Dopamine, dopaminergic system, parkinson's disease, pharmacotherapy and modulation
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Complete synopsis of Dopamine, neuro degenerative condition, dopaminergic system, dopaminergic pathways its modulation and pharmacotherapy, parkinsons disease, parkinsonism
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Dopamine, dopaminergic system, parkinson's disease, pharmacotherapy and modulation
- 1. Moderator Dr Siddhartha Dutta MAMC, New Delhi
- 2. Introduction Dopamine receptors Dopaminergic pathways Pathologies associated with dopamine system Drugs modulating dopaminergic system Dopamine and Reward Signaling ,Addiction, ADHD & Schizophrenia Dopamine and CVS Dopamine and Emesis Summary 2
- 3. Synthesized by George Barger and James Ewens in 1910 Henry Dale characterized the biological properties of DA in the periphery, and described it as a weak, adrenaline- like substance Was considered as just a precursor to Epinephrine and Norepinephrine Function as neurotransmitter discovered by Arvid Carlsson in 1958 3
- 4. Synthesis • DOPA is converted so rapidly into Dopamine that DOPA levels are negligible in the brain • Rate of synthesis is regulated by – Catecholamine acting as inhibitor of TH – Availability of BH4 – Presynaptic DA receptors – Amount of activity in nigrostriatal pathway 4 Rate Limiting Step
- 5. Metabolism • In rats – DOPAC major metabolite • In primates and human – HVA major metabolite • Accumulation of HVA in brain or CSF used as index of function of dopaminergic neurons 5
- 6. 6
- 7. Metabotropic G-protein coupled receptors D1 – like family: ◦ Includes subtypes D1 and D5 ◦ Activation is coupled to Gαs ; activates adenylyl cylcase which leads to increase in concentration of cAMP D2 – like family: ◦ Includes D2, D3 and D4 ◦ Activation is coupled to Gαi ; inhibits adenylyl cyclase leading to decrease in concentration of cAMP 7
- 8. 8
- 11. CNS CVS GIT
- 13. Mesolimbic Pathway Mesocortical Pathway Nigrostriatal Pathway Tuberoinfundibular Pathway
- 15. Mesolimbic Pathway ◦ Associated with pleasure, reward and goal directed behavior Mesocortical Pathway ◦ Associated with motivational and emotional responses Nigrostriatal Pathway ◦ Involved in coordination of movement (part of basal ganglia motor loop) Tuberoinfundibular Pathway ◦ Regulates secretion of prolactin by pituitary gland and involved in maternal behavior 20
- 16. INCREASED DOPAMINE DECREASED DOPAMINE SCHIZOPHRENIA PARKINSON’S DISEASE ADHD IMPULSE CONTROL DISORDER DRUG ADDICTION HYPERPROLACTINEMIA
- 18. Parkinson’s disease is a clinical syndrome consisting of four cardinal features: Bradykinesia Muscular rigidity Resting tremor Postural instability
- 20. Dopamine precursor : Levodopa Peripheral decarboxylase inhibitors: Carbidopa, Benserazide Dopaminergic agonists: Bromocriptine, Ropinirole, Pramipexole, Apomorphine MAO-B inhibitor: Selegiline, Rasagiline COMT inhibitors: Entacapone, Tolcapone Dopamine facilitator: Amantadine
- 22. Drug Pharmacokinetic and interaction effect Adverse effects Levodopa Oral T ½ - 1-2 h Dose: 250- 1200 mg >95% is decarboxylated in the peripheral tissues (mainly gut and liver) Use with COMT or MAO-B inhibitors prolongs duration of effect Ameliorates all symptoms of PD Hypokinesia and rigidity resolve first, later tremor as well significant peripheral dopaminergic effects Postural hypotension Nausea & vomiting inhibit prolactin release Arrhythmias Dyskinesias Behavioral effects Motor fluctuation wearing-off phenomena/end of dose On off phenomena
