Dirty drug

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In pharmacology, a dirty drug is an informal term for drugs that may bind to many different molecular targets or receptors in the body, and so tend to have a wide range of effects and possibly adverse drug reactions. Today, pharmaceutical companies try to make new drugs as selective as possible to minimise binding to antitargets and hence reduce the occurrence of side effects and risk of adverse reactions.

Examples of compounds often cited as "dirty drugs" include tramadol, chlorpromazine, olanzapine, dextromethorphan, ibogaine, and ethanol, all of which bind to multiple receptors or influence multiple receptor systems. There may be instances of advantages to drugs that exhibit multi-receptor activity such as the anti-addictive drug ibogaine that acts within a broad range of neurohormonal systems where activity is also exhibited by drugs commonly associated with addiction including opioids, nicotine, and alcohol. [1] [2] Similarly chlorpromazine is primarily used as an antipsychotic, but its strong serotonin receptor blocking effects make it useful for treating serotonergic crisis such as serotonin syndrome. Dextromethorphan for its part is widely used as a cough medication, but its other actions have led to trials for several conditions such as its use as an adjunct to analgesia, and a potential anti-addictive drug, as well as its occasional recreational use as a dissociative.[ citation needed ]

Kanamycin is an aminoglycoside antibiotic which induces deafness through blockage of the outer hair cells of the cochlea; yet it has many other effects, weakening for instance the collagen and DNA biosynthesis. It acts by inhibiting the synthesis of proteins in susceptible organisms. Kanamycin requires close clinical supervision because of its potential toxicity and adverse side effects to the auditory and vestibular branches of the eighth cranial nerve and to the renal tubules. [3]

Clozapine and latrepirdine are examples of drugs used in the treatment of CNS disorders that have a superior efficacy precisely because of their "multifarious" broadspectrum mode of activity. Likewise, in cancer chemotherapeutics, it has been recognized that drugs active at more than one target have a higher probability of being efficacious. [4] [5] [6] [7] [8] [9] [10] [11]

The anti-histamine and anti-cholinergic effects of atypical and low potency typical antipsychotics, such as the aforementioned clozapine and chlorpromazine, can also mediate against potentially distressing movement disorders such as extrapyramidal symptoms and akathisia associated with dopamine antagonism. In fact, clozapine may even help treat movement problems associated with Parkinson's disease. [12]

Examples of "promiscuous" cancer drugs include: Sutent, Sorafenib, Zactima, and AG-013736.[ citation needed ]

In the field of drugs used to treat depression, the nonselective MAOIs and the TCAs are sometimes believed to have an efficacy that is superior to the SSRIs. [13] SSRIs are usually nevertheless picked as the first-line choice of agent and not the (less-selective) MAOIs and TCAs for several reasons. Firstly, SSRIs are safer in overdose than TCAs. Secondly, MAOIs can cause serious side effects when mixed with certain foods, including life-threatening hypertensive crisis. MAOIs and TCAs generally have more side effects than SSRIs. TCAs in particular have anticholinergic side effects such as constipation and blurred vision, whereas SSRIs have fewer anticholinergic side effects. [14]

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<span class="mw-page-title-main">Antidepressant</span> Class of medication used to treat depression and other conditions

Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction.

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Monoamine oxidase inhibitor</span> Type of medication

Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especially for treatment-resistant depression and atypical depression. They are also used to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.

<span class="mw-page-title-main">Tricyclic antidepressant</span> Class of medications

Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

<span class="mw-page-title-main">Chlorpromazine</span> Antipsychotic medication

Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar disorder, severe behavioral problems in children including those with attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. It can be given orally, by intramuscular injection, or intravenously.

<span class="mw-page-title-main">Maprotiline</span> Antidepressant

Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary amine. In terms of its chemistry and pharmacology, maprotiline is closely related to such-other secondary-amine TCAs as nortriptyline and protriptyline and has similar effects to them, albeit with more distinct anxiolytic effects. Additionally, whereas protriptyline tends to be somewhat more stimulating and in any case is distinctly more-or-less non-sedating, mild degrees of sedation may be experienced with maprotiline.

