Calcium channel blocker
Calcium channel blockers, calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e. as medications to decrease blood pressure in patients with hypertension. CCBs are effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, to reduce chest pain caused by angina pectoris. N-type, L-type, T-type voltage-dependent calcium channels are present in the zona glomerulosa of the human adrenal gland, CCBs can directly influence the biosynthesis of aldosterone in adrenocortical cells, with consequent impact on the clinical treatment of hypertension with these agents. CCBs have been shown to be more effective than beta blockers at lowering cardiovascular mortality, but they are associated with more side effects.
Potential major risks however were found to be associated with short-acting CCBs. Dihydropyridine calcium channel blockers are derived from the molecule dihydropyridine and used to reduce systemic vascular resistance and arterial pressure. Sometimes when they are used to treat angina, the vasodilation and hypotension can lead to reflex tachycardia, which can be detrimental for patients with ischemic symptoms because of the resulting increase in myocardial oxygen demand. Dihydropyridine calcium channel blockers can worsen proteinuria in patients with nephropathy; this CCB class is identified by the suffix "-dipine". Amlodipine Aranidipine Azelnidipine Barnidipine Benidipine Cilnidipine Not available in US Clevidipine Efonidipine Felodipine Isradipine Lacidipine Lercanidipine Manidipine Nicardipine Nifedipine Nilvadipine Nimodipine This substance can pass the blood-brain barrier and is used to prevent cerebral vasospasm. Nisoldipine Nitrendipine Pranidipine Phenylalkylamine calcium channel blockers are selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, are used to treat angina.
They have minimal vasodilatory effects compared with dihydropyridines and therefore cause less reflex tachycardia, making it appealing for treatment of angina, where tachycardia can be the most significant contributor to the heart's need for oxygen. Therefore, as vasodilation is minimal with the phenylalkylamines, the major mechanism of action is causing negative inotropy. Phenylalkylamines are thought to access calcium channels from the intracellular side, although the evidence is somewhat mixed. Fendiline Gallopamil Verapamil Benzothiazepine calcium channel blockers belong to the benzothiazepine class of compounds and are an intermediate class between phenylalkylamine and dihydropyridines in their selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines. Diltiazem While most of the agents listed above are selective, there are additional agents that are considered nonselective.
These include mibefradil, flunarizine and fendiline. Gabapentinoids, such as gabapentin and pregabalin, are selective blockers of α2δ subunit-containing voltage-gated calcium channels, they are used to treat epilepsy and neuropathic pain. Ziconotide, a peptide compound derived from the omega-conotoxin, is a selective N-type calcium channel blocker that has potent analgesic properties that are equivalent to approximate 1,000 times that of morphine, it must be delivered via the intrathecal route via an intrathecal infusion pump. Side effects of these drugs may include but are not limited to: Constipation Dizziness, redness in the face Fluid buildup in the legs and ankle edema Gingival overgrowth Rapid heart rate Slow heart rate Research indicates ethanol is involved in the inhibition of L-type calcium channels. One study showed the nature of ethanol binding to L-type calcium channels is according to first-order kinetics with a Hill coefficient around 1; this indicates ethanol binds independently to the channel.
Early studies showed a link between calcium and the release of vasopressin by the secondary messenger system. Vasopressin levels are reduced after the ingestion of alcohol; the lower levels of vasopressin from the consumption of alcohol have been linked to ethanol acting as an antagonist to voltage-gated calcium channels. Studies conducted by Treistman et al. in the aplysia confirm inhibition of VGCC by ethanol. Voltage clamp recordings have been done on the aplysia neuron. VGCCs were isolated and calcium current was recorded using patch clamp technique having ethanol as a treatment. Recordings were replicated at varying concentrations at a voltage clamp of +30 mV. Results showed. Similar results have shown to be true in single-channel recordings from isolated nerve terminal of rats that ethanol does in fact block VGCCs. Studies done by Katsura et al. in 2006 on mouse cerebral cortical neurons, show the effects of prolonged ethanol
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called blockers. In pharmacology, antagonists have affinity but no efficacy for their cognate receptors, binding will disrupt the interaction and inhibit the function of an agonist or inverse agonist at receptors. Antagonists mediate their effects by binding to the active site or to the allosteric site on a receptor, or they may interact at unique binding sites not involved in the biological regulation of the receptor's activity. Antagonist activity may be reversible or irreversible depending on the longevity of the antagonist–receptor complex, which, in turn, depends on the nature of antagonist–receptor binding; the majority of drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors. The English word antagonist in pharmaceutical terms comes from the Greek ἀνταγωνιστής – antagonistēs, "opponent, villain, rival", derived from anti- and agonizesthai.
