Pathways

Sulfasalazine is a salicylate anti-inflammatory drug used to treat Crohn's disease, severe ulcerative colitis, and rheumatoid arthritis. This drug is metabolized by intestinal bacteria to mesalazine and sulfapyridine, these two compounds carry out the main pharmacological activity of sulfasalazine. The mode of action of sulfasalazine or its metabolites, 5-aminosalicylic acid, and sulfapyridine, is still under investigation but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animals. Sulfasalazine and its metabolites have been shown to inhibit leukotrienes and prostaglandins by blocking the cyclo-oxygenase and lipoxygenase pathways. The enzymes that were investigated include phospholipase A2, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX2), and arachidonate 5-lipoxygenase. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase, or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain. Mesalazine inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Fever is triggered by inflammatory and infectious diseases. Cytokines are produced in the central nervous system (CNS) during an inflammatory response. These cytokines induce COX-2 production that increases the synthesis of prostaglandin, specifically prostaglandin E2 which adjusts hypothalamic temperature control by increasing heat production. Because mesalazine decreases PGE2 in the CNS, it has an antipyretic effect. Antipyretic effects results in increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibitory activities on other non-arachidonic acid derivatives have also been observed, including PPAR gamma, NF-Kb, and IkappaB kinases alpha and beta.

Triazolam is a short-acting benzodiazepine used for the short-term treatment of insomnia (hypnotic agent). This drug binds to various regions of the brain and spinal cord where GABA A receptors are. It binds to an allosteric site between the alpha and gamma subunits of the receptor increasing the inhibitory effects of GABA. Benzodiazepines bind nonspecifically to BNZ1, which acts on sleep, and BNZ2, which acts on muscle relaxation, anticonvulsant activity, motor coordination, and memory. These receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. In consequence, when GABA binds the site, it opens the chloride channel, resulting in a hyperpolarized cell membrane. Since the neuron cell is hyperpolarized, it prevents further excitation of the cell. Triazolam is administered orally as a tablet. Overdosing of triazolam usually has the symptoms of more intense therapeutic effects with extreme overdosage leading to coma, cardio-respiratory depression, and apnoea. Due to its high affinity for plasma proteins, diazepam also has a high volume of distribution and can cross the blood-brain barrier. This drug has been withdrawn in the United Kingdom due to the risk of psychiatric adverse drug reactions. This drug continues to be available in the U.S..

Butabarbital is a barbiturate drug used as a sedative and hypnotic. Butabarbital, or Butisol, is a fast onset barbiturate with short duration of action compared to other barbiturates. This makes butabarbital a useful drug for treating severe insomnia and pre-operative anxiety. Barbiturates like butabarbital potentiate GABA-A receptors and inhibit receptors. GABA-A receptors are predominantly on the post-synaptic membrane, and upon activation, open chloride channels to hyperpolarize the neuron and decreased firing rate. Potentiation of GABAergic neurons produces sedation. Butabarbital binds on the benzodiazepine receptors in the post-synaptic GABA-A ligand-gated chloride channel in different sites of the central nervous system (CNS). This binding will result in an increase on the GABA inhibitory effects which is translated as an increase in the flow of chloride ions into the cell causing hyperpolarization and stabilization of the cellular plasma membrane.

Chlordiazepoxide is a benzodiazepine used to treat the withdrawal symptoms of acute alcoholism, to treat preoperative anxiety, and to treat anxiety over a short term period. Chlordiazepoxide binds to stereospecific benzodiazepine (BZD) binding sites on GABA (A) receptor complexes at several sites within the central nervous system, including the limbic system and reticular formation. This results in an increased binding of the inhibitory neurotransmitter GABA to the GABA(A) receptor. BZDs, therefore, enhance GABA-mediated chloride influx through GABA receptor channels, causing membrane hyperpolarization. The net neuro-inhibitory effects result in the observed sedative, hypnotic, anxiolytic, and muscle relaxant properties. Some side effects of using chlordiazepoxide may include drowsiness, dizziness, and weakness.

Clobazam is a benzodiazepine used as adjunct treatment in seizures associated with Lennox-Gastaut syndrome. It can be found under the brand names Onfi and Sympazan. Clobazam acts on the GABAA receptor to increase GABAnergic transmission, particularly chloride conductance in neurons. This causes neuronal hyperpolarization, resulting in an increase in the action potential threshold and reducing neuron firing frequency. Consequently, the general neuronal activity of the central nervous system is depressed; therefore, clobazam can be used to treat diseases caused by excessive excitatory action potentials. The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve the potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor. Specifically, clobazam binds to the interface of the α2 and γ2-subunit of the GABAA receptor. It has a great affinity for the α2 subunit than the α1 subunit compared to other 1,4‐benzodiazepines. Binding of clobazam to the GABAA receptor causes chloride channels to open, resulting in an influx of chloride and thus hyperpolarization of neurons. Some side effects of using clobazam may include tiredness, drooling, and vomiting.

