Opiates

Fentanyl

Metabolism and excretion

• It interacts with opiate receptors decreasing  pain impulse transmission at the spinal cord level and higher in the  CNS.
• Fentanyl is a potent µ-opiate receptor agonist.
• Also causes peripheral vasodilation increasing venous capacitance and decreases  venous return (chemical phlebotomy) by depressing the responsiveness of alpha-adrenergic receptors
• Fentanyl is metabolized in the liver, excreted by the kidneys, and stored in body fat.
• Human intestinal as well as liver microsomes catalyze fentanyl metabolism and N dealkylation by P4503A4 is the predominant route in both organs. The fraction of fentanyl lozenge that is swallowed likely undergoes significant intestinal, as well as hepatic, first pass metabolism. Intestinal and hepatic first pass metabolism, as well as systemic metabolism, may be subject to individual variability in P450 3A4 expression and to drug interactions involving P450 3A4. ⁽¹⁾
• Fentanyl competitively inhibits metabolism of midazolam by CYP3A4. ⁽²⁾
• CYP3A4*1G polymorphism is related to the pharmacokinetics of fentanyl. Patients with CYP3A4*1G variant alleleA have a lower metabolic rate of fentanyl. ⁽³⁾
• Paracetamol produces a concentration dependent inhibition of fentanyl oxidation to norfentanyl. ⁽⁴⁾
• The amount of CYP3A4 generated metabolites norfentanyl and hydroxyl fentanyl increases with age. Liver microsomes from younger patients metabolize a greater proportion of fentanyl to despropionyl fentanyl than those from older individuals. ⁽⁵⁾

Effect on circulation

• It decreases  both preload and afterload
• It may decrease myocardial oxygen demand
• Anetshetic doses of fentanyl and O2 produce minimal changes in cardiovascular dynamics but that addition of dizepam after large doses of fentanyl results in cardiovascular depression. Fentanyl-O2 anesthesia is an attractive alternative to morphine anesthesia in patients with little cardiac reserve. ⁽⁶⁾
• Fentanyl-droperidol anesthesia causes profound hypotension, marked acidosis, hypercarbia and hypoxia. ⁽⁷⁾
• Fentanyl modulates the respiratory frequency fluctuation of heart rate variability (HRV). This is caused by effects of fentanyl on arterial baroreflex sensitivity. ⁽⁸⁾
•  

Effect on respiration

• Fentanyl produces a dose dependent depression of minute ventilation with apnea at doses > 2.9 µg/kg. ⁽⁹⁾
• The hypothesis of fentanyl causing respiratory depression include:

• Saturation of the body fat compartment in patients with rapid and profound body fat loss (patients with cancer, cardiac or infection-induced cachexia can lose 80% of their body fat).
• Early carbon dioxide retention causing cutaneous vasodilatation (releasing more fentanyl), together with acidosis which reduces protein binding of fentanyl, releasing yet more fentanyl.
• Reduced sedation, losing a useful early warning sign of opioid toxicity and resulting in levels closer to respiratory depressant levels.

• Respiratory rate decreases significantly and end tidal CO2 showeda non significant increase following single doses of epidural fentanyl (1.5 µg/kg). Continuous epidural fentanyl infusion (0.5 µg/kg/hr) started 60 min after the bolus dose had no effect on end tidal CO2 concentration or respiratory rate for up to 18 hours. ⁽¹⁰⁾
• fentanyl added to epidural bupivacaine infusions during labor does not depress neonatal respiration or adversely affect neurobehavioral scores and other indices of neonatal welfare. ⁽¹¹⁾

Drug interactions

• CNS depressants may enhance effects
• Drug interaction is also seen with antihistamines, antiemetics, sedatives, hypnotics, barbiturates and alcohol
• Not to mix in line with heparin

Adverse effects

• Major side effects (more than 10% of patients) include diarrhea, nausea, constipation, dry mouth, somnolence, confusion,  asthenia, and sweating
• Less frequently (3 to 10% of patients) observed side effects include  abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, hallucinations, anxiety, depression, flu-like symptoms,  dyspepsia,  dyspnea,  hypoventilation, apnea, and urinary retention.
• Fentanyl use has also been associated with aphasia.

