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PRESENTATION ON CATECHOL AMINES & TRICYCLIC AMINES Catecholamines? 02 (3,4-dihydroxylphenyl group and an amine group) Catecholamines are hormones produced by the adrenal glands, brain and nerve tissues released into the blood during emotional or physical stress, fright or the ‘fight or flight’ response. They are part nervous system of the sympathetic 02 An amino group attached to an aromatic ring that contains two Hydroxyl groups situated ortho to each other is catechol amine 02 Roles Increase heart rate, Catechol breathing rate, muscle strength, mental alertness and blood pressure, increasing the blood to major organs e.g. the Kidneys, heart and brain. History of Adrenergic drugs 02 In 1896 Oliver and Schafer demonstrated that injection of extracts of adrenal gland caused a rise in arterial pressure. Simultaneous ,biogenic amine adrenaline was isolated From the suprarenal gland as active principle by Dale(1899) 02 Dale observed adrenaline caused two distinct kinds of effects namely vasoconstriction in certain vascular beds and vasodilatation In others. Ahlquist 1948 has shown clearly that several subclasses of adrenoceptor exist in body Adrenaline(epinephrine) was only thought to be the neurotransmitter in the adrenergic nervous system 1940, nor adrenaline (nor epinephrine, NE) was identified with true neurotransmitter at Terminus of the sympathetic nervous system. 02 Defining….! These are the drugs which are chemical agents that exert their principal pharmacological and therapeutic effects by either enhancing or reducing the activity of the various components of the sympathetic division of the ANS 02 Drugs coming under Adrenergic and which are catechol amines only, viz: -Dopamine, -Epinephrine (adrenalin) and -Nor epinephrine -Isoprenaline(Isoproterenol) -Colterol First 3 comes from Tryosine Tyrosine is created from phenylalanine by hydroxylation by the enzyme phenylalanine hydroxylase. Tyrosine is also ingested directly from dietary protein. It is then sent to catecholamine-secreting neurons. Here, many kinds of reactions convert 02 ***Levodopa to dopamine, to nor epinephrine, and eventually to epinephrine. Important features of catecholamine are biosynthesis, uptake and signaling 1. Biosynthesis 2. Release 3. Uptake (transporter) 4. Receptormediated signaling 5. Catabolism Biosynthesis s0 Both epinephrine and Nor epinephrine each possess a chiral carbon 2 atom thus, each can exist as an enationmeric pair of isomers the enantiomer with the (R) configuration is biosynthesized by the body and possess the biological activity. Location 02 1. Adrenergic and dopaminergic neurons in CNS (in sympathetic neurons of ANS) 2. Adrenal medulla Starting material Amino acid L-Tyrosine (into axoplasm) 02 *Acted on by Tyrosine hydroxylase (Tyrosine 3monooxygenase. *Whichleads to the formation of L-dihydroxy phenylalanine(L-dopa). *Second enzymatic step in cateholamine biosynthesis is the decarboxylation of L-dopa to give dopamine. The enzyme that carries out this transformation is L-aromatic amino acid decarboxylase (dopa decarboxylase). 02 *The dopamine formed in the cytoplasm of the neuron is actively transported into storage vesicles, where it is hydroxylated stereo specifically by the cu2+ containing enzyme dopamine betamonooxygenase(dopamine beta-hydroxylase) to give Nor Epinephrine *later Nor epinephrine is converted to epinephrine, which is catalyzed by PNMT(phenyl etanolamne NMethyltransferase). Which is stored in chromaffin cells 1.Cofactor: Molecular oxygen &Tetrahydrobiopterin has been used by Fe2+containing Tyrosine hydroxylase 02 2.Cofactor: above enzyme that used pyridoxal phosphate as a cofactor 3. Cofactor: dopamine beta-hydroxylase requires molecular oxygen and uses ascorbic acid as a cofactor 02 Catecholamines packed into the synaptic vesicles VMAT2: Non-selective and has high affinity to reserpine Reuptake Mechanism 02 Viz: 1. uptake1 2. uptake2 NA released from the nerve terminal is recaptured Uptake1 02 Axonal uptake: An active amine pump is present at the neuronal Membrane which transports NA at high rate.This uptake is the most Important mechanism for terminating postjunctional action of NA Inhibitors: Cocaine, desipramine, guanethidine and H1 antihistamines Granular uptake: cell body of neuron has granules has another amine pump which transports CA from the cytoplasm to with in the granules. This carrier also takes up DA formed in the axoplasm for For further synthesis of Nor epinephrine .Thus it is very Important in maintaining the NA content of the neuron. 