Biochemical receptors are large protein molecules that can be activated by the binding of a ligand such as a hormone or a drug. Receptors can be membrane-bound, as cell surface receptors, or inside the cell as intracellular receptors, such as nuclear receptors including those of the mitochondrion. Binding occurs as a result of non-covalent interactions between the receptor and its ligand, at locations called the binding site on the receptor. A receptor may contain one or more binding sites for different ligands. Binding to the active site on the receptor regulates receptor activation directly; the activity of receptors can be regulated by the binding of a ligand to other sites on the receptor, as in allosteric binding sites. Antagonists mediate their effects through receptor interactions by preventing agonist-induced responses; this may be accomplished by binding to the allosteric site. In addition, antagonists may interact at unique binding sites not involved in the biological regulation of the receptor's activity to exert their effects.
The term antagonist was coined to describe different profiles of drug effects. The biochemical definition of a receptor antagonist was introduced by Ariens and Stephenson in the 1950s; the current accepted definition of receptor antagonist is based on the receptor occupancy model. It narrows the definition of antagonism to consider only those compounds with opposing activities at a single receptor. Agonists were thought to turn "on" a single cellular response by binding to the receptor, thus initiating a biochemical mechanism for change within a cell. Antagonists were thought to turn "off" that response by'blocking' the receptor from the agonist; this definition remains in use for physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H1 receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by alpha-adrenergic receptor activation.
Our understanding of the mechanism of drug-induced receptor activation and receptor theory and the biochemical definition of a receptor antagonist continues to evolve. The two-state model of receptor activation has given way to multistate models with intermediate conformational states; the discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. This means efficacy may depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug. By definition, antagonists display no efficacy to activate the receptors they bind. Antagonists do not maintain the ability to activate a receptor. Once bound, antagonists inhibit the function of agonists, inverse agonists, partial agonists. In functional antagonist assays, a dose-response curve measures the effect of the ability of a range of concentrations of antagonists to reverse the activity of an agonist.
The potency of an antagonist is defined by its half maximal inhibitory concentration. This can be calculated for a given antagonist by determining the concentration of antagonist needed to elicit half inhibition of the maximum biological response of an agonist. Elucidating an IC50 value is useful for comparing the potency of drugs with similar efficacies, however the dose-response curves produced by both drug antagonists must be similar; the lower the IC50 the greater the potency of the antagonist, the lower the concentration of drug, required to inhibit the maximum biological response. Lower concentrations of drugs may be associated with fewer side-effects; the affinity of an antagonist for its binding site, i.e. its ability to bind to a receptor, will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression or for competitive antagonists in radioligand binding studies using the Cheng-Prusoff equation. Schild regression can be used to determine the nature of antagonism as beginning either competitive or non-competitive and Ki determination is independent of the affinity, efficacy or concentration of the agonist used.
However, it is important. The effects of receptor desensitization on reaching equilibrium must als
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine. It does so using molecular oxygen, as well as tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine and epinephrine. Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, the enzyme is present in the central nervous system, peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases. Tyrosine hydroxylase catalyzes the reaction in which L-tyrosine is hydroxylated in the meta position to obtain L-3,4-dihydroxyphenylalanine; the enzyme is an oxygenase. One of the oxygen atoms in O2 is used to hydroxylate the tyrosine molecule to obtain L-DOPA and the other one is used to hydroxylate the cofactor.
Like the other aromatic amino acid hydroxylases, tyrosine hydroxylase use the cofactor tetrahydrobiopterin under normal conditions, although other similar molecules may work as a cofactor for tyrosine hydroxylase. The AAAHs converts the cofactor 5,6,7,8-tetrahydrobiopterin into tetrahydrobiopterin-4a-carbinolamine. Under physiological conditions, 4a-BH4 is dehydrated to quinonoid-dihydrobiopterin by the enzyme pterin-4a-carbinolamine dehydrase and a water molecule is released in this reaction; the NADH dependent enzyme dihydropteridine reductase converts q-BH2 back to BH4. Each of the four subunits in tyrosine hydroxylase is coordinated with an iron atom presented in the active site; the oxidation state of this iron atom is important for the catalytic turnover in the enzymatic reaction. If the iron is oxidized to Fe, the enzyme is inactivated; the product of the enzymatic reaction, L-DOPA, can be transformed to dopamine by the enzyme DOPA decarboxylase. Dopamine may be converted into norepinephrine by the enzyme dopamine β-hydroxylase, which can be further modified by the enzyme phenylethanol N-methyltransferase to obtain epinephrine.
