Nifedipine - DrugBank
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Selectivity of antidepressant agents are based on the neurotransmitters that are thought to influence symptoms of depression.
TCAs have comprehensive effects on various neurotransmitters receptors, which leads to lack of tolerability and increased risk of toxicity. TCAs were the first medications that had dual mechanism of action. The mechanism of action of tricyclic secondary amine antidepressants is only partly understood.
TCAs have dual inhibition effects on norepinephrine reuptake transporters and serotonin reuptake transporters. Increased norepinephrine and serotonin concentrations are obtained by inhibiting both of these transporter proteins.
This is because of a formation of secondary amine TCA metabolites. This interaction seems to be critical for increased availability of norepinephrine in or near the synaptic clefts.
Serotonin–norepinephrine reuptake inhibitor
Actions of imipramine-like tricyclic antidepressants have complex, secondary adaptions to their initial and sustained actions as inhibitors of norepinephrine transport and variable blockade of serotonin transport.
Formation of norepinephrine is reduced by autoreceptors through the rate-limiting enzyme tyrosine hydroxylasean effect mediated by decreased cyclic AMP -mediated phosphorylation -activation of the enzyme. The desensitization of these responses may be due to increased exposure to endogenous norepinephrine or from the prolonged occupation of the norepinephrine transport mechanisms via an allosteric effect.
The adaptation allows the presynaptic synthesis and secretion of norepinephrine to return to, or even exceed, normal levels of norepinephrine in the synaptic clefts. Active transport system regulates the uptake of tryptophan across the blood—brain barrier.
Serotonergic pathways are classified into two main ways in the brain; the ascending projections from the medial and dorsal raphe and the descending projections from the caudal raphe into the spinal cord.
Selective norepinephrine reuptake inhibitors[ edit ] Noradrenergic neurons are located in two major regions in the brain. These regions are locus coeruleus and lateral tegmental. With administration of selective NRIs, neuronal activity in locus coeruleus region is induced because of increased concentration of norepinephrine in the synaptic cleft.
Clinical studies suggest that compounds that increase the concentration in the synaptic cleft of both norepinephrine and serotonin are more successful than single acting agents in the treatment of depression.
Structure–activity relationship - Wikipedia
Nontricyclic antidepressants have improved potency and onset action acceleration in antidepressant response than SSRIs alone, which give the impression that synergism is an efficient property in mediating antidepressant activity.
The non-tricyclic SNRIs have several important differences that are based on pharmacokinetics, metabolism to active metabolites, inhibition of CYP isoforms, effect of drug-drug interactions, and the half-life of the nontricyclic SNRIs. This structural motif has potential for high affinity binding to biogenic amine transports. Selective NRIs contain a substituent in 2' position of the aryloxy ring but SSRIs contain a substituent in 4' position of the aryloxy ring. Atomoxetine, nisoxetine and reboxetine all have a substitution group in the 2' position and are selective NRIs while compounds that have a substitution group in the 4' position like fluoxetine and paroxetine are SSRIs.
Duloxetine contains a phenyl group fused at the 2' and 3' positions, therefore it has dual selective norepinephrine and serotonin reuptake inhibitory effects and has similar potencies for the both transporters.
Cycloalkanol ethylamine scaffold[ edit ] Venlafaxine and desvenlafaxine contain a cycloalkanol ethylamine scaffold. Increasing the electron-withdrawing nature of the aromatic ring provides more potent inhibitory effect of norepinephrine uptake and improves the selectivity for norepinephrine over the serotonin transporter.
The results showed that the strongest electron-withdrawing m-trifluoromethyl analogue exhibited the most potent inhibitory effect of norepinephrine and the most selectivity over serotonin uptake. Further synthesis and testing identified WAY, a potent norepinephrine reuptake inhibitor that exhibited excellent selectivity and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.
Milnacipran[ edit ] Structure of milnacipran.
Thiazide - Wikipedia
Milnacipran is structurally different from other SNRIs. N-methylation of milnacipran in substituent group R4 and R5 reduces the norepinephrine and serotonin activity. A phenyl group in substituent R6 showed effect on norepinephrine transporters. Substituent groups in R6 and R7 with allylic double bond showed significant improved effect on both norepinephrine and serotonin transporters.
Alcohol dependence or alcoholism is a chronic abuse leading to alcohol tolerance, withdrawal symptoms, and severe behaviour impairment DSM-IV, At risk drinking, according to the WHO guidelines, is daily alcohol intake over 40 g three drinks for males and 25 two drinks for females.
Among alcohol-related health problems, hypertension is rather common, but it is under-evaluated in many clinical settings. As alcohol is considered to be a vasodilator Heberden recommended the use of ethanol for the treatment of angina pectoris in Heberden,alcohol-triggered hypertension seems unlikely; unfortunately, the vasodilator effect of alcohol, if any, is completely suppressed by the sympathetic reaction to excess alcohol intake Randin et al.
A close relationship between alcohol abuse and hypertension has been established Puddey et al. In a careful meta-analysis of randomized controlled trials, a dose—response relationship was observed between mean reduction in reported consumption of alcohol and net change in both systolic and diastolic blood pressure SBP, DBP Xin et al.
The hypertensive effect of alcohol seems to be independent of age, as hypertension was observed in alcoholics aged between 18 and 30 years MacMahon, For haemorrhagic stroke, a relationship with heavy drinking has been reported Gorelick et al. Controversy remains regarding the effect of mild-to-moderate alcohol consumption: Increased sympathetic nervous activity, completely suppressing the vasodilator effect of alcohol, seems to be a major factor of hypertension in alcoholics: This hypothesis is supported by the suppression of alcohol-induced hypertension by dexamethasone, a CRH-suppressor Randin et al.
In addition, some vasoactive substances, such as catecholamines, prostacyclin, and endothelin, may be affected Forstermann and Feuerstein, ; Grogan and Kochar, Activation of the renin—angiotensin—aldosterone system is associated with an increased BP sensitivity to sodium Na Vannucchi et al.
Little is known about the relationship between alcohol withdrawal syndrome AWS and hypertension Balster et al.