02 Inhibitor:Reserpine Uptake2(Extra neuronal uptake) 02 Occurs in other tissue cells, but this is not of physiological or Pharmacological importance. It is not inhibited by the uptake 1 Inhibitors. e.g present in a wide variety of cells, including glial, hepatic, and myocardial cells. Uptake of catecholamines: transporter Metabolism 02 Two principle enzymes involved in catecholamine metabolism are 1.Monoamine oxidase(MAO) 2.Catechol-0-methyltransferase (COMT) Source:*MAO is associated with outer membrane of Mitochondria *COMT is found primarily in cytoplasm. or Both can be administered exogenously. 02 MAO oxidatively deaminates a variety of compounds that contain an amino group attached to a terminal carbon. 2 types of MAOs 02 1. MAO-A shows substrate preference for NE and serotonin, 2. MAO-B shows substrate selectivity for β-phenyl ethylamine and benzyl amine. 02 COMT catalyzes the methylation of a variety of catechol containing molecules. Step1: NE is deaminated oxidatively by MAO to give 3,4dihyroxyphenylglycolaldehyde. Step2: Reduced by aldehyde reductase to 3,4dihydroxyphenylethylene glycol. Step3: This (glycol) is primarily metabolite that is released into the circulation, where it undergoes methylation by the COMT that it encounters in non-neuronal tissues. Step4: The product of methylation, 3-methoxy-4hydroxyphenyl-ethylene glycol, is oxidized by alcohol dehydrogenase and aldehyde dehydrogenease to give 3methoxy-4-hydroxymandelic acid( vanillylmandelic acid[VMA]) 02 02 NOTE1: In the oxidative deamination of NE and epinephrine at extra-neuronal sites such as the liver, the aldehyde that is formed is oxidized usually by aldehyde dehydrogenase to give3,4-dihydroxymandelic acid. NOTE2: Methylation by COMT occurs almost exclusively on the meta hydroxyl group of the catechol, regardless of whether the catechol is NE, epinephrine, or one of the metabolic products. e.g. The action of COMT on NE and epinephrine give normetanephrine and metanephine, respectively. 02 NOTE: A converging pattern of NE metabolism of NE and epinephrine in which 3-methoxy-4-hydroxymandelic acid and 3methoxy-4-hydroxyphenylethylene glycol are common end products thus occurs, regardless of whether the first metabolic step is oxidation by MAO or methylation by COMT. 02 Pharmacokinetics: 1.Under normal circumstances 3-methoxy-4-hydroxymandelic acid is the principal urinary metabolite of NE 2.3-methoxy-4-hyroxyphenyethylene glycol are excreted along with varying quantities of other metabolites, both in the free form and as sulfate or glucoronide conjugates 3. Endogenous epinephrine is excreted primarily as metanephrine and 3-methoxy-4hydroxymandelic acid. 02 02 Metabolism of dopamine Major acidic metabolites: A. 3,4-dihydroxy phenylacetic acid (DOPAC) B. Homovallic acid (HVA) Catecholamine receptors 1. Postsynaptic receptors locate on dendrites or cell body, axons or nerve terminals 2. Presynaptic autoreceptors locate on the same neuron: a. terminal auto receptor: control release b. somatodendritic auto receptor: synthesis control c. major autoreceptor type: 2-adrenergic receptor in PNS/CNS; D2-dopamine receptor d. exception: -adrenergic receptor facilitates NE release Autoreceptor: inhibit transmitter release Feature of Dopamine receptors 1. Two subtypes of dopamine receptor: D-1 (short i3, long Cterminal) and D-2 like (long i3, short C-terminal) receptors 2. D2 receptors contain splicing isoform: D2L and D2S (87 bp) 3. D3 receptor has high affinity to atypical neuroleptics; D4 receptor bind tightly with clozapine 4. Chronic antagonist treatment up-regulate D2 receptors; agonist treatment might down-regulate the D2 receptor 5. Pharmacological application: anti-Parkinson (D2 agonist), anti-psychotic (D2 antagonist), addictive drugs (DA transporter) Features of Adrenergic receptors 1. Both NE and epinephrine bind to and receptors 2. 1 locates mainly in the heart and cortex; 2 predominate in the lung and cerebellum; 3 in the adipose tissue (significance in obesity) 3. 1 is a post-synaptic receptor (three subtypes: 1A, 1B and 1D); while 2 is both post- and pre-synaptic receptor (three subtypes: 2A, 2B and 2C) 4. Representative ligands: propranolol ( antagonist), yohimbine ( agonist) GPCR-mediated signal and internalization SAR 02 The parent structure for many of the sympathomeminetic drugs is Beta-phenylethylamine. The manner in which beta-phenyl ethylamine is substituted on the meta and para positions of aromatic ring and on the amino, α and β positions of the aromatic ring . 02 And on the amino, alpha and beta positions of the ethylamine side chain influences not only the mechanism of sympathomemimetic action but also the receptor selectivity of the drug. 02 For alpha the direct-acting sympathomimetic amines, maximal activity is seen in H2N β-phenylethylamine derivatives containing hydroxyl groups in the beta meta and para positions phenylethylamine of the aromatic ring meta para 02 (a catechol) and a beta-hydroxyl group of the correct stereo chemical configuration on the ethylamine portions of the molecule. Phenyl ethylamine is the basic structure for several Adrenergics And modification of that is a result of catechol amines. e.g. Amphetamine, Ephedrin, Noradrenaline, Adrenaline, Isoproterenol, Colterol Albuterol, Ritodrine,Dipivefrin.HCL, Ritodrine.HCL, Aramine etc Direct acting sympathomimetics that exhibit chirality by virtue of the presence of a beta-hydroxyl group (phenylethanolamines) invariably exhibit high stereo selectivity in producing their agonistic effects; i.e one enantiomeric form has more affinity for the receptor than the other form 02 e.g Epinephrine , NE and related 02 compounds, the more potent enantiomer has(R) configuration.