Anticholinergics are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central and peripheral nervous system.

<span class="mw-page-title-main">Serotonin–norepinephrine reuptake inhibitor</span> Class of antidepressant medication

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. Off-label uses include treatments for attention-deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), and migraine prevention. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.

<span class="mw-page-title-main">Promethazine</span> Sedating Antihistamine

Promethazine, sold under the brand name Phenergan among others, is a first-generation antihistamine, sedative, and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold and may also be used for sedating people who are agitated or anxious, an effect that has led to some recreational use. Promethazine is taken by mouth (oral), as a rectal suppository, or by injection into a muscle (IM).

<span class="mw-page-title-main">Imipramine</span> Antidepressant

Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth.

<span class="mw-page-title-main">Ibogaine</span> Psychoactive substance found in plants in the family Apocynaceae

Ibogaine is an psychoactive indole alkaloid obtained either by extraction from plants in the family Apocynaceae such as Tabernanthe iboga, Voacanga africana, and Tabernaemontana undulata or by semi-synthesis from the precursor compound voacangine, another plant alkaloid. The total synthesis of ibogaine was described in 1956. Structural elucidation by X-ray crystallography was completed in 1960.

<span class="mw-page-title-main">Trimipramine</span> Antidepressant

Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or "second-generation" TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs, however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.

<span class="mw-page-title-main">Moclobemide</span> Antidepressant

Moclobemide, sold under the brand names Amira, Aurorix, Clobemix, Depnil and Manerix among others, is a reversible inhibitor of monoamine oxidase A (RIMA) drug primarily used to treat depression and social anxiety. It is not approved for use in the United States, but is approved in other Western countries such as Canada, the UK and Australia. It is produced by affiliates of the Hoffmann–La Roche pharmaceutical company. Initially, Aurorix was also marketed by Roche in South Africa, but was withdrawn after its patent rights expired and Cipla Medpro's Depnil and Pharma Dynamic's Clorix became available at half the cost.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

<span class="mw-page-title-main">Muscarinic antagonist</span> Drug that binds to but does not activate muscarinic cholinergic receptors

A muscarinic receptor antagonist (MRA), also called an antimuscarinic, is a type of anticholinergic agent that blocks the activity of the muscarinic acetylcholine receptor. The muscarinic receptor is a protein involved in the transmission of signals through certain parts of the nervous system, and muscarinic receptor antagonists work to prevent this transmission from occurring. Notably, muscarinic antagonists reduce the activation of the parasympathetic nervous system. The normal function of the parasympathetic system is often summarised as "rest-and-digest", and includes slowing of the heart, an increased rate of digestion, narrowing of the airways, promotion of urination, and sexual arousal. Muscarinic antagonists counter this parasympathetic "rest-and-digest" response, and also work elsewhere in both the central and peripheral nervous systems.

<span class="mw-page-title-main">Noribogaine</span> Principal psychoactive metabolite of the oneirogen ibogaine

Noribogaine, or 12-hydroxyibogamine, is the principal psychoactive metabolite of the oneirogen ibogaine. It is thought to be involved in the antiaddictive effects of ibogaine-containing plant extracts, such as Tabernanthe iboga.

The psychopharmacology revolution covers the introduction of various psychiatric drugs into clinical practice as well as their continued development. Although not exclusively limited to the 1950s period, the literature tends to suggest that this decade was a particularly fruitful time for CNS drug discovery and it has been referred to as a "golden era".

Selective serotonin reuptake inhibitors, or serotonin-specific re-uptake inhibitor (SSRIs), are a class of chemical compounds that have application as antidepressants and in the treatment of depression and other psychiatric disorders. SSRIs are therapeutically useful in the treatment of panic disorder (PD), posttraumatic stress disorder (PTSD), social anxiety disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), and anorexia. There is also clinical evidence of the value of SSRIs in the treatment of the symptoms of schizophrenia and their ability to prevent cardiovascular diseases.