- 23. Drug Pharmacokinetic and interaction effect Adverse effects Levodopa • Oral • T ½ - 1-2 h • Dose: 250- 1200 mg • >95% is decarboxylated in the peripheral tissues (mainly gut and liver) • Use with COMT or MAO-B inhibitors prolongs duration of effect • Ameliorates all symptoms of PD • Hypokinesia and rigidity resolve first, later tremor as well • Nausea & vomiting • inhibit prolactin release • significant peripheral dopaminergic effects Postural hypotension Nausea & vomiting Arrhythmias Dyskinesias Behavioral effcts on-off and wearing-off phenomena Levodopa + Carbidopa 200 mg/ 100mg + 50mg / 25 mg 2-3 times a day • T ½ of levodopa is prolonged & dosage is reduced to ¼ th • Systemic complications of DA are reduced • 'On-off' effect is minimized as cerebral DA levels are more sustained. • Involuntary movements • Behavioral abnormalities • Excess day time sleepiness • Postural hypotension
- 24. agonists features interaction Bromocriptine Oral T ½ -6-10 hrs Dose: 1.25-5 mg O.D If used alone, doses needed are high used only in late cases Reduces symptoms Smooths out fluctuations in levodopa response Nausea and vomiting postural hypotension, dyskinesias Pramipexole Oral T ½- 8 h Starting dose-0.125 mg TDS 1-1.5 mg TDS Reduces symptoms, Smooths out fluctuations in levodopa response dose titration for maximum improvement can be achieved in 1-2 weeks Fewer GI effects Nausea and vomiting Postural hypotension Day time sleepiness Hallucinations Ropinirole Starting dose-0.25mg TDS 4-8 mg TDS Slower rates of neuronal degeneration ?? FDA approved for Restless Leg Syndrome Sudden attack of irresistible sleepiness
- 25. Drug Pharmac okinetics Features and effect Adverse effects Apomorphine S.C 2 mg test dose ↓ 6 mg Inj 3 times daily High affinity - D4 Mod affinity - D2,3,5 low affinity - D1 FDA approved as a "rescue therapy" Lessens motor fluctuations Reduced frequency of on-off effect Restless leg syndrome Nausea and vomiting postural hypotension QT prolongation Injection-site reactions, Hallucinations Dyskinesia Abnormal behavior
- 27. MAO- B inhibitors Pk Features Adverse effects Selegiline Oral 5- 10 mg/ day BD dosing Oral disintegr ating tab Transder mal patch selective and irreversible MAO-B inhibitor Increases dopamine stores in neurons Adjuvant to levodopa 20-30% reduction in levodopa dose May accentuate the adverse motor and cognitive effects of levodopa Metabolites of include amphetamine and methamphetamine, which may cause anxiety, insomnia, and other adverse symptoms Do not exhibit cheese reaction Postural hypotension Dyskinesias, Mental confusion Hallucination C/I in patients with siezures Interactions: rarely serotonin syndrome with meperidine, also with SSRIs, TCA
- 28. MAO- B inhibitors Pk Features Adverse effects Selegiline Oral 5- 10 mg/ day Oral disintegr ating tab Transder mal patch selective and irreversible MAO-B inhibitor Increases dopamine stores in neurons Adjuvant to levodopa 20-30% reduction in levodopa dose May accentuate the adverse motor and cognitive effects of levodopa Metabolites of include amphetamine and methamphetamine, which may cause anxiety, insomnia, and agitation Do not exhibit cheese reaction Postural hypotension Dyskinesias, Mental confusion or hallucination C/I in patients with siezures Interactions: serotonin syndrome with meperidine, also with SSRIs, TCA Rasagiline 5x potent 0.5-1.0 mg tab OD dosing No undesirable amphetamine metabolites Effective in early PD?? Adjunctive therapy significantly reduced levodopa-related "wearing off" symptoms Neuroprotective (Parkinson Study Group, 1993; Yacoubian and Standaert, 2008, Olanow, 2008, ). Stupor, rigidity, agitation, and hyperthermia when administered with Meperidine
- 29. COMT inhibitors Pk Features Adverse effects Entacapone Oral 600- 2000 mg BD or TDS Adjuvants to levodopa-carbidopa Advanced cases Reduces metabolism of levodopa and prolongs its action Increased levodopa conc Nausea Dyskinesias confusion Postural hypotension Tolcapone Oral 100- 300 mg BD or TDS Longer acting Enters CNS Hepatotoxic??
