Browsing Pathways

Atropine is a muscarinic antagonist that is used to treat atrioventricular heart block, bradycardia and for organophosphate anticholinesterase/pesticides poisoning. Atropine is an alkaloid originating from the plant Atropa Betalldonna and can be found in some other plants. Naturally it is a racemic mixture of equal parts d-hyoscyamine and l-hyoscyamine. Althought is is classified as a muscarinic antagonist it is more commonly classified as an anti-cholinergic or an antiparasympathetic drug. Sufficient doses of atropine will inhibit carious types of reflex vagal cardiac asystole as well as bradycardia and asystole produced by choline esters, anticholinesterase agents, parasympathomimetic drugs or cardiac arrest produced by vagus nerve stimulation. It is also possible that atropine may lessen the degree of partial heart block if vagal activity is the etiological (causing or contributing) factor. In clinical dose administrations it counteracts the peripheral dilation and low blood pressure produced by choline esters. If it given by itself it does not exert a large or even effect on blood vessels and/or blood pressure. Atropine binds to and inhibits muscarinic acetylcholine receptors which produces a large range of anticholinergic effects. In the heart (the main use for atropine) muscarinic 2 receptors (M2) receptors reside in the SA and VA node in the atria and ventricles respectively are affected by atropine. Atropine inhibits the binding of acetylcholine and other choline esters causing an inhibitory effect increasing the concentration of cAMP produced. Higher cAMP concentration promote action potentials in the cells as well as increasing calcium influx from membrane channels. All of these downstream effects increase heart rate and blood pressure therefore abolishing bradycardia and low blood pressure. Atropine is administered in an intravenous, endotracheal, intramuscular, or intramedullary injection or subcutaneously.

Oxytocin is a recombinant hormone used to induce or strengthen uterine contractions in pregnant women to aid in labor and delivery or to control postpartum bleeding. Administration of exogenous oxytocin is indicated in the antepartum period to initiate or improve uterine contractions for vaginal delivery in situations where there is fetal or maternal concern. Oxytocin is produced in the hypothalamus and is secreted from the paraventricular nucleus to the posterior pituitary where it is stored. It is then released in pulses during childbirth to induce uterine contractions. The concentration of oxytocin receptors on the myometrium increases significantly during pregnancy and reaches a peak in early labor. Activation of the oxytocin receptor on the myometrial cell leading to activation of the Gq signaling cascade. Gq signaling cascade activates phospholipase C which produces inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate. IP3 activates IP3 receptor on the sarcoplasmic reticulum, leading to calcium moving from the sarcoplasmic reticulum to the cytosol, increasing cytosolic calcium concentration. Calcium also enters the cell through the L-type calcium channel on the cell membrane, which is activated downstream after activation of the oxytocin receptor. Calcium binds to calmodulin activating myosin light chain kinase, leading to phosphorylation of myosin light chain. Phosphorylated myosin light chain binds to actin to form an actinomyosin complex which causes smooth muscle contraction. DAG activates protein kinase C (PKC). PKC activates mitogen-activated protein kinase (MAPK), which activates phospholipase A2, leading to prostaglandin synthesis. Prostaglandins like prostaglandin E2 stimulates uterine muscle contraction. PKC may also promote muscle contraction by phosphorylating CPI-17, the regulatory subunit of myosin light chain phosphatase. Additionally, the transforming protein rhoA is activated with activation of the oxytocin receptor. Transforming protein rhoA activates rho-associated protein kinase. Rho-associated protein kinase also phosphorylates CPI-17. Phosphorylation of myosin light chain phosphatase inactivates it, preventing this enzyme from converting myosin-LC-P to myosin-LC. Myosin-LC causes smooth muscle relaxation. Therefore, by inhibiting myosin light chain phosphatase, the concentration of myosin-LC-P increases and the concentration of myosin-LC decreases, further promoting uterine muscle contraction.

Tacrolimus is a calcineurin inhibitor that is most often used as an immunosuppressive drug for organ transplant patients in order to reduce the activity of the immune system lowering the risk of organ rejection. Tacrolimus is administered orally or through a topical treatment which allows the drug to be absorbed into the bloodstream. Tacrolimus enters T-cells through the ABC or SLC transporters like ABCB1 and works by forming a complex with FKBP12 with inhibits calcineurin with leads to reduced T cell signal transduction and IL-2 transcription. IL-2 is an important mediator for T-cell activation, differentiation and migration which is through mTOR signalling. Lower IL-2 production and signal transduction leads to less activated immune cells leading to a weaker immune system. Tacrolimus also inhibits the transcription for genes encoding IL-3,4,5, GM-SCF, and TNF as well which are also involved in T cell activation. Organ transplant patients take tacrolimus after allogenic organ transplant for liver, kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea and limb transplant.

Sildenafil is a phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. Sexual stimulation causes the release of nitric oxide (NO) from nerves and endothelial cells into the penis. NO activates the enzyme guanylate cyclase.2 The activation of this enzyme is followed by the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP), activating a cascade of protein kinase-dependent phosphorylation events in smooth muscles, ultimately resulting in the dephosphorylation of myosin light chains within smooth muscle. This activity causes the relaxation of smooth muscle within blood vessels, resulting in the desired vasodilatory effect. Phosphodiesterase-5 breaks down cGMP to GMP. Sildenafil inhibits phosphodiesterase-5, preventing the breakdown of cGMP. This increases the concentration of cGMP, increasing the vasodilation and improving blood flow leading to penile erection.