Clorazepic acid or clorazepate is a benzodiazepine used to treat anxiety, partial seizures, and alcohol withdrawal. Clorazepate is indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. It is also used as adjunctive therapy in the management of partial seizures and for the symptomatic relief of acute alcohol withdrawal. Clorazepate is a benzodiazepine with depressant effects on the central nervous system.8 Benzodiazepines are able to enhance the binding of gamma-aminobutyric acid (GABA) to the GABA type A (GABA-A) receptor by binding to a region in the extracellular domain found at the interface between the alpha (α) and gamma (γ) subunits of the GABA-A receptor. The interaction of GABA and the GABA-A receptor promotes channel opening, leading to an increased chloride influx. Consequently, the use of benzodiazepines, such as clorazepate, leads to neuronal hyperpolarization. Clorazepate is a prodrug for nordiazepam which is converted in the liver. Some side effects of using clorazepic acid may include dizziness, nervousness, blurred vision, and headache.

Clotiazepam is a thienodiazepine used to manage anxiety disorders and insomnia. Clotiazepam (marketed under brand name Clozan, Distensan, Trecalmo, Rize, Rizen and Veratran) is a thienodiazepine drug which is a benzodiazepine analog. Clotiazepam binds to the benzodiazepine site of the GABAA receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABAA receptor which results in the pharmacological effects of clotiazepam. Clotiazepam acts at the benzodiazepine receptors (BZD). This agonizes the action of GABA, increasing the frequency of opening of the channel chlorinates and penetration of the ions chlorinates through the ionophore. Increase in membrane polarization decreases the probability of discharge of neurons. Some side effects of using Clotiazepam may include drowsiness, lightheadedness, and vertigo.

Estazolam is a benzodiazepine used for the short-term management of insomnia. Estazolam, a triazolobenzodiazepine derivative, is an oral hypnotic agent with anticonvulsant, hypnotic, and muscle relaxant properties. It has been shown in some cases to be more potent than diazepam or nitrazepam. Benzodiazepines bind nonspecifically to benzodiazepine receptors, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. Some side effects of using estazolam may include grogginess, weakness, dry mouth, and constipation.

Daunorubicin is an aminoglycoside used to induce remission of nonlymphocytic leukemia and acute lymphocytic leukemia (ALL). This drug is a very toxic anthracycline antineoplastic isolated from Streptomyces peucetius and is administered by injection into a vein. It inhibits cellular reproduction by interfering with DNA replication. Also, it may contribute to the induction of apoptosis by increasing the oxidative stress of the cell through the generation of reactive oxygen species and free radicals. Daunorubicin carries significant toxicities including cytopenias, hepatotoxicity, and extravasation reactions. Like other anthracyclines, daunorubicin exhibits cardiotoxicity that is in proportion to the cumulative dose of the drug. Daunorubicin acts by forming many complexes with DNA, by intercalation between base pairs, and it inhibits topoisomerase II (2-alpha and 2-beta) activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II normally catalyzes. By doing this, the cell will not be able to continue its replication and will die through apoptosis.

Etomidate is a short-acting intravenous anesthetic indicated for the induction of anesthesia and supplementation of subpotent anesthesia during short operative procedures. Imidazole derivative anesthetic and hypnotic with little effect on blood gases, ventilation, or the cardiovascular system. It has been proposed as an induction anesthetic. Etomidate is a non-barbiturate hypnotic that acts at the level of the reticular-activating system to produce anesthesia. Etomidate is an imidazole compound that appears to depress CNS function via GABA. Duration of action is intermediate between thiopental and methohexital, and recovery from a single dose is rapid with little residual depression. Like the barbiturates and propofol, etomidate is does not induce analgesia. Etomidate induces unconsciousness within one circulation time. Recovery is rapid as a result of extensive redistribution and rapid metabolism. Etomidate binds at a distinct binding site associated with a Cl- ionopore at the GABAA receptor, increasing the duration of time for which the Cl- ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. Some side effects of using etomidate may include hives, fatigue, weight loss, and difficulty breathing.