- 30. Drugs Pk Features Adverse effects Glutamate (NMDA receptor) antagonist Amantadine Oral T ½ 8 to 12 hrs 100 mg BD Promotes presynaptic synthesis & release of DA in brain Suppresses motor fluctuations & abnormal movements Smoothen wearing off Anticholinergic property Insomnia Restlessness Confusion Nightmares Hallucination Livedo reticularis Ankle edema
- 34. Occasional substance use is an impulse choice driven by positive reinforcement of the drug’s expected effect This teaches the brain to anticipate reward on subsequent exposure to the drug When the substance is taken, pleasure will be experienced again, usually followed by regret
- 35. With repeated exposure to the drug neurobiological changes occur in the brain leads to craving, reduced reward on drug exposure withdrawal during abstinence (negative reinforcement) This leads to craving which is released by drug ingestion
- 36. Nucleus Accumbens Occurs due to increased release of dopamine caused by the psychotropic substances like morphine heroin Cannabis cocaine nicotine
- 39. Decrease In Dopamine Level in Anterior frontal cortex ◦ An area associated with cognitive function such as Attention Concentration
- 40. Defects in “dopamine transporters” in brain Dopamine transporter density (DTD) The transporters take up too much dopamine before it can be passed from one brain cell to another Decreased dopamine activity
- 41. Methylphenidate and Amphetamine Increase both dopamine and norepinephrine levels in brain Methylphenidate-5 mg at morning & lunch gradually increased to 60 mg 10-30 mg/ day amphetamine Adverse effects Restlessness, dizziness, tremor, hyperactive reflexes, talkativeness, irritability, insomnia & euphoria. Confusion, aggressiveness & delirium
- 42. Dopaminergic Tubero-infundibular tract & hypophyseal portal system
- 43. Bromocriptine Start at a low dose (1.25 mg) at bedtime After 1 week, a morning dose of 1.25 mg can be added. If clinical symptoms persist or prolactin levels remain elevated, the dose can be increased gradually, every 3-7 days 5 mg BD or TDS as tolerated Cabergoline Ergot derivative with a longer t1/2 (65 hours) Higher affinity & greater selectivity for the D2 receptor ( 4x potent) than bromocriptine Induces remission 0.25 mg twice/week or 0.5 mg once/week can be ↑ to 2mg twice or thrice /week
- 44. Defective dopamine neurotransmission – relative excess of central dopaminergic activity An increase in DA function in the mesolimbic system (postive symptom) Decreased function in the mesocortical DA system (negative symptoms) Behavior similar to the behavioral effects of psychostimulants 54
- 45. Came to existence from the fortuitous discovery of chlorpromazine's therapeutic efficacy in schizophrenia Carlsson – Postsynaptic D2 receptor antagonism was the common mechanism that explained antipsychotic properties Reserpine, exhibited antipsychotic properties by decreasing dopaminergic neurotransmission High risk for drug-induced psychosis with drugs that directly increase synaptic dopamine availability, including cocaine, amphetamines & L-dopa
- 46. Synaptic DA availability Val{108/158} Met polymorphism of COMT DA neurotransmission (dysbindin)
- 47. Antipsychotic Typical Mechanism of action Toxicity Phenothiazines: • Chlorpromazine • Fluphenazine • Thioridazine • Thioxanthenes • Thiothixene • flupenthixol Blockade of D2>>5HT2A Also blocker of alpha 1, M, H1 Akathisia, Dystonia, Parkinson symptom Tardive dyskinesia, Hyperprolactinemia Butyrophenones • Haloperidol • Droperidol • Domperidone Blockade of D2>>5HT2A Alpha 1and minimal M 1blockade Extrapyrimidal dysfunction