Since L-DOPA is the precursor for the neurotransmitters dopamine and adrenaline, tyrosine hydroxylase is therefore found in the cytosol of all cells containing these catecholamines. This initial reaction catalyzed by tyrosine hydroxylase has been shown to be the rate limiting step in the production of catecholamines; the enzyme is specific, not accepting indole derivatives -, unusual as many other enzymes involved in the production of catecholamines do. Tryptophan is a poor substrate for tyrosine hydroxylase, however it can hydroxylate L-phenylalanine to form L-tyrosine and small amounts of 3-hydroxyphenylalanine; the enzyme can further catalyze L-tyrosine to form L-DOPA. Tyrosine hydroxylase may be involved in other reactions as well, such as oxidizing L-DOPA to form 5-S-cysteinyl-DOPA or other L-DOPA derivatives. Tyrosine hydroxylase is a tetramer of four identical subunits; each subunit consists of three domains. At the carboxyl terminal of the peptide chain there's a short alpha helix domain that allows tetramerization.
The central ~300 amino acids make up a catalytic core, in which all the residues necessary for catalysis are located, along with a non-covalently bound iron atom. The iron is held in place by two histidine residues and one glutamate residue, making it a non-heme, non-iron-sulfur iron-containing enzyme; the amino terminal ~150 amino acids make up a regulatory domain, thought to control access of substrates to the active site. In humans there are thought to be four different versions of this regulatory domain, thus four versions of the enzyme, depending on alternative splicing, though none of their structures have yet been properly determined, it has been suggested that this domain might be an intrinsically unstructured protein, which has no defined tertiary structure, but so far no evidence has been presented supporting this claim. It has however been shown that the domain has a low occurrence of secondary structures, which doesn't weaken suspicions of it having a disordered overall structure.
As for the tetramerization and catalytic domains their structure was found with rat tyrosine hydroxylase using X-ray crystallography. This has shown how its structure is similar to that of phenylalanine hydroxylase and tryptophan hydroxylase. Tyrosine hydroxylase activity is increased in the short term by phosphorylation; the regulatory domain of tyrosine hydroxylase contains multiple serine residues, including Ser8, Ser19, Ser31 and Ser40, that are phosphorylated by a variety of protein kinases. Ser40 is phosphorylated by the cAMP-dependent protein kinase. Ser19 is phosphorylated by the calcium-calmodulin-dependent protein kinase. MAPKAPK2 has a preference for Ser40, but phosphorylates Ser19 about half the rate of Ser40. Ser31 is phosphorylated by ERK1 and ERK2, increases the enzyme activity to a lesser extent than for Ser40 phosphorylation; the phosphorylation at Ser19 and Ser8 has no direct effect on tyrosine hydroxylase activity. But phosphorylation at Ser19 increases the rate of phosphorylation at Ser40, leading to an increase in enzyme activity.
Phosphorylation at Ser19 causes a two-fold increase of activity, through a mechanism that requires the 14-3-
Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, reduce the likelihood of dementia, heart failure, mortality from cardiovascular disease. There are many classes of antihypertensives. Among the most important and most used drugs are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, beta blockers. Which type of medication to use for hypertension has been the subject of several large studies and resulting national guidelines; the fundamental goal of treatment should be the prevention of the important endpoints of hypertension, such as heart attack and heart failure. Patient age, associated clinical conditions and end-organ damage play a part in determining dosage and type of medication administered.
The several classes of antihypertensives differ in side effect profiles, ability to prevent endpoints, cost. The choice of more expensive agents, where cheaper ones would be effective, may have negative impacts on national healthcare budgets; as of 2018, the best available evidence favors low-dose thiazide diuretics as the first-line treatment of choice for high blood pressure when drugs are necessary. Although clinical evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most people, an ACE inhibitor is recommended by NICE in the UK for those under 55 years old. Diuretics help the kidneys eliminate excess water from the body's tissues and blood. Loop diuretics: bumetanide ethacrynic acid furosemide torsemide Thiazide diuretics: epitizide hydrochlorothiazide and chlorothiazide bendroflumethiazide methyclothiazide polythiazide Thiazide-like diuretics: indapamide chlorthalidone metalozone Xipamide Clopamide Potassium-sparing diuretics: amiloride triamterene spironolactone eplerenoneIn the United States, the JNC8 recommends thiazide-type diuretics to be one of the first-line drug treatments for hypertension, either as monotherapy or in combination with calcium channel blockers, ACE inhibitors, or angiotensin II receptor antagonists.