(100fold more potent) Easson-Stedman hypothesis Explanation of stereo selectivity of three important pharmacophoric groups , i.e.; 1)Catechol group 2) Amino group 3) β-hydroxyl group Explanation : 02 More potent enantiomer is capable of assuming a conformation that results in the arrangement in space of the catechol group, the amino group, and the beta-hydroxyl group in a fashion resembling that of (-)-(R)-NE. 02 This explanation of stereo selectivity is based on the presumed interaction of these three critical pharmacophoric groups with three complementary binding areas on the receptor and is called as Easson-stedman hypothesis Presence of amino group in phenyl ethylamine is important for direct agonist activity. 02 The amino group should be separated from the aromatic ring by two carbon atoms for optimal activity. Both 10 and 20 amines are found among the potent directacting agonist, but 30 or quaternary amines tend to be poor direct agonists. 02 Bulk of nitrogen substituent increases, α-receptor agonist activity decreases and β-receptor activity increases. HO H2N OH HO NH HO H N OH HO OH noradrenaline OH adrenaline OH isoproterenol 02 alpha meta The nature of substituent can also affect H2N β1 and β2 receptor selectivity. para N-tert butyl group enhances β2 selectivity. beta 02 phenylethylamine e.g N-tert-butylnorepinephrine(Colterol) is 9-10 times as potent an agonist at tracheal β2 receptors than at cardiac β1 receptors. Large substituents on the amino group also protect the amino group from undergoing oxidative deamination by MAO. Methyl or Ethyl substitution on the α carbon of ethylamine side chain reduces direct receptor agonist activity at both α and β receptors. 02 alpha meta H2N para How ever, α alkyl group beta increases the duration of action of the phenylethylamine phenyl ethylamine agonist by making the compound resistant to metabolic deamination by MAO. Receptor selectivity 02 •α-methyl or ethyl substitution results in compounds with selectivity toward the β2 receptor •α-methyl substitution gives compounds with selectivity toward the α 2 receptor. 02 Another effect , introduction of chiral center, which has pronounced effects on the sterochemical requirements for activity. e.g. alpha-methylnorepinephrine, it is the erythro(1R, 2s) isomer that possesses significant activity at alpha receptors. 02 α-methylnorepinephrine Stability of catechol amines 02 Solution of catecholamine drugs are often stabilized by addition of an antioxidant(reducing agent) such as Ascorbic acid or sodium bisulfate, why? Catechol amines under go oxidation in the presence of oxygen (air) or with other oxidizing agents to produce othroquinone-like compounds, which undergo further reactions to give mixtures of colored products . 02 02 ADVERSE REACTIONS & THERAPEUTIC USES OF CA 02 Nor Epinephrine(Nor Adrenaline) Cardiovascular 02 •The drug can produce profound hypertension, local vasoconstriction, and tissue hypoxia. •NE-induced hypertension typically presents as headache, photophobia, stabbing chest pain, pallor, intense sweating, and/or vomiting. 02 •Adequate intravascular volume replacement is strongly recommended before, during, and upon withdrawal of therapy. Inadequate intravascular volume before and during NE therapy can result in decreased perfusion of vital organs, including the heart, liver, and kidney. Inadequate intravascular volume upon NE withdrawal can result in recurrent and profound hypotension. Hypotension, tissue hypo perfusion, and tissue hypoxia can produce ischemic injury and systemic lactic acidosis. Nervous system 02 Side effects include headache, anxiety, and photophobia. Local Phentolamine is an effective antidote to nor epinephrine extravasation. To prevent sloughing and necrosis in areas in which extravasation has taken place, it is recommended that the area be infiltrated as soon as possible with 10 mL to 15 mL of saline solution containing from 5 mg to 10 mg of phentolamine, an adrenergic receptor antagonist 02 Therapeutic effects 02 Anti-Inflammatory agent role in Alzheimer’s Disease The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally defuses from "varicosities". As such it provides an endogenous Anti-inflamamtory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus Up to 70% of norepinephrine projecting cells are lost in Alzheimer’s Disease. 