- 48. Antipsychotic Atypical Mechanism of action toxicity • Aripiprazole • Clozapine • Olanzapine • Quetiapine • Risperidone • Ziprasidone • Paliperidone • Iloperidone Blockade of 5HT2A>D2 Alpha1& M 1blockade variable H1 blockade Agranulocytosis(Clozapi ne) Weight gain lower seizure threshold Catract QT prolongation
- 50. D1 and D2 β 1 & α1 agonist Effect on CVS is dose dependent Low dose 1-2 mcg/kg/min Moderate dose 3-10mcg/kg/min High dose >10 mcg/kg/min D 1 renal and mesenteric blood vessels dilates β 1 ↑ H.R ↑ contractility ↑ AV conduction α₁ action predominates vasoconstriction ↑ G.f.r. ↑ Renal blood flow Natriuresis ↑ C.O & SBP TPR unaltered TPR ↑
- 51. C.O & SBP with little effect on DBP No effect on nonvascular α₁ receptors Does not penetrate blood-brain barrier-no CNS effects Management of low cardiac output states associated with compromised renal function IV infusion (0.2-1 mg/min) which is regulated by monitoring BP and rate of urine formation
- 52. Dopamine -only IV, preferably into a large vein calibrated infusion pump Dosage Initially at a rate of 2-5 mcg/kg per min; this rate may be increased gradually up to 20-50 mcg/kg per min or more Monitoring of arterial and venous pressures and the ECG Adverse effects & precautions Nausea, tachycardia, anginal pain, arrhythmias, HTN headache Extravasation of DA during infusion may cause ischemic necrosis and sloughing
- 53. Agonist for peripheral D1 receptors and antagonist to α2 receptors No significant affinity for D2, α 1 or β receptors Rapidly acting(4 mins) and short duration of action (< 10 minutes) vasodilator used for control of severe hypertension Dilates Coronary arteries, renal afferent and efferent arterioles and mesenteric arteries Dosage Calibrated infusion pump @ 01-1.6 g/kg per min Adverse effects are related to the vasodilation and include headache, flushing, dizziness, and tachycardia or bradycardia
- 54. Synthetic analog related to DA D1 and D2 receptors as well as at β2 receptors Patients with severe congestive heart failure, sepsis, and shock Patients with low cardiac output, significantly increases stroke volume with a decrease in SVR Tachycardia and hypotension can occur, usually only at high infusion rates
- 57. Blocks D2-receptors, agonist at 5HT4 and in high doses blocks 5-HT3 Antiemetic action Accelerate gastric emptying (prokinetic) Raises LES pressure Increases intestinal peristalsis
- 58. PK Orally it acts in ½ to 1 hr 10 min after I.M. and 2 min after I.V. inj Action lasts for 4-6 hours Interactions Hastens the absorption of many drugs, e.g. aspirin, diazepam(facilitating gastric emptying) It reduces absorption of digoxin Blocks D2 in basal ganglia, abolishes the therapeutic effect of levodopa Adverse effects Sedation, dizziness, loose stools, muscle dystonias Long-term use can cause parkinsonism, galactor rhoea and gynaecomastia.
- 59. Prokinetic action is not blocked by atropine and is based only on D2 blockade in upper g.i.t. Crosses BBB poorly levodopa or bromocriptine, it counteracts their dose limiting emetic action without affecting the therapeutic effect in parkinsonism Oral 10-40 mg TDS, BA ~15% due to FPM EPS are rare, but hyperprolactinaemia can occur Cardiac arrhythmias on rapid i.v. injection.
- 60. Metoclopramide or Domperidone ?
- 61. Phenothiazines & Butyrophenones Phenothiazines Prochlorperazine Promethazine Phenothiazines are antipsychotics with potent antiemetic property due to D2 antagonism. Butyrophenone Droperidol Droperidol used for postop. nausea & vomiting, but cause QT prolongation.