There are fixed-dose combination drugs, such as ACE thiazide combinations. Despite thiazides being cheap and effective, they are not prescribed as as some newer drugs; this is because they have been associated with increased risk of new-onset diabetes and as such are recommended for use in patients over 65 where the risk of new-onset diabetes is outweighed by the benefits of controlling systolic blood pressure. Another theory is that they are off-patent and thus promoted by the drug industry. Calcium channel blockers block the entry of calcium into muscle cells in artery walls. Dihydropyridines: amlodipine cilnidipine clevidipine felodipine isradipine lercanidipine levamlodipine nicardipine nifedipine nimodipine nisoldipine nitrendipine non-dihydropyridines: diltiazem verapamilJNC8 recommends calcium channel blockers to be a first-line treatment either as monotherapy or in combination with thiazide-type diuretics, ACE inhibitors, or angiotensin II receptor antagonists for all patients regardless of age or race.
The ratio of CCBs' anti-proteinuria effect, non-dihydropyridine to dihydropyridine was 30 to -2. ACE inhibitors inhibit the activity of angiotensin-converting enzyme, an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor. Captopril enalapril fosinopril lisinopril moexipril perindopril quinapril ramipril trandolapril benazeprilA systematic review of 63 trials with over 35,000 participants indicated ACE inhibitors reduced doubling of serum creatinine levels compared to other drugs, the authors suggested this as a first line of defense; the AASK trial showed that ACE inhibitors are more effective at slowing down the decline of kidney function compared to calcium channel blockers and beta blockers. As such, ACE inhibitors should be the drug treatment of choice for patients with chronic kidney disease regardless of race or diabetic status. However, ACE inhibitors should not be a first-line treatment for black hypertensives without chronic kidney disease.
Results from the ALLHAT trial showed that thiazide-type diuretics and calcium channel blockers were both more effective as monotherapy in improving cardiovascular outcomes compared to ACE inhibitors for this subgroup. Furthermore, ACE inhibitors were less effective in reducing blood pressure and had a 51% higher risk of stroke in black hypertensives when used as initial therapy compared to a calcium channel blocker. There are fixed-dose combination drugs, such as ACE thiazide combinations. Notable side effects of ACE inhibitors include dry cough, fatigue, headaches, loss of taste and a risk for angioedema. Angiotensin II receptor antagonists work by antagonizing the activation of angiotensin receptors. Azilsartan candesartan eprosartan irbesartan losartan olmesartan telmisartan valsartan FimasartanIn 2004, an article in the BMJ examined the evidence for and against the suggestion that angiotensin receptor blockers may increase the risk of myocardial infarction; the matter was debated in 2006 in the medical journal of the American Heart Association.
To date, there is no consensus on whether ARBs have a tendenc
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of the widening of blood vessels; the process is important in staunching hemorrhage and acute blood loss. When blood vessels constrict, the flow of blood is restricted or decreased, thus retaining body heat or increasing vascular resistance; this makes the skin turn paler because less blood reaches the surface, reducing the radiation of heat. On a larger level, vasoconstriction is one mechanism by which the body regulates and maintains mean arterial pressure. Medications causing vasoconstriction known as vasoconstrictors, are one type of medicine used to raise blood pressure. Generalized vasoconstriction results in an increase in systemic blood pressure, but it may occur in specific tissues, causing a localized reduction in blood flow; the extent of vasoconstriction may be severe depending on the substance or circumstance.
Many vasoconstrictors cause pupil dilation. Medications that cause vasoconstriction include: antihistamines and stimulants. Severe vasoconstriction may result in symptoms of intermittent claudication; the mechanism that leads to vasoconstriction results from the increased concentration of calcium within vascular smooth muscle cells. However, the specific mechanisms for generating an increased intracellular concentration of calcium depends on the vasoconstrictor. Smooth muscle cells are capable of generating action potentials, but this mechanism is utilized for contraction in the vasculature. Hormonal or pharmacokinetic components are more physiologically relevant. Two common stimuli for eliciting smooth muscle contraction are circulating epinephrine and activation of the sympathetic nervous system that directly innervates the muscle; these compounds interact with cell surface adrenergic receptors. Such stimuli result in a signal transduction cascade that leads to increased intracellular calcium from the sarcoplasmic reticulum through IP3-mediated calcium release, as well as enhanced calcium entry across the sarcolemma through calcium channels.