Contraindications

• Hypovolemia
• Hypotension
• Head injury
• Myasthenia gravis (causes severe muscle rigidity)
• Patients ho are taking MAOI (anti depressants like Nardil , Parnate)

Precautions

• Respiratory depression
• Severe heart disease
• Geriatrics
• Pediatrics
• Pregnancy
• May worsen bradycardia or heart block in inferior MI
• Liver failure/ kidney failure

Morphine

Metabolism and excretion

• Morphine can be taken  orally, sublingually, buccaly, rectally, subcutaneously, intravenously, intrathecally or epidurally and inhaled via a nebulizer.
• For medical purposes, intravenous (IV) injection is the most common method of administration.
• Morphine is subject to extensive first pass metabolism, so, if taken orally, only 40–50% of the dose reaches the central nervous system.
• Morphine is metabolized primarily in the liver and approximately 87% of a dose of morphine is excreted in the urine within 72 hours of administration.
• Morphine is metabolized primarily into morphine-3-glucoronide (M3G) and morphine-6-glucoronide (M6G) via glucoronidation by phase II metabolism enzyme UDP-glucoronosyl transferase-2B7 (UGT2B7).
• About 60% of morphine is converted to M3G, and 6–10% is converted to M6G.
• M3G is responsible for side effects, hyperalgesia/ allodynia and myoclonus seen after high dose of morphine treatment. ⁽¹⁾
• Morphine may also be metabolized into small amounts of normorphine, codeine and hydromorphone.
• Morphine metabolism to hydromorphone is highly variable within a subject and also between subjects. This variabililty contributes to unpredictable side effects. Thus, patient should be closely monitored when on morphine therapy. ⁽²⁾
• One third of the elimination of morphine from the fetal baboon is attributable to metabolism, one third to passive placental transfer and one third undefined. There is no evidence for saturation of metabolism. ⁽³⁾
• M3G may antagonize the analgesic efefcts of morphine and M6G, also causes neurotoxic symptoms like hyperalgesia, allodynia and myoclonus. These symptoms have been sporadically reported in humans treated primarily with high doses of morphine. ⁽⁴⁾

Effect on circulation

• Morphine reduce pre load, heart rate and after load
• Net effect is reduction in myocardial oxygen demand
• Opiod receptor stimulation results in a reduction in infarct size similar to that produced by ischemic preconditioning. The effect of morphine is mediated via opioid receptor K_ATP channel linked mechanism in the rat heart. Glibenclamide abolishes its protection. ⁽⁵⁾
• In human subjects, morphine induces a peripheral venous and arterial dilation by a reflex reduction in sympathetic alpha adrenergic tone. Morphine does not appear to act as a peripheral alpha adrenergic blocking agent but seems to attenuate the sympathetic efferent discharge at a central nervous system level. ⁽⁶⁾
• Morphine produces transient peripheral vasodilation and cardiovascular stimulation in patients with heart disease. Changes were more prominent in patients with valvular heart disease. Nitrous oxide added to morphine produces cardiovascular depression in all patients before operation and after cardiopulmonary bypass. ⁽⁷⁾

Effect on respiration

• Morphine causes respiratory depression
• It depresses the ventilator responses to hypoxemia which could be dangerous in patients with chronic obstructive pulmonary disease (COPD) and long standing hypercapnia
• The respiratory and cardiovascular depressant effectr of morphine results from inhibition of acetylcholine release from neurons in the central nervous system. Pretreatment with physiostigmine completely prevented fall in blood pressure and blood pH and rise in PaCO2. Neostigmine potentiated the bradycardia induced by morphine and did not antagonize its hypotensive and respiratory depressant effects. ⁽⁸⁾
• The decrease in morphine induced respiratory depression under chronic pain is mediated by the enhancement of 5-HT 4a receptor systems in the brainstem. ⁽⁹⁾
• Central chemosensitivity to hypercapnia and hypoxia are blunted by opioids at the levels of the retrotrapezoid nuscleus, medullary raphe nucleus and nucleus tractus solitarius. opioids also decrease central drive to both respiratory pump muscles and the upper airway dilator muscles. Opioid induced respiratory depression can be reversed by naloxone, 5-HT4(a) agonists and ampakines. ⁽¹⁰⁾