Notas del editor
- 1950s were stores of DA were found in tissues, suggesting DA had a signaling function of its own. By decade's end, Carlsson and Montagu had each identified DA stores in the brain Hornykiewicz discovered the DA deficit in the parkinsonian brain, fueling interest in the role of DA in neurological diseases and disorders Arvid Carlsson (born 25 January 1923) is a Swedish neuropharmacologist who is best known for his work with the neurotransmitter dopamine and its effects in Parkinson's disease. For his work on dopamine, Carlsson was awarded the Nobel Prize in Physiology or Medicine in 2000,
- DA is closely related to melanin, a pigment that is formed by oxidation of DA, tyrosine, or L-DOPA. Melanin exists in the skin and cuticle and gives the substantia nigra its namesake dark color
- Two enzymes that play major roles in the degradation of dopamine are mao and (COMT). MAO is located on the outer membrane of mitochondria. Two MAO isozymes MAO-A : Which preferentially deaminates serotonin and norepinephrine. MAO-B : Which deaminates dopamine, histamine, and a broad spectrum of phenylethylamines. COMT is located in the cytoplasm and is widely distributed throughout the brain and peripheral tissues. It has a wide substrate specificity, catalyzing the transfer of methyl groups from S-adenosyl methionine to the m-hydroxyl group of most catechol compounds. The predominant metabolites of dopamine is Homovanillic acid (HVA)
- DA is sequestered by VMAT2 in storage granules and released by exocytosis. Synaptic DA activates presynaptic autoreceptors and postsynaptic D1 and D2 receptors. Synaptic DA may be taken up into the neuron via the DA and NE transporters (DAT, NET), or removed by postsynaptic uptake via OCT3 Cytosolic DA is subject to degradation by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH) in the neuron, and by catechol-O-methyl tranferase (COMT) and MAO/ALDH in non-neuronal cells
- D1 receptor is also located in the kidney, retina, and cardiovascular systemthe neostriatum expresses the highest levels of D1 D1 receptor has been shown to interact with a variety of other proteins, including A1 adenosine receptors, NMDA receptors, Na+,K+-ATPase, calnexin, and caveolin (
- Auto receptors Stimulation of somatodendritic autoreceptors slows the firing rate while stimulation of those in nerve terminals inhibits dopamine release and synthesis
- Incertohypothalamic Pathway Medullary Periventricular Retinal Olfactory bulb
- most common form of parkinsonism is idiopathic PD, first described by James Parkinson in 1817 as paralysis agitans, or the "shaking palsy." The pathological hallmark of PD is the loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta, with the appearance of intracellular inclusions known as Lewy bodies 70-80% of dopaminergic neurons required to cause symptomatic PD Without treatment, PD progresses over 5-10 years to a rigid, akinetic state Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism.
- impairment of postural balance leading to disturbances of gait and falling which usually abates during voluntary movement)
- DA released in the striatum tends to increase the activity of the direct pathway and reduce the activity of the indirect pathway, wherea net effect of the reduced dopaminergic input in PD is to increase markedly the inhibitory outflow from the SNpr and GPi to the thalamus and reduce excitation of the motor cortex.
- Secondary symptoms of posture,gait, handwriting, speech, facial expression, mood, self care and interest in life are gradually normalized he effectof levodopa on behaviour has been described as a 'general alerting response'. In some patients this progresses to excitement frank psychosis may occur. 1 Gastric emptying: if slow, levodopa is exposed to degrading enzymes present in gut wall and liver for a longertime-less is availabl o penetrate blood-brain barrier. ii) Amino acids present in food compete for the same carrier for absorption: blood levels are lower when taken with meals. Levodopa undergoes high first pass metalism in g.i. mucosa and liver Interactions----Pyridoxine: Abolishes therapeutic effec: .enhancing peripheral decarboxylation Phenothiazines, butyrophenones, met, pramie reverse therapeutic effect of levodopa by blocking DA receptors. Nonselective MAO inhibitors: prevent degradation of peripherally synthesized DA .' NA-hypertensive crisis can occur. Antihypertensives: postural hypotensic·: Atropine, and other anticholinergic dr- _ have additive antiparkinsonian action with . doses of levodopa, but retard its absorptic·:- more time is available for peripheral degrad< : -efficacy of levodopa may be reduced.
