Methyldopa Synthesis Essay

Indication

For use in the treatment of hypertension.

Structured Indications
Pharmacodynamics

Methyldopa is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect. Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed. Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy. Methyldopa reduces both supine and standing blood pressure. Methyldopa usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.

Mechanism of action

Although the mechanism of action has yet to be conclusively demonstrated, the resultant hypotensive effect is most likely due to the drug's action on the CNS. Methyldopa is converted into the metabolite, alpha-methylnorepinephrine, in the CNS, where it stimulates the central inhibitory alpha-adrenergic receptors, leading to a reduction in sympathetic tone, total peripheral resistance, and blood pressure. Reduction in plasma renin activity, as well as the inhibition of both central and peripheral norepinephrine and serotonine production may also contribute to the drug's antihypertensive effect, although this is not a major mechanism of action. This is done through the inhibition of the decarboxylation of dihydroxyphenylalanine (dopa)—the precursor of norepinephrine—and of 5-hydroxytryptophan (5-HTP)—the precursor of serotonin—in the CNS and in most peripheral tissues.

Absorption

Absorption from the gastrointestinal tract is variable but averages approximately 50%.

Volume of distribution
Not Available
Protein binding

Low (less than 20%).

Metabolism

Hepatic, extensively metabolized. The known urinary metabolites are: a-methyldopa mono-0-sulfate; 3-0-methyl-a-methyldopa; 3,4-dihydroxyphenylacetone; a-methyldopamine; 3-0-methyl-a-methyldopamine and their conjugates.

Route of elimination

Methyldopa is extensively metabolized. The known urinary metabolites are: α-methyldopa mono-O-sulfate; 3-0-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; 3-0-methyl-α-methyldopamine and their conjugates. Approximately 70 percent of the drug which is absorbed is excreted in the urine as methyldopa and its mono-O-sulfate conjugate. Methyldopa crosses the placental barrier, appears in cord blood, and appears in breast milk.

Half life

The plasma half-life of methyldopa is 105 minutes.

Clearance
  • Renal cl=130 mL/min [healthy]
Toxicity

The oral LD50 of methyldopa is greater than 1.5 g/kg in both the mouse and the rat. Symptoms of overdose include bloating, constipation, diarrhea, dizziness, extreme drowsiness, gas, light-headedness, nausea, severely low blood pressure, slow heartbeat, vomiting, and weakness.

Affected organisms
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available
Clinical data
Trade namesAldomet, Aldoril, Dopamet, others
SynonymsL-α-Methyl-3,4-dihydroxyphenylalanine
AHFS/Drugs.comMonograph
MedlinePlusa682242
Pregnancy
category
  • AU:A
  • US:B (No risk in non-human studies)
Routes of
administration
by mouth, IV
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilityapproximately 50%
MetabolismLiver
Onset of action4 to 6 hrs[1]
Biological half-life105 minutes
Duration of action10 to 48 hrs[1]
ExcretionKidney for metabolites
Identifiers

IUPAC name

  • (S)-2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propanoic acid
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEMBL
ECHA InfoCard100.008.264
Chemical and physical data
FormulaC10H13NO4
Molar mass211.215 g/mol
3D model (JSmol)

SMILES

  • C[C@](CC1=CC(=C(C=C1)O)O)(C(=O)O)N

InChI

  • InChI=1S/C10H13NO4/c1-10(11,9(14)15)5-6-2-3-7(12)8(13)4-6/h2-4,12-13H,5,11H2,1H3,(H,14,15)/t10-/m0/s1 N
  • Key:CJCSPKMFHVPWAR-JTQLQIEISA-N N
 NY (what is this?)  (verify)

Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure.[1] It is one of the preferred treatments for high blood pressure in pregnancy.[1] For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred.[1] It can be given by mouth or injection into a vein.[1] Onset of effects is around 5 hours and they last about a day.[1]

Common side effects include sleepiness.[1] More severe side effects include red blood cell breakdown, liver problems, and allergic reactions.[1] Methyldopa is in the alpha-2 adrenergic receptor agonist family of medication.[1] It works by stimulating the brain to decrease the activity of the sympathetic nervous system.[1]

Methydopa was discovered in 1960.[2] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[3] The wholesale cost in the developing world is about 4.31 to 9.48 USD per month.[4] In the United States it costs less than 25 USD per month.[5]

Medical uses[edit]

Methyldopa is used in the clinical treatment of the following disorders:

[edit]

Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day.[6] Side effects may include:

  • Psychological
    • Depression or even suicidal ideation, as well as nightmares
    • Apathy or anhedonia, as well as dysphoria
    • Anxiety, especially of the social anxiety variant
    • Decreased alertness, awareness, and wakefulness
    • Impaired attention, focus, and concentration
    • Decreased desire, drive, and motivation
    • Fatigue or lethargy or malaise or lassitude
    • Sedation or drowsiness or somnolence or sleepiness
    • Agitation or restlessness
    • Cognitive and memory impairment
    • Derealization or depersonalization, as well as mild psychosis
    • Sexual dysfunction including impaired libido, desire, and drive
  • Physiological
    • Dizziness, lightheadedness, or vertigo
    • Miosis or pupil constriction
    • Xerostomia or dry mouth
    • Gastrointestinal disturbances such as diarrhea or constipation
    • Headache or migraine
    • Myalgia or muscle aches, arthralgia or joint pain, or paresthesia ("pins and needles")
    • Restless legs syndrome (RLS)
    • Parkinsoniansymptoms such as muscle tremors, rigidity, hypokinesia, or balance or postural instability
    • Akathisia, ataxia, dyskinesia as well as even tardive dyskinesia, or dystonia
    • Bell's palsy or facialparalysis
    • Sexual dysfunction consisting of impaired erectile dysfunction or anorgasmia
    • Hyperprolactinemia or excess prolactin, gynecomastia/breast enlargement in males, or amenorrhoea or absence of menstrual cycles in females
    • Bradycardia or decreased heart rate
    • Hypotension or decreased blood pressure (though this may also be considered a therapeutic benefit)
    • Orthostatic hypotension (also known as postural hypotension)
    • Hepatitis, hepatotoxicity, or liverdysfunction or damage
    • Pancreatitis or inflammation of the pancreas
    • Warm autoimmune hemolytic anemia or deficiency in red blood cells (RBCs)
    • Myelotoxicity or bone marrow suppression, potentially leading to thrombocytopenia or blood plateletdeficiency or leukopenia or white blood cell (WBC) deficiency
    • Hypersensitivity such as lupus erythematosus, myocarditis, or pericarditis
    • Lichenoid reactions such as skin lesions or rashes
    • Pallor

Rebound/withdrawal[edit]

Reboundhypertension via withdrawal on account of tolerance upon the abrupt discontinuation of methyldopa has been reported.[7]

Mechanism of action[edit]

Methyldopa has a dual mechanism of action:

Pharmacokinetics[edit]

Methyldopa exhibits variable absorption from the gastrointestinal tract. It is metabolized in the liver and intestines and is excreted in urine.

History[edit]

When methyldopa was first introduced, it was the mainstay of antihypertensive treatment, but its use has declined on account of relatively severe adverse side effects, with increased use of other safer and more tolerable agents such as alpha blockers, beta blockers, and calcium channel blockers. Additionally, it has yet to be associated with reducing adverse cardiovascular events including myocardial infarction and stroke, or overall all-cause mortality reduction in clinical trials.[8] Nonetheless, one of methyldopa's still current indications is in the management of pregnancy-induced hypertension (PIH), as it is relatively safe in pregnancy compared to many other antihypertensives which may affect the fetus.

See also[edit]

  • Difluoromethyldopa
  • D-DOPA (dextrodopa)
  • L-DOPA (levodopa; trade names Sinemet, Pharmacopa, Atamet, Stalevo, Madopar, Prolopa, etc.)
  • L-DOPS (droxidopa)
  • Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.)
  • Norepinephrine (noradrenaline; Levophed, etc.)
  • Epinephrine (adrenaline; Adrenalin, EpiPed, Twinject, etc.)

References[edit]

External links[edit]

Wikimedia Commons has media related to Methyldopa.

Adrenergic receptormodulators

α1
  • Antagonists:Abanoquil
  • Adimolol
  • Ajmalicine
  • Alfuzosin
  • Amosulalol
  • Anisodamine
  • Arotinolol
  • Atiprosin
  • Atypical antipsychotics (e.g., brexpiprazole, clozapine, olanzapine, quetiapine, risperidone)
  • Benoxathian
  • Buflomedil
  • Bunazosin
  • Carvedilol
  • Corynanthine
  • Dapiprazole
  • Domesticine
  • Doxazosin
  • Ergolines (e.g., ergotamine, dihydroergotamine, lisuride, terguride)
  • Etoperidone
  • Eugenodilol
  • Fenspiride
  • Hydroxyzine
  • Indoramin
  • Ketanserin
  • L-765,314
  • Labetalol
  • mCPP
  • Mepiprazole
  • Metazosin
  • Monatepil
  • Moxisylyte
  • Naftopidil
  • Nantenine
  • Neldazosin
  • Niaprazine
  • Nicergoline
  • Niguldipine
  • Pardoprunox
  • Pelanserin
  • Perlapine
  • Phendioxan
  • Phenoxybenzamine
  • Phentolamine
  • Phenylpiperazineantidepressants (e.g., hydroxynefazodone, nefazodone, trazodone, triazoledione)
  • Piperoxan
  • Prazosin
  • Quinazosin
  • Quinidine
  • Ritanserin
  • Silodosin
  • Spiperone
  • Talipexole
  • Tamsulosin
  • Terazosin
  • Tiodazosin
  • Tolazoline
  • Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin)
  • Tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine)
  • Trimazosin
  • Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine, thioridazine)
  • Urapidil
  • WB-4101
  • Zolertine
α2
  • Antagonists:1-PP
  • Adimolol
  • Amesergide
  • Aptazapine
  • Atipamezole
  • Atypical antipsychotics (e.g., asenapine, brexpiprazole, clozapine, lurasidone, paliperidone, quetiapine, risperidone, zotepine)
  • Azapirones (e.g., buspirone, gepirone, ipsapirone, tandospirone)
  • BRL-44408
  • Buflomedil
  • Cirazoline
  • Efaroxan
  • Esmirtazapine
  • Fenmetozole
  • Fluparoxan
  • Idazoxan
  • mCPP
  • Mianserin
  • Mirtazapine
  • NAN-190
  • Olanzapine
  • Pardoprunox
  • Phentolamine
  • Phenoxybenzamine
  • Piperoxan
  • Piribedil
  • Rauwolscine
  • Rotigotine
  • SB-269970
  • Setiptiline
  • Spiroxatrine
  • Sunepitron
  • Tolazoline
  • Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine, thioridazine)
  • Yohimbine
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