This medication is used to treat severe cystic acne (also known as nodular acne) that has not responded to other treatment (e.g., benzoyl peroxide or clindamycin applied to the skin or tetracycline or minocycline taken by mouth). It belongs to a class of drugs known as retinoids. It works by decreasing facial oil (sebum) production. High amounts of sebum can lead to severe acne.
Severe forms of acne (such as nodular or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterial and topical therapy.
Pharmacological & Pharmacodynamic Properties:
isotretinoin induces apoptosis (programmatic cell death) in various cells in the body. Cell death may be instigated in the meibomian glands, hypothalamic cells, hippocampus cells and important for treatment of acne n sebaceous gland cells.Isotretinoin has a low affinity for retinoic acid receptors (RAR) and retinoid X receptors (RXR), but may be converted intracellularly to metabolites that act as agonists of RAR and RXR nuclear receptors.
One study suggests the drug amplifies production of neutrophil gelatinase-associated lipocalin (NGAL) in the skin, which has been shown to reduce sebum production by inducing apoptosis in sebaceous gland cells, while exhibiting an antimicrobial effect on Propionibacterium acnes. The drug decreases the size and sebum output of the sebaceous glands Isotretinoin is the only available acne drug that affects all four major pathogenic processes in acne, which distinguishes it from alternative treatments (such as antibiotics) and accounts for its efficacy in severe, nodulocystic cases. The effect of Isotretinoin on sebum production can be temporary,or remission of the disease can be "complete and prolonged."
Isotretinoin has been speculated to down-regulate the enzyme telomerase and hTERT, inhibiting "cellular immortalization and tumorigenesis.In a 2007 study, Isotretinoin was proven to inhibit the action of the metalloprotease MMP-9 (gelatinase) in sebum without any influence in the action of TIMP1 and TIMP2 (the tissue inhibitors of metalloproteases).It is already known that metalloproteases play an important role in the pathogenesis of acne.
A possible biological basis for the case reports of depression involves decreased metabolism in the orbitofrontal cortex (OFC) of the frontal lobe. It has also been found that decreased OFC metabolism was correlated with headaches.People reporting headache as a side effect often report comorbid neuropsychiatric symptoms, especially depression; a statistically significant relationship between headache and depression has been established.It is suggested that people sensitive to isotretinoin-induced CNS effects may also be susceptible to other psychiatric side effects such as depression
Studies in mice and rats have found that retinoids, including isotretinoin, bind to dopaminergic receptors in the central nervous system.Isotretinoin may affect dopaminergic neurotransmission by disrupting the structure of dopamine receptors and decreasing dopaminergic activity.The dopaminergic system is implicated in numerous psychological disorders, including depression. Isotretinoin is also thought to affect the serotonergic system - it increases expression of 5-HT1A receptors in the pre-synaptic neuron, which inhibit serotonin secretion. Isotretinoin also directly and indirectly increases the translation of the serotonin transporter protein (SERT), leading to increased reuptake and consequently reduced synaptic availability of serotonin.
Inhibition of hippocampal neurogenesis may also play a role in the development of isotretinoin-induced depression. A further effect of isotretinoin on the brain involves retinoic acid function in the hypothalamus, the hormone regulatory centre of the brain and part of the hypothalamus-pituitary-adrenal axis, a key part of the body's stress response. Other brain regions regulated by retinoic acid and potentially disrupted by isotretinoin include the frontal cortex and the striatum.
Pharmacokinetics and pharmacodynamics
Oral Isotretinoin is best absorbed when taken with a high-fat meal, because it has a high level of lipophilicity.The efficacy of isotretinoin doubles when taken after a high-fat meal compared to when taken without food. Due to Isotretinoin's molecular relationship to Vitamin A, it should not be taken with Vitamin A supplements due to the danger of toxicity through cumulative overdosing. Accutane also negatively interacts with tetracycline, another class of acne drug, and with micro-dosed ('mini-pill') progesterone preparations, norethisterone/ethinylestradiol , St. John's Wort, phenytoin, and systemic corticosteroids.
Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly albumin. Three metabolites of Isotretinoin are detectable in human plasma after oral administration: 4-oxo-isotretinoin, retinoid acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Isotretinoin also oxidizes, irreversibly, to 4-oxo-isotretinoin which forms its geometric isomer 4-oxo-tretinoin. After an orally-administered, 80 mg dose of liquid suspension 14C-isotretinoin, 14C-activity in blood declines with a half-life of 90 hours.The metabolites of isotretinoin and its conjugates are then excreted in the subject's urine and faeces in relatively equal amounts.After a single, 80 mg oral dose of Isotretinoin to 74 healthy adult subjects under fed conditions, the mean ±SD elimination half-life (t1/2) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in people with cystic acne.