- Secondary symptoms of posture,gait, handwriting, speech, facial expression,mood, self care and interest in life are gradually normalized he effectof levodopa on behaviour has been described as a 'general alerting response'. In some patients this progresses to excitement frank psychosis may occur. 1 Gastric emptying: if slow, levodopa is exposed to degrading enzymes present in gut wall and liver for a longertime-less is availabl o penetrate blood-brain barrier. ii) Amino acids present in food compete for the same carrier for absorption: blood levels are lower when taken with meals. Levodopa undergoes high first pass metalism in g.i. mucosa and liver Interactions----Pyridoxine: Abolishes therapeutic effec: .enhancing peripheral decarboxylation Phenothiazines, butyrophenones, met, pramie reverse therapeutic effect of levodopa by blocking DA receptors. Nonselective MAO inhibitors: prevent degradation of peripherally synthesized DA .' NA-hypertensive crisis can occur. Antihypertensives: postural hypotensic·: Atropine, and other anticholinergic dr- _ have additive antiparkinsonian action with . doses of levodopa, but retard its absorptic·:- more time is available for peripheral degrad< : -efficacy of levodopa may be reduced.
- Enz conversion of these drugs arent required they dony=t depend on the functional capacity of the dopaminergic neurons Bromo-----'first dose has occurred in some patients, especially those on antihyperten sive medication( potent agonist on D2) startin with low doses with low doses (1 .25 mg once at night) and gradually increasing as needed upto 5-10 mg thrice daily. smoothen 'end of dose' and 'on-off' fluctuations. Prami- dose titration for maximum improvement can be achieved in 1-2 weeks, while the same may take several months with bromocriptine. (D3Agonist)
- Adrenergic a 1D, 2B, and 2C approved as a "rescue therapy" for the acute intermittent treatment of "off" episodes in patients with a fluctuating response to dopaminergic therapy pre- and post-treatment anti-emetic therapy. Oral trimethobenzamide (d2 anta at CTZ), dose of 300 mg three times daily, should be started 3 days prior to the initial dose of apomorphine and continued at least during the first 2 months of therapy Profound hypotension and loss of consciousness when apomorphine was administered with ondansetron; hence, the concomitant with 5-HT3 antagonist class is contraindicated potential adverse effects, use of apomorphine is appropriate only when other measures, such as oral DA agonists or COMT inhibitors, have failed to control the "off" episodes
- MAO-A and MAO-B) are present in the periphery and inactivate monoamines of intestinal origin, the isoenzyme MAO-B is predominant in striatum and platelets is responsible for most of the oxidative metabolism of DA in the brain inhibition of MAO-B in the brain is a reduction in the overall catabolism of DA, which may reduce the formation of potentially toxic free radicals CA accumulation and hype4tensive reaction does not develop, while :cerebral degradation of DA is retarded. T:-: responsible for the therapeutic eff delivery routes are intended to reduce hepatic first-pass metabolism and limit the formation of the amphetamine metabolites. cheese effect," the potentially lethal potentiation of catecholamine action observed when patients on nonspecific MAO inhibitors(phenelzine, tranylcypromine, and isocarboxazid) ingest indirectly acting sympathomimetic amines such as the tyramine found in certain cheeses and wine Adjunctive therapy significantly reduced levodopa-related "wearing off" symptoms in advanced PD
- MAO-A and MAO-B) are present in the periphery and inactivate monoamines of intestinal origin, the isoenzyme MAO-B is predominant in striatum and is responsible for most of the oxidative metabolism of DA in the brain inhibition of MAO-B in the brain is a reduction in the overall catabolism of DA, which may reduce the formation of potentially toxic free radicals