02 Epinephrine 02 Serious Reactions •pulmonary edema •arrhythmias •HTN •angina •cerebral hemorrhage (IV) •tissue necrosis (SC, IM) 02 Common Reactions palpitations tachycardia nausea/vomiting pallor sweating dizziness weakness tremor headache apprehension nervousness anxiety 02 02 Therapeutic uses 02 Cardiac arrest Adrenaline is used as a drug to treat cardiac arrest and other cardiac dysrhythmias resulting in diminished or absent cardiac output. Its actions are to increase peripheral resistance via α₁ receptor-dependent vasoconstriction and to increase cardiac output via its binding to β₁ receptors. Shock and anaphylaxis Allergy patients undergoing immunotherapy may receive an adrenaline rinse before the allergen extract is administered, thus reducing the immune response to the administered allergen 02 Epinephrine ampule 1 mg (Suprarenin) Because of various expression of α₁or β₂receptors, depending on the patient, administration of adrenaline may raise or lower blood pressure, depending whether or not the net increase or decrease in peripheral resistance can balance the positive inotropic and chronotropic effects of adrenaline on the heart, effects which respectively increase the contractility and rate of the heart. 02 Use in local anesthetics 02 •Epinephrine is added to injectable forms of a number of local anesthetics, such as bupivacaine and lidocaine, as a vasoconstrictor to retard the absorption and therefore prolong the action of the anesthetic agent. •Some of the adverse effects of local anesthetic use, such as tachycardia and tremor, may be caused by epinephrine Treating Croup 02 Racemic epinephrine has historically been used for the treatment of croup. Racemic epinephrine is a 1:1 mixture of the (D) and (L) isomers of epinephrine. The L form is the active component. 02 Racemic epinephrine works by stimulation of the α-adrenergic receptors in the airway with resultant mucosal vasoconstriction and decreased subglottic edema and by stimulation of the βadrenergic receptors with resultant relaxation of the bronchial smooth muscle Dopamine 02 Serious Reactions •anaphylaxis •asthma exacerbation •extravasation necrosis •Gangrene Common Reactions •hypotension •tachycardia •headache •nausea •vomiting •conduction abnormalities •necrosis at injection site 02 Therapeutic Effects Used in Parkison’s disease.. Cocaine and Heroin…areDopamine reuptake inhibitor The combination of heroin and cocaine is known by users as a "speed-ball." This combination of drugs is extremely dangerous, and users show very rapid psychological and physiological deterioration. 02 Synthesis of Catechol amines 02 Levodopa Since dopamine does not cross the blood-brain barrier, it has no therapeutic utility. How ever , its immediate metabolic precursor, levodopa, is transported into the brain by the large, neutral amino acid transporter and permeates into straital tissues where it is decarboxylated to dopamine 02 OH 02 O O NBS O acetone C(CH3)2 C(CH3)2 OH BrH2C O 4-methyl catechol O CH3-SO-CH2-S-CH3 NaH THF O C(CH3)2 O H+ O HCN O CH2 HOH2C NC C(CH3)2 C(CH3)2 NH3 O H3C-OHS-CH2C O CH H3CS 02 NH2 H+ 6N HCL HO Reduction HO NH2 Levodopa COOH 95% of levodopa is decarbocylated Aromatic to L-amino acid decarboxylase dopamine mediated byHOan enzyme that is pyridoxin-dependant, HO MAO Dopamine Aldehyde dehydrogenase NH2 COMT HO HO NH2 HO COOH H3OC 3,4-Dihydroxyphenyl acetic acid MAO 3-Methoxytyramine COMT HO COOH H3OC 3-Methoxy-4-hyroxy phenyl acetic acid(HVA) Isoproterenol 02 Isoprenaline(Isoproterenol) HO ClH2C-OC-O O -HCL HO Cl HO Fries rearrangement Cl chloroacetyl chloride catechol 02 HO HO HO Pd, H2 H N COCH2NHCH(CH3)2 OH OH OH isoprenaline H2N-CH(CH3)2 HO COCH2Cl Colterol 02 Bitolteral mesylate(Tornalate) HO COCH3 HO Br2 CH3COCl HO H2NC(CH3)3 HO HO COCH2NHC(CH3)3 HO O H3C H3C C COCl O COCH2NHC(CH3)3 O H3C Pd-C, H2 C O Esterases HO O H3C Pd-C, H2 02 CHCH2NHC(CH3)3 OH HO C O CHCH2NHC(CH3)3 Colterol OH O H3C C O Bitolterol It is a prodrug of colterol a selective beta2 agonist. The ester provides increase lipid solubility and proglonged duration of action.It is administered b inhalation for bronchial astham and the ester groups are hydrolysed by esterases to active colterol 02 Epinephrine(Adrenaline) Synthesis 02 VIP points 1.Amanditine .HCl is an Antiviral drug but It is a drug which “Enhances the Dopamine level at Synapses . 02 2.Levodopa when administred with carbidopa enchances the activity by increasing the Plasma t/2 life of drug from 0.5-1hrs to 1-2 to 3hrs. And also increases the dopamine reaching brain. 02 02 Tricyclic amines 02 02 Serval classes of drugs contains, tricylic amine structure they may be notated as follows.. Classification 1. Anti Depressants. 2. Anti Histamines. 3. Anti Psychotics. 4. Miscellaneous drugs. 