Hydrocodone and pseudoephedrine

Uses

Hydrocodone is an opioid agonist used as an analgesic and antitussive agent.

Hydrocodone is indicated for the management of acute pain, sometimes in combination with acetaminophen or ibuprofen, as well as the symptomatic treatment of the common cold and allergic rhinitis in combination with decongestants, antihistamines, and expectorants.

Pseudoephedrine is an alpha and beta adrenergic agonist used to treat nasal and sinus congestion, as well as allergic rhinitis.

Pseudoephedrine is a sympathomimetic amine used for its decongestant activity.

Hydrocodone and pseudoephedrine is also used to associated treatment for these conditions: Cough, Cough caused by Allergic Rhinitis, Cough caused by Common Cold, Nasal Congestion caused by Allergic Rhinitis, Nasal Congestion caused by Common Cold, Pain, Acute, Pain, Chronic, Rhinitis caused by Common Cold, Severe Pain, Moderate Pain, Upper respiratory symptoms caused by Allergic Rhinitis, Upper respiratory symptoms caused by Common ColdAllergic Rhinitis (AR), Allergies, Common Cold, Common Cold Associated With Cough, Common Cold/Flu, Cough, Cough caused by Common Cold, Eye allergy, Fever, Flu caused by Influenza, Headache, Irritative cough, Nasal Allergies, Nasal Congestion, Nasal Congestion caused by Common Cold, Pain, Perennial Allergy, Priapism, Respiratory Allergy, Rhinorrhoea, Seasonal Allergic Rhinitis, Seasonal Allergies, Sinus Congestion, Sinusitis, Sneezing, Sore Throat, Symptoms of Acute Bronchitis Accompanied by Coughing, Throat irritation, Upper Respiratory Tract Infection, Upper respiratory tract congestion, Upper respiratory tract signs and symptoms, Dry cough, Minor aches and pains, Sinus pain, Watery itchy eyes, Airway secretion clearance therapy

How Hydrocodone and pseudoephedrine works

Hydrocodone binds to the mu opioid receptor (MOR) with the highest affinity followed by the delta opioid receptors (DOR). Hydrocodone's agonist effect at the MOR is considered to contribute the most to its analgesic effects. Both MOR and DOR are Gi/o coupled and and produces its signal through activation of inward rectifier potassium (GIRK) channels, inhibition of voltage gated calcium channel opening, and decreased adenylyl cyclase activity. In the dorsal horn of the spinal cord, activation of pre-synaptic MOR on primary afferents the inhibition of calcium channel opening and increased activity of GIRK channels hyperpolarizes the neuron and prevents release of neurotransmitters. Post-synaptic MOR can also prevent activation of neurons by glutamate through the aforementioned mechanisms.

Hydrocodone can also produce several actions in the brain similarly to other opioids. Activation of MOR in the periaquaductal gray (PAG) inhibits the GABAergic tone on medulo-spinal neurons. This allows these neurons, which project to the dorsal horn of the spinal cord, to suppress pain signalling in secondary afferents by activating inhibitory interneurons. MOR can also inhibit GABAergic neurons in the ventral tegmental area, removing the inhibitory tone on dopaminergic neurons in the nucleus accumbens and contributing to the activation of the brain's reward and addiction pathway. The inhibitory action or MOR likely contributes to respiratory depression, sedation, and suppression of the cough reflex.

Activation of DOR may contribute to analgesia through the above mechanisms but has not been well studied.

Pseudoephedrine acts mainly as an agonist of alpha adrenergic receptors and less strongly as an agonist of beta adrenergic receptors.[A10896] This agonism of adrenergic receptors produces vasoconstriction which is used as a decongestant and as a treatment of priapism. Pseudoephedrine is also an inhibitor of norepinephrine, dopamine, and serotonin transporters.

The sympathomimetic effects of pseudoephedrine include an increase in mean arterial pressure, heart rate, and chronotropic response of the right atria. Pseudoephedrine is also a partial agonist of the anococcygeal muscle. Pseudoephedrine also inhibits NF-kappa-B, NFAT, and AP-1.

Toxicity

Overdosage with hydrocodone presents as opioid intoxication including respiratory depression, somnolence, coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death.

In case of oversdosage the foremost priority is the maintenance of a patent and protected airway with the provision of assisted ventilation if necessary. Supportive measures such as IV fluids, supplemental oxygen, and vasopressors may be used to manage circulatory shock. Advanced life support may be necessary in the case of cardiac arrest or arrhythmias. Opioid antagonists such as naloxone may be used to reverse the respiratory and circulatory effects of hydrocodone. Emergency monitoring is still required after naloxone administration as the opioid effects may reappear. Additionally, if used in an opioid tolerant patient, naloxone may produce opioid withdrawal symptoms.

The oral LD₅₀ of pseudoephedrine is 2206mg/kg in rats and 726mg/kg in mice.

Patients experiencing an overdose of pseudoephedrine may present with giddiness, headache, nausea, vomiting, sweating, thirst, tachycardia, precordial pain, palpitations, difficulty urinating, muscle weakness, muscle tension, anxiety, restlessness, insomnia, toxic psychosis, cardiac arrhythmias, circulatory collapse, convulsions, coma, and respiratory failure. Treat overdose with symptomatic and supportive treatment including removal of unabsorbed drug.

Volume of Distribution

The apparent volume of distribution ranges widely in published literature. The official FDA labeling reports a value of 402 L. Pharmacokinetic studies report values from 210-714 L with higher values associated with higher doses or single dose studies and lower values associated with lower doses and multiple dose studies. Hydrocodone has been observed in human breast milk at levels equivalent to 1.6% of the maternal dosage. Only 12 of the 30 women studied had detectable concentrations of hydromorphone at mean levels of 0.3 mcg/kg/day.

The apparent volume of distribution of pseudoephedrin is 2.6-3.3L/kg.

Elimination Route

The absolute bioavailability of hydrocodone has not been characterized due to lack of an IV formulation. The liquid formulations of hydrocodone have a Tmax of 0.83-1.33 h. The extended release tablet formulations have a Tmax of 14-16 h. The Cmax remains dose proportional over the range of 2.5-10 mg in liquid formulations and 20-120 mg in extended release formulations. Administration with food increases Cmax by about 27% while Tmax and AUC remain the same. Administration with 40% ethanol has been observed to increase Cmax 2-fold with an approximate 20% increase in AUC with no change in Tmax. 20% alcohol produces no significant effect.

A 240mg oral dose of pseudoephedrine reaches a C_max of 246.3±10.5ng/mL fed and 272.5±13.4ng/mL fasted, with a T_max of 6.60±1.38h fed and 11.87±0.72h fasted, with an AUC of 6862.0±334.1ng*h/mL fed and 7535.1±333.0ng*h/mL fasted.

Half Life

The half-life of elimination reported for hydrocodone is 7-9 h.

The mean elimination half life of pseudoephedrine is 6.0h.

Clearance

Official FDA labeling reports an apparent clearance of 83 L/h. Pharmacokinetic studies report values ranging from 24.5-58.8 L/h largely dependent on CYP2D6 metabolizer status.

A 60mg oral dose of pseudoephedrine has a clearance of 5.9±1.7mL/min/kg.

Elimination Route

Most hydrocodone appears to be eliminated via a non-renal route as renal clearance is substantially lower than total apparent clearance. Hepatic metabolism may account for a portion of this, however the slight increase in serum concentration and AUC seen in hepatic impairment indicates a different primary route of elimination.

55-75% of an oral dose is detected in the urine as unchanged pseudoephedrine.

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