- COMT transfers a methyl group from the donor S-adenosyl-L-methionine, producing the pharmacologically inactive compounds 3-O-methyl DOPA (from levodopa) and 3-methoxytyramine Advanced and fluctuating PD Smoothen wearing off Increases on time, decreases off time Improves activity of daily living and helps to reduce the dose of levodo Hepatotoxic ----Use only in patients not responding satisfactorily to other treatments. Requires monitoring of liver function cases of fulminant hepatic failure in patients taking tolcapone pa
- an antiviral agent used for the prophylaxis and treatment of influenza A release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein. In certain cases, Amantadine is also known to prevent virus assembly during replica Advanced and fluctuating PD It indirectly acts to stimulate DA availability by decreasing the glutamate mediated tonic inhibition of DA release in mesolimbic pathway Increases on time, decreases off time Improves activity of daily living and helps to reduce the dose of levodopa
- Nucleus Accumbens is a centre for reward
- cocaine binds to the dopamine, and does not allow it to be recycled. Effect ends after 30 mins, and the person is left craving to feel as he once did Progressively a tolerance builds up dopamine is also released when something pleasurable yet unexpected occurs, after the first time, the person expects the effect, thus less dopamine is released, and the experience is less satisfying. Drug seeking behavior of rats , negATIVE consequenses don’t affect an addicted brain as it does to a normal brain
- some genetic links between dopamine receptors, the dopamine transporter and ADHD
- higher concentrations of proteins called dopamine transporters. These transporters temporarily prevent dopamine from going on to the next cell. This lessens the effects of dopamine, in spite of high levels of dopamine in brain cells
- Psychostimulants-> 70% of those who use these stimulants see improvements in ADHD symptoms Pemoline is structurally dissimilar to methylphenidate but elicits similar changes in CNS function with minimal effects on the cardiovascular system. can be given once daily because of its long t1/2. Clinical improvement may require treatment for 3-4 weeks. Use of pemoline has been associated with severe hepatic failure
- In the ant pituitary, spontaneous prolactin release from lactotrophs is tonically inhibited by activation of D2 receptors Features : Amenorrhoea, Galactorrhoea, Anovulation, loss of libido
- Infertility, decreased libido, sexual dysfunction (in both men and women), erectile dysfunction, infertility, and gynecomastia in MEN dopamine antagonists are another cause of hyperprolactinemia. Hyperprolactinemia inhibits the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus (by increasing the release of dopamine from the arcuate nucleus), which in turn inhibits the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland and results in diminished gonadal sex hormoneproduction (termed hypogonadism) Dopamine receptor blockers Atypical antipsychotics: risperidone Phenothiazines: chlorpromazine, perphenazine Butyrophenones: haloperidol Thioxanthenes Metoclopramide Dopamine synthesis inhibitors α-Methyldopa Catecholamine depletors Reserpine Opiates H2 antagonists Cimetidine, ranitidine Imipramines Amitriptyline, amoxapine Serotonin reuptake inhibitors Fluoxetine Calcium channel blockers Verapamil Estrogens TRH
- Incre mesolimb pos symptomshallucination, delusion, agitated , dis organised speech Decre mesocortical prefrontal cort neg symptoms & cognitive symptom apathy alogia(poverty of speech) avolition(severe lack of initiative or motivation)
- Reserpine, derived from Rauwolfia, exhibited antipsychotic properties by decreasing dopaminergic neurotransmission(irreversibly blocks the vesicular monoamine transporter (VMAT), free momoamines are acted upon by MAO).; however, unlike D2 receptor antagonists, reserpine exerted its effects through depletion of monoamines from presynaptic nerve terminals dopamine theory of psychosis was reinforced by the high risk for drug-induced psychosis among substances that directly increased synaptic dopamine availability, including cocaine, amphetamines, and the Parkinson's disease treatment L-dopa (Carlsson, 1978).
