimulating some responses and diminishing others.
• Their most significant actions include:
  • Vasodilation
  • Increased vascular permeability
  • Sensitization of afferent C fibers to pain stimuli
  • Pyrogenicity (inducing fever)

Effects of Prostanoids on Inflammation

• PGE2, PGI2, and PGD2 are potent vasodilators and synergize with other inflammatory vasodilators.
• This combined dilator action on precapillary arterioles contributes to the redness and increased blood flow in areas of acute inflammation.
• Prostanoids do not directly increase postcapillary venule permeability but potentiate the effects of histamine and bradykinin on vascular leakage.
• They do not directly cause pain but sensitize afferent C fibers to the effects of bradykinin and other noxious stimuli.
• The anti-inflammatory and analgesic effects of aspirin-like drugs (NSAIDs) stem primarily from their ability to block these actions.
• Prostaglandins of the E series are pyrogenic, with high concentrations found in cerebrospinal fluid during infection, and the increase in temperature (attributed to cytokines) is mediated by PGE2 release.
• NSAIDs possess antipyretic actions by inhibiting PGE2 synthesis in the hypothalamus.
• Some prostaglandins have anti-inflammatory effects that are crucial during the resolution phase of inflammation, such as PGE2, which decreases lysosomal enzyme release, toxic oxygen metabolite generation from neutrophils, and histamine release from mast cells.

This quiz examines the principles of molecular pharmacology and the role of local hormones in cell communication. Key topics include drug interactions, receptor binding, signal transduction, and the biological effects of local hormones like thyroxine and insulin. Test your knowledge on these essential concepts in pharmacology.