The rise in intracellular calcium complexes with calmodulin, which in turn activates myosin light-chain kinase. This enzyme is responsible for phosphorylating the light chain of myosin to stimulate cross-bridge cycling. Once elevated, the intracellular calcium concentration is returned to its normal concentration through a variety of protein pumps and calcium exchangers located on the plasma membrane and sarcoplasmic reticulum; this reduction in calcium removes the stimulus necessary for contraction, allowing for a return to baseline. Factors that trigger vasoconstriction can be of endogenous origin. Ambient temperature is an example of the former. Cutaneous vasoconstriction will occur because of the body's exposure to the severe cold. Examples of endogenous factors include the autonomic nervous system, circulating hormones, intrinsic mechanisms inherent to the vasculature itself. Examples include stimulants, amphetamines and cocaine. Many are used in medicine to treat hypotension and as topical decongestants.
Vasoconstrictors are used clinically to increase blood pressure or to reduce local blood flow. Vasoconstrictors mixed with local anesthetics are used to increase the duration of local anesthesia by constricting the blood vessels, thereby safely concentrating the anesthetic agent for an extended duration, as well as reducing hemorrhage; the routes of administration vary. They may be both topical. For example, pseudoephedrine is taken orally and phenylephrine is topically applied to the nasal passages or eyes. Examples include: Vasoconstriction is a procedure of the body that averts orthostatic hypotension, it is a part of a body negative feedback loop. For example, vasoconstriction is a hypothermic preventative in which the blood vessels constrict and blood must move at a higher pressure to prevent a hypoxic reaction. ATP is used as a form of energy to increase this pressure to heat the body. Once homeostasis is restored, the blood pressure and ATP production regulates. Vasoconstriction occurs in superficial blood vessels of warm-blooded animals when their ambient environment is cold.
Vasoconstriction can be a contributing factor to erectile dysfunction. An increase in blood flow to the penis causes an erection. Improper vasoconstriction may play a role in secondary hypertension. Addison's disease Inotrope Hypertension Nitric oxide Pheochromocytoma Shock Vasodilation Postural orthostatic tachycardia syndrome Hemostasis Definition of Vasoconstriction on HealthScout Cannabis arteritis revisited--ten new case reports Are coronary heart disease and peripheral arterial disease associated with tobacco or cannabis consumption Vasoconstrictor effects of Cannabis appear to inhibit Migraine attacks
Simplified molecular-input line-entry system
The simplified molecular-input line-entry system is a specification in the form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules; the original SMILES specification was initiated in the 1980s. It has since been extended. In 2007, an open standard called. Other linear notations include the Wiswesser line notation, ROSDAL, SYBYL Line Notation; the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems.
In 2007, an open standard called "OpenSMILES" was developed by the Blue Obelisk open-source chemistry community. Other'linear' notations include the Wiswesser Line Notation, ROSDAL and SLN. In July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is considered to have the advantage of being more human-readable than InChI; the term SMILES refers to a line notation for encoding molecular structures and specific instances should be called SMILES strings. However, the term SMILES is commonly used to refer to both a single SMILES string and a number of SMILES strings; the terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms are not mutually exclusive. A number of valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol. Algorithms have been developed to generate the same SMILES string for a given molecule; this SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, is termed the canonical SMILES.
These algorithms first convert the SMILES to an internal representation of the molecular structure. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database; the original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, double bond geometry; these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES.
A notable feature of these rules is. The term isomeric SMILES is applied to SMILES in which isotopes are specified. In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph; the chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree; the resultant SMILES form depends on the choices: of the bonds chosen to break cycles, of the starting atom used for the depth-first traversal, of the order in which branches are listed when encountered. Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which: are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, have no formal charge, have the number of hydrogens attached implied by the SMILES valence model, are the normal isotopes, are not chiral centers.
All other elements must be enclosed in brackets, have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or. Hydrogen may be written as a separate atom; when brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1 by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is written as digit.