- Met polymorphism of catechol-O-methyltransferase, which increases DA catabolism) DA neurotransmission (dystrobrevin binding protein 1 or dysbindin,
- The sedative effect is produced promptly, while antipsychotic effect takes weeks to develop. Moreover, tolerance develops to the sedative but not to the a Phenothiazines and thioxanthenes also block Dl, D3 and D4receptors,antipsychotic effect. Acute muscle dystonia earliest app symptom Akathisia- most common symptom
- Sedation—max—cpz & min ziprasidone and aripiprazole Wt gain in typical –all expect haloperidol Wt gain, hyperlipidaemia, new onset dm —all except zipra lesser risk with ari, illoperidone and asenapine Siezures-clo, olan, cpz lesswith risperidone and quetiapine Post hypotns & inhibn of ejaculatn- thioridazine Anticholinergic se– max with thioridazine, cpz, clozapine qT prolongation—asenapine, ziprasidone & paliperidone Retinal degen– thioridazine Cataract- quetiapine Cholestatic jaundice—cpz
- periphery, it is synthesized in epithelial cells of the proximal tubule and is thought to exert local diuretic and natriuretic effects Activation of D1 receptors---renal tubular cells---- decreases Na+ transport by cAMP-dependent and cAMP-independent mechanisms. Increasing cAMP production in the proximal tubular cells and the medullary part of the thick ascending limb of the loop of Henle inhibits the Na+-H+ exchanger and the Na+,K+-ATPase pump. The renal tubular actions of DA that cause natriuresis may be augmented by the increase in renal blood flow and the small increase in the gfr increase in hydrostatic pressure in the peritubular capillaries and reduction in oncotic pressure may contribute to diminished reabsorption of Na+ by the proximal tubular cells.
- D1 in renal and mesenteric blood vessels are the most sensitive: i.v. infusion of low dose of DA dilates these vessels(raising inracellular cAMP). This increases g.f.r. and Na+ excretion(d1 on proximal tubular cell) excretion by inhibiting the activity of various Na+ transporters, including the apical Na+-H+ exchanger and the basolateral Na+,K+-ATPase Tpr usually is unchanged when low or intermediate doses of DA are given, probably because of the ability of DA to reduce regional arterial resistance in some vascular beds, such as mesenteric and renal, Positive inotropic (direct l3 and Dl action + that due to NA release),
- Cardiogenic or septic shock and severe CHF wherein it increases BP and urine outflow sloughingRarely, gangrene of the fingers or toes has followed prolonged infusion of the drug. DA should be avoided or used at a much reduced dosage (one-tenth or less) if the patient has received a MAO inhibitor. Careful adjustment of dosage also is necessary in patients who are taking tricyclic antidepressants
- in shock, hypovolemia should be corrected by transfusion of whole blood, plasma, or other appropriate fluid. Untoward effects due to overdosage generally are attributable to excessive sympathomimetic activity patients require clinical assessment of myocardial function, perfusion of vital organs such as the brain, and the production of urine. peripheral vasoconstriction may be encountered during dopamine infusion Reduction in urine flow, tachycardia, or the development of arrhythmias may be indications to slow or terminate the infusion
- potent DA t receptor agonist that produces renal vasodilation and a reduction in systemic arterial blood pressure without compromising renal function fenoldopam reduces cardiac afterload in the presence of maintained or increased RBF and increased sodium and water excretion, IT may also be useful in the treatment of CCF malignant hypertension180/120 with end-organ damage) in hospitalized patients for not more than 48 hours. Accelerated hypertension is defined as a recent significant increase over baseline blood pressure that is associated with target organ damage
- It also inhibits of neuronal re-uptake of norepinephrine 0.5 - 6 microgram/kg/min
- 5 ht 3—from ecl cells --Vagus from gut-- nts(h1,m1,5ht3)----vc( m1, h1, nk1, 5ht3
- Central(ctz) and peripheral Da (D2 receptors) is an inhibitory transmitter in the g.i.t.- normally acts to delay gastric emptying also appears to cause gastric dilatation and LES relaxation nausea and vomiting Metoclopramide blocks D2 receptors and hastens gastric emptying and enhancing LES tone by augmenting ACh release. However, clinically this action is secondary to that exerted through 5HT4 receptors.
- Rapidly absorbed orally, enters brain, crosses placenta and is secreted in milk CINV___A higher dose (1-2 mg i.v.) is often needed, but is effective when phenothiazines and antihistamines do not work Promethazine, diphenhydramine, diazepam lorazepam injected i.v. along with meclopramide supplement its antiemetic action and to reduce the attending dystonic reaction Dexamethasone i.v. also augments the effect of metoclopramide.
- drug is considered necessary, choice of drug may be dictated by other considerations such as a person's preference, adverse-effect profile and cost. As CTZ is outside BBB both have antiemetic effects. But as metoclopramide crosses BBB it has adverse effects like extrapyramidal side effects.. Domperidone is well tolerated.