Nortriptyline is a tricyclic antidepressant used to treat major depression. Nortriptyline hydrochloride, the active metabolite of amitriptyline, is a tricyclic antidepressant (TCA). This drug is also used off-label and it includes the treatment of chronic pain, myofascial pain, neuralgia, and irritable bowel syndrome. Nortriptyline exerts antidepressant functions by inhibiting the reuptake of serotonin and norepinephrine in the neurons. It is possible by its binding to the sodium-dependent noradrenaline transporter and to the sodium-dependent serotonin transporter. This drug displays a more selective reuptake inhibition for noradrenaline, which may explain increased symptom improvement after nortriptyline therapy. As with other tricyclics, nortriptyline displays an affinity for other receptors including mACh receptors, histamine receptors, and 5-HT receptors, in addition to other receptors. This drug is administered as a tablet or as an oral solution.

Bromfenac is a nonsteroidal anti-inflammatory drug (NSAID) for ophthalmic use. Non-ophthalmic formulations of bromfenac were withdrawn in the US in 1998 due to cases of severe liver toxicity. The mechanism of its action is due to the ability of bromfenac to block prostaglandin synthesis by inhibiting cyclooxygenase 1 and 2 with selectivity for COX-2 over COX-1. Prostaglandins are mediators of certain kinds of intraocular inflammation. In studies performed in animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilation, increased vascular permeability, leukocytosis, and increased intraocular pressure.

Magnesium sulfate is a drug used to treat convulsions during pregnancy, nephritis in children, magnesium deficiency, and tetany. It can be found under the brand names Concept Ob, Suprep Bowel Prep Kit, and Tis-U-sol. A small colorless crystal used as an anticonvulsant, a cathartic, and an electrolyte replenisher in the treatment of pre-eclampsia and eclampsia. It causes direct inhibition of action potentials in myometrial muscle cells. Excitation and contraction are uncoupled, which decreases the frequency and force of contractions. Magnesium is the second most plentiful cation of the intracellular fluids. It is essential for the activity of many enzyme systems and plays an important role with regard to neurochemical transmission and muscular excitability. Magnesium sulfate reduces striated muscle contractions and blocks peripheral neuromuscular transmission by reducing acetylcholine release at the myoneural junction. Additionally, Magnesium inhibits Ca2+ influx through dihydropyridine-sensitive, voltage-dependent channels. This accounts for much of its relaxant action on vascular smooth muscle. Possible side effects may include skin rash, itching, confusion, and drowsiness.

Milnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI). It is used in the management of fibromyalgia, major depressive disorder, generalized anxiety disorder, chronic musculoskeletal pain and diabetic peripheral neuropathy. It is generally believed that 5HT and NE participate in the modulation of endogenous analgesic mechanisms by way of the descending inhibitory pain pathways in the brain and spinal cord. Although the specific mechanism of action remains unclear, some studies have proposed that low levels of 5HT may be associated with increased sensitivity to pain - a condition that could subsequently be improved by milnacipran's capacity to enhance the presence of 5HT by inhibiting its reuptake via serotonin transporters at synaptic clefts. Furthermore, in the CNS it is also generally believed that NE released from descending pathways can mitigate pain sensations via eliciting inhibitory effects on alpha-2A-adrenoceptors on central terminals of primary afferent nociceptors, by direct alpha-2-adrenergic action on pain-relay neurons, and by alpha-1-adrenoceptor-mediated activation of inhibitory interneurons. Such NE pain mitigation is consequently also enhanced by milnacipran's ability to enhance the presence of NE by inhibiting its reuptake via norepinephrine transporters at synaptic clefts

Clemastine is a first-generation ethanolamine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. H1-antihistamines act on H1 receptors in T-cells to inhibit the immune response, in blood vessels to constrict dilated blood vessels, and in smooth muscles of lungs and intestines to relax those muscles. Allergies causes blood vessel dilation which causes swelling (edema) and fluid leakage. Clemastine also inhibits the H1 histamine receptor on bronchiole smooth muscle myocytes. This normally activates the Gq signalling cascade which activates phospholipase C which catalyzes the production of Inositol 1,4,5-trisphosphate (IP3) and Diacylglycerol (DAG). Because of the inhibition, IP3 doesn't activate the release of calcium from the sarcoplasmic reticulum, and DAG doesn't activate the release of calcium into the cytosol of the endothelial cell. This causes a low concentration of calcium in the cytosol, and it, therefore, cannot bind to calmodulin.Calcium bound calmodulin is required for the activation of myosin light chain kinase. This prevents the phosphorylation of myosin light chain 3, causing an accumulation of myosin light chain 3. This causes muscle relaxation, opening up the bronchioles in the lungs, making breathing easier.

Tolterodine is a muscarinic receptor antagonist used to treat overactive bladder with urinary incontinence, urgency, and frequency. It can be found under the brand names Detrol and Detrusitol. Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels. Tolterodine has a pronounced effect on bladder function. The main effects of tolterodine are an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure, consistent with an antimuscarinic action on the lower urinary tract. Tolterodine is an antimuscarinic medication that selectively and competitively binds to muscarinic M3 receptors in the bladder, thereby decreasing bladder contraction by decreasing detrusor muscle tone and increasing internal urethral sphincter tone. Possible side effects of using tolterodine may include dry mouth, headache, vertigo, and vomiting. Tolterodine can be administered as an oral capsule or tablet.