02 These are main classes of drugs which contain tricyclic amine sturctures . Tricylic compound of Antidepressants 02 First generation drugs **Dibenazepines derivatives of Antidepressants e.g. Imiprmaine, desipramine(pertfroane) clomipramine(anafranil) 02 **Dibenzocycloheptanes derivatives of Antidepressants e.g. Amitriptyline(Elavil),Nortriptyline(Aventyl) **Diabenzodiazepine derivatives: e.g. Dibenzepine, Noveril, doxepin HCl Amitriptyline 02 History •Initially Amitriptyline is used in ankylosing spondylitis for pain relief and in some European countries it is officially approved as a preventive for patients with frequent/chronic migraines, usually 25 to 75 mg. It is also used as a preventive for patients with recurring biliary dyskinesia (sphincter of Oddi dysfunction), usually 10 mg daily. •The most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs 02 MOA Amitriptyline additionally functions as a 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, α1-adrenergic, H1, and mACh receptor antagonist, and σ1 receptor agonist. 02 Recently, amitriptyline has been demonstrated to act as an agonist of the TrkA and TrkB receptors. 02 It promotes the heterodimerization of these proteins in the absence of NGF and has potent neurotrophic activity both in-vivo and in-vitro in mouse models Side effects 02 Common side effects of using amitriptyline are mostly due to its anticholinergic activity. weight gain, dry mouth, changes in appetite, drowsiness, muscle stiffness, nausea, constipation, nervousness, dizziness, blurred vision, urinary retention, insomnia and changes in sexual function. Some rare side effects include tinnitus, hypotension, mania, psychosis, sleep paralysis, hypnagogia, hypnopompia, heart block, arrhythmias, lip and mouth ulcers, extrapyramidal symptoms,, and hepatic toxicity 02 02 02 Imipramine 02 Sold as: Antideprin, Deprimin, Deprinol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil Imipramine is mainly used in the treatment of major depression and enuresis. 02 It has also been evaluated for use in panic disorder History Imipramine was, in the late 1950s, the first tricyclic antidepressant to be developed (by Ciba-Geigy). It was first tried against psychotic disorders, such as schizophrenia, but proved insufficient. As an antidepressant, it did well in most severe cases of depression. 02 It is not surprising, therefore, that Imipramine is also known to cause a high rate of manic and hypo manic reactions, especially in patients with preexisting bipolar disorder. 02 Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In pediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis MOA 02 The mechanisms of Imipramine's medicinal action include Nor-epinephrine (NE) Reuptake inhibition (strong). Serotonin (SE) Reuptake inhibition (moderate to strong). Epinephrine Imipramine antagonizes adreno-receptors (II), thus sometimes causing increased heart rate (contributed to by other effects as well), orthostatic hypotension, and a general decrease in the responsiveness of the central nervous system (hence, a contribution to its potent anti-anxiety properties). Dopamine Reuptake and release at D1 and D2 receptors, Enhancement of brain dopamine activity has been implicated in Imipramine's ability to stimulate motor activity Histamine Imipramine is an antagonist at histamine H1 receptors. This contributes to the acute sedative effect that it has in most people. In turn, its anti-histaminergic and general calming effects take place immediately, and, thus, Imiparmine is sometimes prescribed as a sleep aid in low doses. 02 02 Acetylcholine (ACh) Imipramine is an anticholinergic. Thus, it is prescribed with caution to the elderly and with extreme caution to those with pyschosis, anticholinergics increases the potential of Imipramine to cause hallucinations, confusion and delirium in this population. Imipramine is an antagonist at M2 muscarinic acetylcholine receptors . The blockade of cholinergic (muscarine) receptors is known to cause Euphoria. potentially contributing to the mood lifting effects of Imipramine as well. 02 Antimuscarinic effect is also responsible for rapid heart rate (tachycardia). Imipramine has been shown to interact with opioid systems in the central nervous system, possibly explaining some of its painrelieving properties. Adverse reactions 02 •Allergy: isolated cases ofpneumonitis(fever, chills, cough, difficulty with breathing, unusual weight loss, feeling sick, puffy, swollen face, tongue or body) •Arrhythmias: irregular heart rhythms. •Weight gain has been reported frequently 02 • Isolated cases of enlarged mammary glands,production or over-production of breast milk, increased or decreased blood sugar levels Low levels of salt in the blood have been reported, usually in elderly patients. •Tremor has been reported frequently. Headache, confusion, orthostatic hypotension (resulting in dizziness upon standing), numbness/tingling, agitation, anxiety, restlessness, mood swings, exaggerated behavior, delusions and hallucinations have been reported occasionally and are more common in the elderly or in patients on high doses. •Aggressiveness, weakness, lack of co-ordination, sudden muscle spasms, difficulty speaking have been reported in isolated cases. If the medicine is stopped too quickly, there is the possibility the user may suffer from feeling or being sick, stomach pains, diarrhea, headache, sleeplessness, nervousness, anxiety, irritability and increased sweating. 