Alpha-1 blockers constitute a variety of drugs that reduce the effect alpha-1-adrenergic receptors. They are used to treat benign prostatic hyperplasia and post-traumatic stress disorder. Alpha-1 adrenergic receptors occur in vascular smooth muscle, the central nervous system, other tissues; when alpha blockers bind to these receptors in vascular smooth muscle, they cause vasodilation. Over the last 40 years, a variety of drugs have been developed from non-selective alpha-1 antagonists to selective alpha-1 antagonists and alpha-1 inverse agonists; the first drug, used was a non-selective alpha blocker, named phenoxybenzamine and was used to treat BPH. Several selective alpha-1 antagonists are available; as of 2018, prazosin is the only alpha-1 blocker known to act as an inverse agonist at all alpha-1 adrenergic receptor subtypes. Drugs that act as selective antagonists at specific alpha-1 adrenergic receptor subtypes have been developed. Benign prostatic hyperplasia is an enlarged prostate gland.
Alpha-1 blockers are the most used medicine to treat BPH. Alpha-1 blockers are first line treatment for the symptoms of BPH in men. Doxazosin, terazosin and tamsulosin have all been well established in treatment to reduce lower urine tract symptoms caused by benign prostatic hyperplasia, they are all believed to be effective for this purpose. First generation alpha-1 blockers, like prazosin are not recommended to treat lower-urinary-tract symptoms because of their blood-pressure-lowering effect. Second and third generations are recommended though. In some cases alpha-1 blockers have been used in combined therapy with 5-alpha reductase blockers. Dutasteride and tamsulosin are on the market as combined therapy and results have shown that they improve symptoms versus monotherapy. Alpha-1 blockers are used as second line treatment for high blood pressure, they are not thought to be good as first line treatment because there are other more selective agents, although they can be good for treating men with hypertension and BPH.
Doxazosin have shown to improve symptoms of BPH in elderly and reduce blood pressure at the same time. BPH is common in men over 60 years old and hypertension as well. Terazosin is safe and effective to use against hypertension and BPH but is of first generation while doxazosin is second generation alpha-1 blockers. Post-traumatic stress disorder is a disabling condition that can be caused by after some kind of life-threatening trauma, it is common in veteran soldiers. Prazosin, used as antihypertension but because of the alpha-1 adrenergic activity of Prazosin, that activity has been connected to fear and startle responses. Prazosin has been established as an effective and safe, brain active alpha-1 adrenergic receptor antagonist, it can be used against trauma nightmares, sleep disturbance and chronic PTSD. As Alpha-1-a blockers affect the symptoms of BPH more than the Alpha-1 blockers, the adverse effects seem to be more linked to the reproductive system while minimizing the effect on the blood-pressure system.
Hypotension and its complications are a constant risk, however though a selective alpha-1a blocker is being used. It is therefore important when starting treatment with an alpha-1 blocker to monitor the blood pressure to minimize the risk for adverse effects connected to low blood pressure. By reducing alpha-1-adrenergic activity of the blood vessels, these drugs may cause hypotension and interrupt the baroreflex response. In doing so, they may cause dizziness, lightheadedness, or fainting when rising from a lying or sitting posture. For this reason, it is recommended that alpha blockers should be taken at bedtime; the risk of first dose phenomenon may be reduced or eliminated by gradual-dose titration, since the adverse effects of Prazosin are dose-related. This is the case for Tamsulosin and it may be assumed that the others alpha-1 blockers work in a similar manner, since Tamsulosin is an alpha-1-a blocker and Prazosin is an alpha-1 blocker; the risk for floppy iris syndrome during cataract surgery is elevated when the patient is using an alpha-1 blocker.
This is the case for Tamsulosin and other alpha-1-a blockers, since alpha-1-a receptors are present in the iris dilator muscle, which allows unopposed action of the parasympathetically innervated iris constrictor muscle and loss of iris tone. This however can be treated if the eye surgeon is experienced and has knowledge of the use of alpha-1 blocker. Contraindication: Allergies or hypersensitivity to alpha-1 blockers or any of the active ingredient, that includes angiodema induced by the drug. Patients with a history of orthostatic hypotension or severe hepatic impairment. Interactions: No interactions were recorded when administered with atenolol and theophylline. Furosemide has drop effect on plasma level for tamsulosin, a rise in plasma level with cimetidine. No dose adjustment needs to be done. Drugs that inhibit CYP3A4 can increase drug exposure for tamsulosin, alfuzosin and silodosin. Grapefruit is a powerful inhibitor of the CYP3A4 enzyme, so concurrent use is not recommended as it may increase the plasma levels of the Alpha-1 blockers which are metabolised by the CYP3A4 enzyme.