Effect on other system

• It causes euphoria, nervousness, relaxation, drowsiness, or sleepiness
• Chronic morphine treatment increases the synthesis and the intraneuronal destruction of newly synthesized DA and 5-HT without changing the rate of functional utilization of the monoamines. ⁽¹¹⁾

Drug interactions

• Effect of morphine may be potentiated by alkalizing agent and antagonized by acidifying agent
• Analgesic effect of morphine is potentiated by chlorpromazine and methocarbamol
• CNS depressants such as anesthetics, hypnotics, barbiturates, phenothiazines, chloral hydrate, glutethimide, sedatives, MAO inhibitors, antihistamines, Beta blockers, alcohol, furazolidine and other narcotics may enhance the depressant effect of morphine.
• Morphine mat increase anticoagulant activity of coumarin and other anticoagulants

Adverse effects

• Constipation, nausea, vomiting and abdominal cramps
• Sedation
• Morphine leads to release of histamine in the skin leading to warmth, flushing and urticaria or allergic eruptions across the skin
• Shrunken pupil
• Euphoria, hallucinations, delirium, dizziness and confusion
• Biliary colic and subsequent severe abdominal pain
• Addiction (psychological and physical dependence)
• Tolerance
• Withdrawal syndrome

Contraindications

• Acute respiratory depression
• Renal failure (due to accumulation of metabolites morphine-3-glucoronide and morphine-6-glucoronide)
• Chemical toxicity
• Raised intracranial pressure, including head injury (risk of worsening respiratory depression)
• Biliary colic

Hydromorphone

Metabolism and excretion

• Hydromorphone is metabolized to hydromorphone-3-glucoronide which has no analgesic effects.
• hm-3-glucoronide can produce excitatory neurotoxic effects such as restlessness, myoclonus and hyperalgesia.
• Metabolite build up can occur in patients with compromised kidney function, or sometimes in older patients
• Hydromorphone is a recently described minor metabolite of morphine. There is a wide variability between and within subjects in morphine metabolism to hydromorphone which explains the unpredictable adverse effects. ⁽¹⁾
• Interpretation of low urinary concentrations of hydromorphone in combination with high concentrations of morphine in morphine treated pain patients should not be considered as conclusive evidence of hydromorphone misuse. ⁽²⁾
• Enzymatic conversion of hydrocodone to hydromorphone is catalyzed by cytochrome P 450 2D6 which is inactive in about 7% of poor metabolizers and can be inhibited by quinidine pretreatment in the remainder (extensive metabolizers). There is only a small role of hydromorphone in eliciting abuse related responses to oral hydrocodone. ⁽³⁾
• Hydromorphone is an intermediary metabolite in the degradation of morphine by Pseudomonas putida M10. The enzyme Morphinone reductase has a potential application as a biocatalyst for the synthesis of highly potent analgesic hydromorphone and the antitussive hydrocodone. ⁽⁴⁾

Effect on circulation

• Circulatory depression
• It decrease pre load, heart rate and afterload
• Administration of medetomidine-hydromorphone is associated with increase in systolic arterial pressure (SAP), mean arterial pressure (MAP), diastolic arterial pressure (DAP), mean pulmonary arterial pressure (MPAP), central venous pressure (CVP), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), core body temperature and PaCO2. It decreases heart rate (HR), cardiac output (CO), stroke volume (SV), stroke index (SI), respiratory rate (RR), pH and PaO2. ⁽⁵⁾

Effect on respiration

• Respiratory depression
• Respiratory depression is more likely when opioid therapy begins, when the dosage is raised significantly. Hydromorphone is 8-10 times more potent than morphine and has faster onset. It accumulates on repeated dosing, thus a small amount of drug can have unpredictable effect. ⁽⁶⁾
• In healthy individuals without suspected sleep apnea, oral hydromorphone in standard dosages does not significantly increase sleep disordered breathing. ⁽⁷⁾ 

Drug interactions

• CNS depressants, such as other opioids, anesthetics, sedatives, hypnotics, barbiturates, phenothiazines, chloral hydrate, dimenhydrinate and glutethimide may enhance the depressant effects of hydromorphone. 
• MAO inhibitors (including procarbazine), first-generation antihistamines (brompheniramine, promethazine, diphenhydramine, chlorpheniramine), beta- blockers and alcohol may also enhance the depressant effect of hydromorphone.