02 02 Metabolism 02 02 Desipramine It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants. Desipramine is an active metabolite of imipramine 02 02 The mechanism of action seems to involve the activation, through norepinephrine reuptake inhibition, of descending pathways in the spinal cord that block pain signals from ascending to the brain. It may also be used to treat symptoms of cocaine withdrawal. Dangers Along with amitriptyline and imipramine, desipramine is one of the most toxic antidepressants still available on the market. 02 Cardiac arrhythmia Antidepressant desipramine hydrochloride(Norpramin) , is prescribed carefully in patients with family history of dysrhythmia or sudden cardiac death. 02 Desipramine overdose is more likely to result in death than overdose with other tricyclic antidepressants The "warnings" and "overdosage" sections of the drug's labeling are being changed to reflect these potential adverse events. Genotoxicity 02 Desipramine is associated with an increased risk of Breast cancer in women. Metabolism It undergoes metablic N-demethylation to form desipramine, which appear to have a somewhat shorter onset of action than imipramine and less sedating. The compound as a tendency toward a high 5HT/NE uptake block ratio. 02 Doxepin (Adapine, Deptran, Sinquan 02 and Sinequan) History Doxepin was synthesized by Stach and Spingler from the German drug manufacturer C. F. Boehringer & Söhne GmbH in Mannheim. It was tested from 1963 to 1968 in different German and Swiss psychiatric institutions and was approved in Germany and elsewhere thereafter. The antidepressive effects were found to be excellent. Strong anxiolytic and sedative properties were also demonstrated. Doxepin has been in clinical use for several decades. The drug plays an important role in many indications today, not only in psychiatry/neurology. 02 Mechanism of action: 02 •Doxepin inhibits the reuptake of serotonin and norepinephrine. • Its actions of the reuptake of dopamine are negligible. • Doxepin also has antagonistic effects at a variety of receptors: Extremely strong: H1, H2 Strong: 5-HT2, α1-adrenergic, mACh Moderate: 5-HT1 Weak: D2, α2-adrenergic 02 Like other tricyclic antidepressants, doxepin also blocks sodium channels possibly accounting for its analgesic action. Additionally, doxepin exerts a strong local anaestic action. 02 Side effects CNS : fatigue, dizziness, drowsiness, lightheadedness, confusion, nightmares, agitation, increased anxiety, insomnia, seizures (infrequently), delirium, rarely induction of hypomania and schizophrenia (stop medication immediately), extrapyramidal side-effects (rarely), abuse in patients with polytoxikomania (rarely), tinnitus 02 Anticholinergic : dry mouth, obstipation, even ileus (rarely), difficulties in urinating, sweating, precepitation of glaucoma Antiadrenergic : hypotension, postural collapse (if patient arises too fast from lying/sitting position to standing), arrhythmias (sinustachycardia, bradycardia, av-blockade) Allergic/toxic : skin rash, photosensitivity, liver damage of the cholostatic type (rarely), hepatitis (extremely rare), leuko- or thrombopenia (rarely), agranulocytosis (very rarely), hypoplastic anemia (rarely) 02 Others : frequently increased appetite, weight gain, rarely nausea, frequently impaired sexual function in men (impotence, ejaculation-difficulties), rarely hypertension, rarely polyneuropathy, in both sexes breast-enlargement and galactorrhea (rarely) 02 Anti depressants –S.A.R Maximum potency of antidepressant dihydrobenzepine occures whenthe basic nitrogen is separated from the tricyclic nucleus by a propylene bridge(3 carbon distance is necessary) . Side chain -CH2-CH2-CH2-NH2 Branching of propylene chain e.g. trimipramine has little effect on antidepressant activity. Activity is confined to methyl-subsituted or unsubstitued amines. Larger alky groups abolish activity and introduce toxicity. Side chain with quinuclidine, morpholine nuclei claimed to be potent. •Secondary amines and tertiary amines are important in side because of their inhibitory reuptake activity of Nor epinephrine and 5-HT respectively. •Introduction of substituent at 3-position has little effect. 