**2.1 Morphine**

International Union of Pure and Applied Chemistry (IUPAC) name: (4R,4aR,7S,7aR,12bS)-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12 methanobenzofuro[3,2-e]isoquinoline-7,9-diol.


Morphine is one of the major opium alkaloids isolated from plant *Papaver somniferum L.*, produced synthetically and metabolized by codeine and heroin in the body. It binds to μ, δ, and κ receptors, which are widely distributed in CNS and peripheral tissue, and produce effects such as analgesia, anxiolysis, euphoria, sedation, respiratory depression, and contraction of smooth muscles of GI tract. Morphine is used in the management of severe pain, treatment of acute pulmonary edema and anesthetic procedures [56]. It can be administered orally, rectally, intramuscularly, intravenously, subcutaneously, epidurally, and intrathecally.

Absorption of morphine is variable, an almost complete absorption mainly done in the upper intestine as well as in the rectal mucosa. Morphine presents significant first-pass metabolism and oral bioavailability within 17–33% [57]. Morphine distributes to brain, skeletal muscle, liver, kidneys, lungs, intestinal tract, and spleen [58]. Hepatic metabolism occurs via glucuronic acid conjugation primarily to morphine-6-glucuronide (M6G, 10–15%) and morphine-3-glucuronide (M3G, 45–55%). Other metabolites include morphine-3,6-diglucuronide, morphine-3-ethereal sulphate, normorphine, normorphine-6-glucuronide, normorphine-3-glucuronide and codeine. M6G and normorphine show active analgesic effect by binding to opioid receptors, but M6G, which is formed more than normorphine, can contribute to analgesic effect of morphine. M3G does not contribute to the analgesic effect of morphine, because it has low affinity to opioid receptors [59]. Half-life elimination is variable according to age group: in neonates 4.5–13.3 h, in children 1–2 h, and in adults 2–4 h. Excretion occurs with urine (2–12%) and feces (7–10%).

Morphine leads to death in amounts of 0.15–0.2 g (sc) or 0.3–0.4 g (oral) in adults. Babies and young children are much more susceptible, and death has been observed at doses of 30 mg [60]. Morphine blood concentration within 10–100 μg/dL is toxically; if it is above 400 μg/dL is lethally [61].

Common adverse reactions are drowsiness, headache, constipation, nausea, vomiting, urinary retention. Although less common adverse reactions, such as depression, insomnia, paresthesia, dizziness, anxiety, abnormal dreams, confusion, seizure, myoclonus, agitation, amnesia, euphoria, pain, dyspnea, hypoventilation,

respiratory depression, tremor, fever, flu-like symptoms, rhinitis, edema, hypotension, syncope, palpitations, skin rash, amblyopia, blurred vision, conjunctivitis, diplopia, miosis, nystagmus, amenorrhea, impotence, gynecomastia, urinary hesitancy, diaphoresis, anorexia, biliary colic, dyspepsia, gastroesophageal reflux disease, hiccups, xerostomia, anemia, thrombocytopenia can be seen.

Contraindications are hypersensitivity to morphine, significant respiratory depression, acute or severe bronchial asthma in the absence of resuscitative equipment, GI obstruction.

*Effects on reproduction*: Prolonged morphine use can cause secondary hypogonadism, which can lead to infertility in both sexes [62].

*Effects on pregnancy*: It is known that, morphine crosses the placenta. Morphine exposure was associated with conoventricular septal defects, atrioventricular septal defects, hypoplastic left heart syndrome, spina bifid, and gastroschisis within a 4 month period, 1 month before and 3 months after conception [63]. In addition, the use of it in the first trimester may reduce fetal heart rate from non-teratogenic effects [64]. Use of morphine late in pregnancy may result in decreased fetal breathing movements or withdrawal signs in the newborn [65, 66]. Withdrawal signs are hypothermia, hyperthermia, diarrhea, vomiting, anorexia, weight gain, high-pitched crying, hyperactivity, increased muscle tone, increased wakefulness, abnormal sleep pattern, irritability, sneezing, seizure, tremor, yawning and etc. [67, 68].

*Effects on lactation*: Both morphine and an active metabolite, M6G, can be detected in breast milk [69]. According to previous study, a milk:plasma ratio of morphine was 2.85, and the estimated maximum concentration in milk was 500 ng/mL [70]. Respiratory depression or drowsiness were not common in infants of breastfeeding mothers receiving morphine [71]. Although not preferred in lactation, it should be used as soon as possible and at the lowest dose if necessary [72].

#### **2.2 Noscapine**

IUPAC name: (3S)-6,7-dimethoxy-3-[(5R)-4-methoxy-6-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-5-yl]-3H-2-benzofuran-1-one.


Noscapine, also known as narcotine, is the second opioid alkaloid according to its density in raw *Papaver somniferum L.* plant, was first isolated by Robiquet in 1817 [73]. Noscapine has no morphine-like effect, no affect on morphine withdrawal and has mild analgesic effect [74]. It is used to suppress cough frequency and intensity in bronchial asthma and pulmonary emphysema as it has central antitussive activity such as codeine [74, 75]. It is thought that noscapine exerts its antitussive effect through σ receptor which is one of the other opioid receptors. Repeated exposure to noscapine does not lead to dependence and tolerance to its antitussive effect does not develop. The potential for antineoplastic treatment is being investigated because of its antimitotic effect [76]. In the animal study, noscapine increased histamine release, leading to bronchoconstruction and hypotension, even convulsions [77]. There are also studies showing that teratogen [78]. Noscapine is used orally in the form of a combined preparation to reduce these effects.

Noscapine in terms of antitussive potency, onset, and duration of action is similar to codeine, one of the main opium alkaloids [74]. Noscapine has a relatively low bioavailability due to a first-pass metabolism [79]. Noscapine is inactivated by

## *Opium Alkaloids DOI: http://dx.doi.org/10.5772/intechopen.91326*

converting into meconin and o-demethylated metabolites. Meconin is major urinary metabolite of noscapine [80].

Adverse reactions are not expected when used in therapeutic doses [74]. When taken in high doses, drowsiness, headache, nausea, vasomotor rhinitis, conjunctivitis may be seen [81].

*Effects on reproduction and pregnancy* is unknown.

*Effects on lactation*: It is thought to have no negative effects on infant [82].