Adverse effects

•  Analgesia, drowsiness, mental clouding
• Changes in mood, euphoria or dysphoria
• Respiratory depression
• Cough suppression
• Decreased gastrointestinal motility, nausea, vomiting
• Increased cerebrospinal fluid pressure, increased biliary pressure
• Pinpoint constriction of the pupils
• Increased parasympathetic activity
• Transient hyperglycemia

Contraindications

• Patient with hypersensitivity to hydromorphone
• Respiratory depression
• Status asthmaticus
• Also contraindicated for use in obstetric analgesia

Methadone

Metabolism and excretion

• Methadone has a slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs.
• It is potent an dhas high efficacy, excellent absorption from the gastrointestinal tract, no known active metabolites, very low cost and noth oral and intravenous formulations. The weak noncompetitive N-methyl-d-aspartate receptor antagonism possessed by methadone may further enhance the analgesia of the drug. ⁽¹⁾
• Methadone has a typical elimination half life of 15 to 60 hours with a mean of around 22.
• Methadone is metabolized in the liver, the main step is N-demethylation by CYP3A4 to EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyroolidine), an inactive metabolite. The activity of CYP3A4 varies considerably among individuals and such variability is responsible for methadone variability. CYP2D6 and CYP1A2 is also involved in methadone metabolism. ⁽²⁾
• The metabolism rates vary greatly between individuals ranging from as few as 4 hours to as many as 130 hours or even 190 hours.
• This variability is apparently due to genetic variability in the production of the associated enzymes CYP3A4, CYP2B6 and CYP2D6.
• CYP2B6 enzyme is responsible for the bulk of methadone metabolism in humans, particularly the S-methadone isomer. Therefore, not only overall plasma levels but also the ratio of plasma methadone isomers is controlled by CYP2B6. ⁽¹⁾
• Metabolism to and response to methadone varies with each patient. Transition to methadone and dosage titration should be completed slowly and with frequent monitoring. After starting methadone therapy or increasing the dosage, systemic toxicity may not become apparent for several days. ⁽³⁾
• A longer half-life frequently allows for administration only once a day in Opioid detoxification and maintenance programs.
• Patients who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects.
• The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day

Effect on circulation

• Low blood pressure
• Heart problems like chest pain, fast/ pounding heart beat
• Cardiac arrhythmias
• With use of methadone, there is a significant reduction in the fetal heart baseline rate, with a significant reduction in the number of accelerations and episodes of high variation. ⁽⁴⁾
• Methadone increases both QTc interval and QT dispersion. Increased QT dispersion reflects heterogenous cardiac repolarization and occurs with nonantiarrhythmic agents like synthetic opioids. ⁽⁵⁾
• Methadone causes QTc prolongation in a dose dependent manner. Daily dose of less than 60 mg methadone is safer cardac dose. It is necessary to closely monitor patients under MMT, especially those receiving higher methadone doses, with constant scheduled ECGs before and during treatment. ⁽⁶⁾

Effect on respiration

• Trouble breathing
• Slow and shallow breathing (hypoventilation)
• There is dose dependent inhibition of respiration with methadone. ⁽⁷⁾
• Nalagesic dosages of methadone depresses ventilation and ventilatory responsiveness to hypercapnia and abolishes the increase in respiratory drive elicited by the resistance. Patients who recieve methadone maintenance therapy exhibits no changes in either ventilatory responses or respiratory drive after intake of their daily doses of the drug. ⁽⁸⁾
• Methadone is responsible for life threatening poisonings with respiratory depression. There is large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationship is helpful in providing quantitative data regarding respiratory response to methadone in poisoning. ⁽⁹⁾

Drug interactions

Common medications known to interact with methadone include:

• Amphetamine/ dextroamphetamine
• Zolpidem, lorazepam, clonazepam
• Duloxetine
• Cyclobenzaprine
• Furosemide
• Pregabalin, gabapentin
• Esmoprazole
• Sertralinea
• Cholecalciferol
• Levothyroxine
• Promethazine and fluoxtine