3-Cholroimipramine is similar to imiprmaine. •2,8 dimethyl or 3,7-dichloro are inactive. •Ring nitrogen of desipramine can be replaced by carbon to give active compounds. •Introduction of 10,11 –double bond into nortriptyline enhances antidepressant activity. •Nortriptyline and Protriptyline with exocyclic and indocyclic double bonds respectively differs in their metabolism pattern. The later one is lesser metabolized. •Several amitriptyline analogues with replacement of c11 with O, S, SO2 , NH, NCH3 are clinically effective antidepressants. Other drugs which are Anti depressants 02 Trimipramine Cianopramine Butriptyline Nortriptyline Amineptine 02 Anti Histamines 02 Phenothiazine derivatives e.g. Promethazine(phenergan), Trimeprazine(Temasril) Alimemazine 02 Promethazine(phenergan) 02 Phenergan, Promethegan, Romergan, Fargan, Farganesse, Prothiazine, Avomine, Atosil, Receptozine, Lergigan) Is a first-generation H1 receptor antagonist. It has a strong sedative effect and in some countries is prescribed for insomnia whenbenzodiazipines are contraindicated. It is available OTC in the UK,Australia Canada switzerland and many other countries, but by prescription in the U.S 02 Mechanism of action 02 •Promethazine is a phenothiazine derivative that competitively blocks histamine H1 receptors without blocking the secretion of histamine. •It also is a very weak dopamine antagonist. 02 •It has sedative, anti-motion-sickness, anti-emetic, and anticholinergic effects. •Used medically as an antihistamine and antiemetic. Side effects 02 •Confusion in the elderly drowsiness, dizziness, fatigue, more rarely vertigo •Dry mouth •Respiratory depression in patients under age of 2 and in those with severely compromised pulmonal function •Constipation 02 •Chest Discomfort/Pressure. (typically in cases when patient is already taking medication for high blood pressure) •Euphoria (very rare, except with high IV doses and/or coadministration with opioids/CNS depressants). •Paresthesia •Short temper/Irritability Synthesis 02 02 Other drugs which are Anti histamines 02 Alimemazine clobenzepam oxomemazine tandamine Isothipendyl propiomazine 02 dacemazine Antipsychotics phenothiazine derivatives e.g. Diethazine, chlorpromazine 02 Sulfur substituted e.g. chlorprothixene Benzoquinolines e.g. Benzo quinamide 02 Chlorpromazine(CPZ) 02 Marketed in the United States as Thorazine and elsewhere as Largactil) is a typical antipsychotic. First synthesized on December 11, 1950, chlorpromazine was the first drug developed with specific antipsychotic action, and would serve as the prototype for the phenothiazine class of drugs Chlorpromazine works on a variety of receptors in the CNS producing anticholinergic, antidopaminergic, antihistaminic, and weak antiadrenergic effects 02 History 02 In 1933, the French pharmaceutical company Laboratories Rhône-Poulenc began to search for new anti-histamines. The chemist Paul Charpentier produced a series of compounds and selected the one with the least peripheral activity, known as RP4560 or chlorpromazine, on 11 December 1950 02 The first published clinical trial was that of Jean Delay and Pierre Deniker at the Hôpital Sainte-Anne in Paris in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents. The response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour. Chlorpromazine, in widespread use for 50 years, remains a "benchmark" drug in the treatment of schizophrenia, an effective drug although not perfect 02 Uses Chlorpromazine is classified as a low-potency typical antipsychotic and in the past was used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of bipolar disorder as well as amphetamineinduced psychoses. 02 Chlorpromazine has also been used in porphyria and as part of tetanus treatment. It still is recommended for short term management of severe anxiety and aggressive episodes. Resistant and severe hiccups, severe nausea/emesis and preanesthetic conditioning are other uses.Symptoms of delirium in medically hospitalized AIDS patients have been effectively treated with low doses of chlorpromazine. Adverse effects 02 •The main side effects of chlorpromazine are due to its anticholinergic properties •These include sedation, slurred speech, dry mouth, constipation, urinary retention and possible lowering of seizure threshold 02 •lowers blood pressure with accompanying dizziness •Three types of skin disorders are observed: hypersensitivity reaction, contact dermatitis, and photosensitivity(abnormal pigmentation of the skin) on exposure to sun. •Have significant effects on gonadal hormones including significantly lower levels of estradiol and progesterone in women whereas men display significantly lower levels of testosterone and DHEA •Cardiac arrhythmia and apparent sudden death have been associated with therapeutic doses of chlorpromazine, however they are rare cases. • Patients on chlorpromazine therapy exhibit abnormalities on the electrocardiographic T and U waves. These major cardiac arrhythmias that are lethal are a potential hazard even in patients without heart disease who are receiving therapeutic doses of antipsychotic drugs. Metabolism •The cytochrome P450 isoenzymes 1A2 and 2D6 are needed for metabolism of chlorpromazine. • CYP 2D6 is the main enzyme catalyzing 7-hydroxylation of chlorpromazine, the reaction being partially catalyzed by CYP1A2. 