Immunology for Dummies

Just kidding it's Molecular and Cellular Immunology by A. Abbas.

I read a book on molecular and cellular immunology one holiday and it was such a fantastic read. I definitely developed an interest in it.

The epidermis is highly keratinised to prevent systemic absorption. Drugs that absorb systemically in concentrations high enough to exert an effect are quite rare, and the epidermis does quite a good job as a barrier.

Because the implants aren't in your skin. They're subcutaneous, which lies underneath the dermal layers. People who are overweight have greater subcutaneous fat content, so it might not be as visible.

Drugs when applied topically can absorb systemically. For products like Aspercreme, however, they only need localised effect, so they don't need to get into systemic circulation in appreciable amounts. They just need to cross through the skin and into the local area (i.e., muscle). They passively absorb through the skin via two ways:

1. transcellularly, where they cross through the cell membrane and through the skin cells, or

2. paracellularly, where they cross in junctions between cells.

For the latter, there are excipients like ethanol or glycerin (which is found in Aspercreme) that can help open up these junctions to facilitate paracellular diffusion through the epidermis. Thick ointment formulations also help in the same way. The active drug, salicylate, won't help with nerve pain but it can provide a localised anti-inflammatory effect -- the advantage with localised effect is the drug compound itself doesn't need to be so potent. Nonetheless, the active drug still has to have some favourable physicochemical properties -- it has to be highly lipophilic, but still sufficiently hydrophilic, to cross transcellularly, and it needs to have a small molecular weight to fit through functions, etc. The use of a triethanolamine salt for salicylic acid also helps, as it helps to stabilise the drug (think of it as the rocket that propels the shuttle before detaching). Triethanolamine salicylate has been shown to perfuse tissue.

Interestingly, methylsalicylate is another form of salicylic acid used in topical preparation. There are enzymes called esterases in the skin that will cleave up molecules by their ester linkages. Methylsalicylate contains an ester group that gets hydrolysed by these esterases when absorbing, turning into the active salicylic acid.

The 4 ringed structure also helps improve lipophilicity of the molecule, which is especially important because steroids need to cross the membrane into the cytoplasm to bind to nuclear receptors. They also help stabilize the molecule into a planar structure to facilitate membrane penetration.

Other ligands of nuclear receptors are produced from Acetyl CoA, like cholecalciferol (vitamin D3) and retinoids. As with nuclear receptors, steroids have a long genetic history. It seems estrogen receptors were among the first steroid receptors to appear, and mutations brought about more diverse roles for steroids.

Here is a nice article I found