Adverse effects

• Thrombus
• Diarrhea or constipation
• Flushing
• Perspiration and sweating
• Heat intolerance
• Dizziness or fainting
• Weakness
• Chronic fatigue, sleepiness and exhaustion
• Sleep problems like drowsiness, trouble falling asleep and trouble staying asleep
• Constricted pupil
• Dry mouth
• Nausea and vomiting
• Low blood pressure
• Hallucination or confusion
• Headache, light headedness or fainting
• Loss of apetite, in extreme cases anorexia
• Gynaecomastia
• Memory loss
• Stomach pain
• Itching
• Difficulty urinating
• Swelling of hands, arms, feet and legs
• Mood changes
• Blurred vision
• Decreased libido, missed menstrual periods, difficulty in reaching orgasm and impotence
• Skin rashes
• Seizures
• Sudden death

Contraindications

• Known hypersensitivity to methadone
• Patients with respiratory depression
• Patients with acute bronchial asthma or hypercarbia

Sufentanil

Metabolism and excretion

• The pharmacokinetics of Sufentanil can be described as a three-compartment model, with a distribution time of 1.4 minutes, redistribution of 17.1 minutes and an elimination half-life of 164 minutes.
• The liver and small intestine are the major sites of biotransformation.
• Approximately 80% of the administered dose is excreted within 24 hours and only 2% of the dose is eliminated as unchanged drug.
• Plasma protein binding of sufentanil, related to the alpha1 acid glycoprotein concentration, was approximately 93% in healthy males, 91% in mothers and 79% in neonates.
• Metabolism is by hepatic P450 enzyme CYP3A4 (N delkylation, O-demethylation)
• The major metabolic pathways include oxidative N-dealkylation at the piperidine nitrogen, oxidative N delkylation of the piperidine ring from the phenylpropanamide nitrogen, oxidative O-demethylation, and aromatic hydroxylation. TH emajor metabolite were N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, N-[4-(hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide, and N-phenylpropanamide. ⁽¹⁾
• Sufentanil is used in anesthetic management of patients undergoing orthotopic liver transplanatation (OLT). The total clerance of sufentanil is greater than its hepatic clerance. There is extrahepatic metabolism of sufentanil in patients undergoing OLT. ⁽²⁾
• Excreted in urine

Effect on circulation

• It causes bradycardia
• It may cause QT prolongation, ST segment elevation, ventricular tachycardia, severe cardiac arrhythmias
• Sufentanil produces depression in systolic function but without hemodynamic instability or myocardial lactate production. ⁽³⁾
• Apart from hypotension on induction of anesthesia, propofol-sufentanil anaesthesia produced anaestehtic conditions equivalent to enflurane-sufentanil anaesthesia for CABG surgery. ⁽⁴⁾
• Increasing the dose of sufentanil up to 20 µg/kg does not result in better suppression of the endocrine an dmetabolic changes associated with cardiac surgery. ⁽⁵⁾
• Fetal heart rate changes are more frequent after combined spinal epidural analgesia (CSE) using 7.5 micro g of intrathecal sufentanil as compared with other forms of neuraxial labor analgesia. ⁽⁶⁾

Effect on respiration

• It causes respiratory depression (slow and shallow breathing)
• Sufentanil when given in large doses, particularly if administered rapidly, can cause significant respiratory skeletal muscle rigidity that may adversely affect the anesthetist’s ability to ventilate
• 30 micrograms of epidural sufentanil is preferable to the higher dose with regard to both respiratory and non respiratory side effects. Even with the low dose, monitoring of ventilation is advisable for a minimum of 2 h. ⁽⁷⁾
• Sufentanil provide better patient comfort with less respiratory depression than does fentanyl. ⁽⁸⁾
• Delta receptors are involved in sufentanil related respiratory impairment, play a minor role in opioid-induced attenuation of sensory input to the brain. Highly selective delta-antagonists can revresethe respiratory depressant effect of potent opioids while maintaining analgesia. ⁽⁹⁾
• Pretreatment with 30 mg/kg naloxone does not reverse the i.v. or i.t. sufentanil induced antinociception and respiratory depression. Subcutaneous pretreatment with doses up to 30 mg/kg naloxone only partially anatagonized the i.v. sufentanil induced nociception while a complete reversal was present of the opioid induced hypercapnia and hypoxia. With regard to i.t. sufentanil, doses up to 30 mg/kg naloxonazine were unable to reduce the antonociception. The respiratory depression was partiallt affected; with 30 mg/kg naloxonazine, the i.t. sufentanil induced hypercapnia returned to baseline levels whereas the sufentanil induced hypoxia was minimally affected. ⁽¹⁰⁾

