Browsing Pathways

The monoamine oxidase is an enzyme that catalyzes the oxidative deamination of many amines like serotonin, norepinephrine, epinephrine, and dopamine. There are 2 isoforms of this protein: A and B. The first one is found in cells located in the periphery and breakdown serotonin, norepinephrine, epinephrine, dopamine, and tyramine. The second one, the B isoform, breakdowns phenylethylamine, norepinephrine, epinephrine, dopamine, and tyramine. This isoform is found in the extracellular tissues and mostly in the brain. The mechanism of action of the MAOIs is still not determined, it is thought that they act by increasing free serotonin and norepinephrine concentrations and/or by altering the concentrations of other amines in the CNS. mine oxidases are divided into two subfamilies based on the cofactor they contain. Amine oxidases catalyze oxidative deamination reactions, producing ammonia and an aldehyde. These enzymes are critical to both homeostatic and xenobiotic metabolic pathways and are involved in the biotransformation of aminergic neurotransmitters (such as catecholamines, histamine, and serotonin) as well as toxins and carcinogens in foods and the environment. The monoamine oxidases (MAOs) are well studied and have been targets for drug therapy for more than 60 years. MAOs are flavin-containing mitochondrial enzymes distributed throughout the body. In humans, two isoenzymes of MAO have been identified, encoded by two genes located on the X chromosome: MAO-A and MAO-B. Each isoenzyme can be distinguished by certain substrate specificities and anatomic distribution (Table 4.9), although MAO-A has the distinction of being the sole catecholamine metabolic enzyme in sympathetic neurons. In neural and other selective tissues, MAOs catalyze the first step in the degradation of catecholamines into their aldehyde intermediaries, which is further processed by catechol-O-methyltransferase. The ubiquity of biogenic amines and their central role in neural and cardiovascular function make MAOs highly relevant to clinical anesthesia. The interactions between MAO inhibitors and drugs commonly used in anesthesia have been well described. Although genetic polymorphisms in MAO genes exist and are of great interest in the fields of neurology and psychiatry, to date none have been identified that specifically concern the handling of anesthetic agents.

Dopamine is a neurotransmitter that can be taken as a tablet for hemodynamic imbalances caused by many heart problems and diseases. Dopamine is a precursor to norepinephrine in the sympathetic nervous system. Dopamine enters the sympathetic neuron through a sodium-dependent dopamine transporter.. In the neuron, it is catalyzed by Dopamine beta-hydroxylase to synthesize norepinephrine. Norepinephrine is stored in synaptic storage sites where norepinephrine was already being stored. When the neuron is depolarized, this accumulation of norepinephrine is released into the synapse. In the synapse, dopamine prevents the re-uptake of norepinephrine by inhibiting Sodium-dependent noradrenaline transporter. The norepinephrine activates Beta-1 adrenergic receptor which is coupled to the G-protein signalling cascade. Activation of the receptor activates the cascade which leads to activated protein kinase through activation of adenylate cyclase. Protein kinase activates calcium channels in the membrane, causing the channels to open and allow Ca2+ into the cell. This causes a high concentration of Ca2+ to be present in the cardiomyocyte which activates activates the ryanodine receptor on the sarcoplasmic reticulum. This transports more Ca2+ into the cytosol. The high concentration of Ca2+ binds to troponin to cause cardiac muscle contractions and therefore, an increased heart rate. This helps conditions like Arrhythmia, myocardial infarctions, open-heart surgery, and trauma-induced hypotension. Dopamine has also been found to increase the amount of circulating epinephrine which can activate the release of norepinephrine in the heart, further increasing heart contractions. Dopamine cannot cross the blood-brain barrier so it is incapable of activating any dopamine receptors in the brain. It can only access the receptors present outside the brain which is why the drug mainly works through norepinephrine in noradrenergic neurons outside the brain, and especially in the heart. Low doses of dopamine cause vasodilation while can help with renal failure and related conditions.

Coagulation of the blood can be initiation from two different pathways that both result in formation of thrombin which converts blood soluble fibrinogen into the insoluble fibrin clot at the site of injury. The intrinsic pathway is activated by trauma inside vasculature and is activated by platelets, exposed endothelium and collagen. In the liver the coagulation factors VII, IX, and X are produced there as they are vitamin K-dependent proteins. Exposed collagen from broken vessels binds to factor XII activating it to XIIa which converts prekallikrein and factor XI to kallikrein and factor XIa respectively. The extrinsic pathway is activated by the external trauma of blood escaping the vasculature system as the membrane-bound protein tissue factor (TF) is exposed to factors VII or VIIa in the plasma forming a strong activator complex. This activator complex of VIIa and TF converts factor X to the activated form. Both the intrinsic and extrinsic pathways lead to the prothrombinase complex as both pathways activate factor X, an important player in the complex. The prothrombinase complex converts prothrombin to thrombin further allowing the conversion of insoluble fibrinogen into fibrin. Fibrin at first is loose and unstable and is stabilized by coagulation factor XIIIa which cross-links them to form the fibrin clot/mesh that stops blood leaking from the vasculature system. The activated proteins are colored orange.

Activation of the 5-HT2A and 5-HT2C receptors in the neurons typically leads to the activation of Gq proteins. Gq proteins stimulate phospholipase C (PLC), leading to the production of inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 induces calcium release from intracellular stores, leading to increased intracellular calcium levels. Increased intracellular calcium and DAG activation of protein kinase C (PKC) can lead to the modulation of various signaling pathways. The net effect on neuronal excitability can vary involving both excitatory and inhibitory influences depending on the context and the specific neuron, brain region and down stream signaling pathways involved. 5-HT2A receptor activation via Gq protein signaling can have excitatory effects in some neurons, particularly in the cerebral cortex and certain excitatory circuits. In the cortex, activation of 5-HT2A receptors can enhance neuronal excitability, synaptic transmission, and plasticity.

Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. The nicotinic receptors are considered cholinergic receptors, since they respond to acetylcholine. Nicotinic receptors get their name from nicotine which does not stimulate the muscarinic acetylcholine receptors but selectively binds to the nicotinic receptors instead. As ionotropic receptors, nAChRs are directly linked to ion channels. New evidence suggests that these receptors can also use second messengers (as metabotropic receptors do) in some cases. Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors. Opening of the channel allows positively charged ions to move across it; in particular, sodium enters the cell and potassium exits. The net flow of positively charged ions is inward. The nAChR is a non-selective cation channel, meaning that several different positively charged ions can cross through. The activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movement of cations causes a depolarization of the plasma membrane (which results in an excitatory postsynaptic potential in neurons) leading to the activation of voltage-gated ion channels. On the other hand, the entry of calcium acts, either directly or indirectly, on different intracellular cascades. This leads, for example, to the regulation of activity of some genes or the release of neurotransmitters.

Hydroxyurea is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Hydroxyurea passes through the liver and is then excreted from the body mainly through the kidney.

Potassium bicarbonate is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Potassium bicarbonate passes through the liver and is then excreted from the body mainly through the kidney.

Urea C-14 is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Urea C-14 passes through the liver and is then excreted from the body mainly through the kidney.

Propylene glycol is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Propylene glycol passes through the liver and is then excreted from the body mainly through the kidney.

Silver sulfadiazine is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Silver sulfadiazine passes through the liver and is then excreted from the body mainly through the kidney.