References

  1. ↑ Popik, Piotr; Skolnick, Phil (1999). "Pharmacology of Ibogaine and Ibogaine-Related Alkaloids". In Cordell, Geoffrey A. (ed.). The Alkaloids: Chemistry and Biology. Vol. 52. pp. 197–231. doi:10.1016/S0099-9598(08)60027-9. ISBN   978-0-12-469552-8.
  2. ↑ Alper, Kenneth R (2001). "Ibogaine: A review". The Alkaloids: Chemistry and Biology. Vol. 56. pp. 1–38. doi:10.1016/S0099-9598(01)56005-8. ISBN   978-0-12-469556-6. PMID   11705103.
  3. ↑ "Kanamycin".
  4. ↑ Musk, Philip (2004). "Magic Shotgun Methods for Developing Drugs for CNS Disorders". Discovery Medicine. 4 (23): 299–302. PMID   20704963.
  5. ↑ Roth, Bryan L.; Sheffler, Douglas J.; Kroeze, Wesley K. (2004). "Magic shotguns versus magic bullets: Selectively non-selective drugs for mood disorders and schizophrenia". Nature Reviews Drug Discovery. 3 (4): 353–9. doi:10.1038/nrd1346. PMID   15060530. S2CID   20913769.
  6. ↑ Buccafusco, Jerry J. (2009). "Multifunctional receptor-directed drugs for disorders of the central nervous system". Neurotherapeutics. 6 (1): 4–13. doi:10.1016/j.nurt.2008.10.031. PMC   5084252 . PMID   19110195.
  7. ↑ Enna, S. J.; Williams, M. (2009). "Challenges in the Search for Drugs to Treat Central Nervous System Disorders". Journal of Pharmacology and Experimental Therapeutics. 329 (2): 404–11. doi:10.1124/jpet.108.143420. PMID   19182069. S2CID   11395584.
  8. ↑ Frantz, Simon (2005). "Drug discovery: Playing dirty". Nature. 437 (7061): 942–3. Bibcode:2005Natur.437..942F. doi: 10.1038/437942a . PMID   16222266. S2CID   4414021.
  9. ↑ Hopkins, Andrew L. (2009). "Drug discovery: Predicting promiscuity". Nature. 462 (7270): 167–8. Bibcode:2009Natur.462..167H. doi:10.1038/462167a. PMID   19907483. S2CID   4362713.
  10. ↑ Hopkins, A; Mason, J; Overington, J (2006). "Can we rationally design promiscuous drugs?". Current Opinion in Structural Biology. 16 (1): 127–36. doi:10.1016/j.sbi.2006.01.013. PMID   16442279.
  11. ↑ Hopkins, Andrew L (2008). "Network pharmacology: The next paradigm in drug discovery". Nature Chemical Biology. 4 (11): 682–90. doi:10.1038/nchembio.118. PMID   18936753.
  12. ↑ Factor, S. A.; Friedman, J. H. (1 July 1997). "The emerging role of clozapine in the treatment of movement disorders". Movement Disorders. 12 (4): 483–496. doi: 10.1002/mds.870120403 . ISSN   0885-3185. PMID   9251065. S2CID   11255051.
  13. ↑ Jain, Rakesh (2004). "Single-Action Versus Dual-Action Antidepressants". Primary Care Companion to the Journal of Clinical Psychiatry. 6 (Suppl 1): 7–11. PMC   486947 . PMID   16001091.
  14. ↑ Fujishiro, Jun; Imanishi, Taiichiro; Onozawa, Kaname; Tsushima, Masaki (2002). "Comparison of the anticholinergic effects of the serotonergic antidepressants, paroxetine, fluvoxamine and clomipramine". European Journal of Pharmacology. 454 (2–3): 183–8. doi:10.1016/S0014-2999(02)02557-8. PMID   12421645.
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