Drug interactions

• Beta blockers
• Codeine
• Tranquilizers
• Antihistamines like diphenhydramine
• Anti anxiety drugs
• Muscle relaxants
• Cimetidine

Adverse effects

• Nausea and vomiting
• Constipation
• Sweating, flushing of face, neck and upper thorax
• Pruritis, urticaria
• Mental clouding, depression, sedation
• Anticholinergic side effects (dry mouth, palpitation, tachycardia)
• Urinary retention, oligouria

Precaution

• Drug allergy
• Heart disease
• Liver disease
• Kidney problem
• Head injury
• Drug or alcohol dependency

Pethidine

Metabolism and excretion

• Pethidine is quickly hydrolysed in the liver to pethidinic acid and is also demethylated to norpethidine, which has half the analgesic activity of pethidine but a longer elimination half-life (8–12 hours). 
• In pregnant women, the apparent blood half life of pethidine is not different from that in healthy controls, however, apparent volume of distribution and total body clearance are reduced. In the neonate, the apparent half life is 2 to 7 times longer than in adults with values ranging from 7 to 32 h. ⁽¹⁾
• Pethidine’s metabolites are further conjugated with glucuronic acid and excreted into the urine.
• The excretion of pethidine and its metabolite norpethidine is increased in acid urine an ddecreased in alkaline urine. Acidification of the urine with ammonium chloride is indicated in the therapy of cases of pethidine poisoning in patients with reduced metabolic breakdown of the drug by the microsomal enzyme systems within the liver cells. ⁽²⁾
• Chronic methaqualone treatment causes enhancement of microsomal drug metabolizing enzymes catalyzed N-demethylation of pethidine. ⁽³⁾

Effect on circulation

• Hypotension and bradycardia
• Heart rate and direct mean arterial pressure remain unchanged but arterial pressure variability decreased in ventilated infants. ⁽⁴⁾
• When the effects of intramuscularly administered pethidine on indices of fetal heart rate (FHR) variability was assessed, the interval index decreased significantly with maximum effect 40 minutes after the injection. The differential index aslo showed decreasing trend, ith maximum at 40 minutes. Both indices returned to pre-injection level after 60 minutes. ⁽⁵⁾
• Labor pains are not sensitive to systemically administered pethidine. It only cause heavy sedation. ⁽⁶⁾
• Pethidine is a good analgesic and does not cause statistically significant change in haemodynamic responses. ⁽⁷⁾

Effect on respiration

• It causes respiratory depression
• Pethidine causes significant respiratory depression seen as an increase in fractional inspiratory-expiratory oxygen difference and P_ETCO2 and as a decrease in MV and respiratory rate. ⁽⁸⁾
• Pethidine administration intramuscularly causes increase in mean respiratory rate and decrease in mean minute volume and tidal volume. ⁽⁹⁾
• Pethidine causes temporary decrease in the cAMP levels ornithine decarboxylase activity of the fetal developing brain. ⁽¹⁰⁾

Drug interactions

• Alcohol
• Antipsychotics like chlorpromazine, haloperidol
• Barbiturates
• Benzodiazapines
• Anti epileptics like valproate
• Morphine and codeine
• Antihistamines like hydroxyzine
• Zopiclone
• Tricyclic anti depressants like amitriptyline
• Domperidone
• Metoclopramide

Adverse effects

• Nausea and vomiting
• Constipation
• Dry mouth
• Headache and dizziness
• Constricted pupil
• Facial flushing
• Hallucination
• Euphoria

Contraindications

• Obstructive pulmonary disease
• Liver disease
• Kidney disease
• Head injury and patients with raised intracranial pressure
• Phaeochromocytoma
• Patients on MAO inhibitors
• Patient on linezolid

Precaution

• Elderly patients and new born
• Premature infants
• Kidney disease
• Liver disease
• Asthma
• Patients with epilepsy
• Patients with ulcerative colitis or crohn’s disease
• Hypothyroidism
• Prostatic hypertrophy