02 02 •Chlorpromazine is typically degraded by the liver by the action of cytochrome-P450 family enzymes, usually CYP2D6. Less than 1% of the unchanged drug is excreted via the kidneys in the urine. In which 20-70% is excreted as conjugated or unconjugated metabolites, whereas 5-6% is excreted in feces. There are on the order of 10 or more major metabolites generated by the hepatic pathway in appreciable concentrations. The three most common appear in the following image. 02 • • • N-demethylated species, 7-hydroxylated form, and finally chlorophenothiazine, in which the entire R1 side chain is missing. Mechanism of action 02 Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic receptors: Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms; in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extra pyramidal effects. •serotonin receptors (5-HT1 and 5-HT2), with anxiolytic, and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), 02 •histamine receptors (H1 receptors, accounting for sedation, antiemetic effect, vertigo, fall in blood pressure and weight gain), 02 •α1- and α2-adrenergic receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism— controversial). •M1 and M2 muscarinic acetylcholine receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects). 02 Synthesis 02 Other drugs 02 Cis-Chlorprothixen 02 Fluotracen clomipramine ciclindole Triflupromazine zotepine L-mepromazine 02 Miscellaneous drugs 02 Carbamazepine is a dibenzazepine 02 Carbamazepine (CBZ) is an anticonvulsant and mood stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia. History Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953.Schindler then synthesized the drug in 1960, before its anti-epileptic properties had been discovered. Carbamazepine was first marketed as a drug to treat trigeminal neuralgia (formerly known as tic douloureux) in 1962. It has been used as an anticonvulsant in the UK since 1965, and has been approved in the U.S. since 1974. Dr. Okuma, working independently, did the same thing with success. As they were also epileptologists, they had some familiarity with the anti-aggression effects of this drug. Carbamazepine would be studied for bipolar disorder throughout the 1970s. 02 Sold as: Tegretol, Biston, Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal, 02 Stazepine, Telesmin, Teril, Timonil, Trimonil, Epimaz, Carbama/Carbamaze (New Zealand), Amizepin (Poland), Hermolepsin (Sweden), and Degranol (South Africa) Metabolism Carbamazepine exhibits autoinduction: it induces the expression of the hepatic microsomal enzyme system CYP3A4, which metabolizes carbamazepine itself. 02 After enough carbamazepine has been presented to the liver tissue, the CYP3A4 activity increases, speeding up drug clearance and shortening the half-life Mechanism of action 02 The mechanism of action of carbamazepine and its derivatives is relatively well understood. Voltage-gated sodium channels are the molecular pores that allow brain cells (neurons) to generate action potentials, the electrical events that allow neurons to communicate over long distances. After the sodium channels open to start the action potential, they inactivate, essentially closing the channel. 02 •Carbamazepine stabilizes the inactivated state of sodium channels, meaning that fewer of these channels are available to subsequently open, making brain cells less excitable (less likely to fire). •Carbamazepine has also been shown to potentiate GABA receptors made up of alpha1, beta2, gamma2 subunits. Adverse effects Common adverse effects include drowsiness, headaches and migraines, motor coordination impairment and/or upset stomach. Carbamazepine preparations typically greatly decrease a person's alcohol tolerance. Less common side effects include cardiac arrhythmias, blurry or double vision and/or the temporary loss of blood cells or platelets and in rare cases can cause aplastic anemia. With normal use, small reductions in white cell count and serum sodium are common, however, in rare cases, the loss of platelets may become life-threatening 02 02 There are also reports of an auditory side effect for carbamazepine use, whereby patients perceive sounds about a semitone lower than previously Carbamazepine may cause Syndrome of inappropriate antidiuretic hormone (SIADH), since it both increases the release and potentiates the action of ADH (vasopressin). Synthesis 02 02 02 02 Thanks for your patience……….!