15 Neuropharmacology
Abstract
The neurointensivist’s expertise in medical management is equivalent to the expertise in surgical management of the nervous system. Not only are systemic conditions treated to improve the organs of the body, the systemic conditions are treated to ensure that the brain and spinal cord receive the optimal delivery of nutrients. Treating one organ does not preclude understanding how the treatment affects the brain. Some medications, although excellent for the heart, might harm the brain and lead to a less desirable overall outcome. Neuropharmacology allows the clinician to meticulously calculate the treatment of the nervous system injury and prevent other primary and secondary injuries.
Case Study
A 45-year-old man was an unrestrained driver of a motorcycle that was involved in an accident. He is taken to the trauma center with a Glasgow Coma Scale score of 8; his pupils are sluggish and reactive. He is intubated. He has multiple fractures and an elevated intracranial pressure of 30 mm Hg and cerebral perfusion pressure of 55 mm Hg.
See end of chapter for Case Management.
15.1 Introduction
Treating the neurosurgical patient requires forethought and very close attention to detail, and therefore each form of treatment, whether surgical or medical management, must be meticulously calculated, as even the simplest decisions can drastically change the patient’s outcome. In patients who have suffered a primary injury to the brain, once the initial insult has been addressed, the role of treatment shifts to the prevention of secondary injury caused by hypotension, hypoxia, hyperemia, hypertension, electrolyte imbalances, or infection, just to name a few. This chapter examines the medications used in the prevention and treatment of primary and secondary brain injuries.
15.2 Hemodynamic Agents
15.2.1 Hypertension
Hypertension is a chronic disease that can cause a severe acute neurological injury or can exponentially exacerbate secondary injury to the central nervous system (CNS). Treatment of chronic hypertension and/or transient hypertension is based on understanding the underlying cause. In a patient with traumatic brain injury, blood pressure is tightly regulated to allow a therapeutic range of cerebral perfusion pressure (CPP), normalize intracranial pressure (ICP) and prevent rebleeding or hemorrhagic stroke in dead necrotic brain parenchyma. In patients with ischemic stroke “permissive hypertension is allowed to a systolic blood pressure limit (usually 160–180 mm Hg) to allow profusion to penumbra. Though there are many pharmaceutical agents that can be used to treat hypertension, knowing each agent’s mechanism of action can yield favorable results and prevent unintended outcomes from inherent side effects of these agents. Always remember to order blood pressure and heart rate parameters when writing for a drug. 1 , 2 Furthermore, it is vitally important that when blood pressure control is paramount not to order blood pressure medication as “BID,” “TID,” and so forth, but to write for the specific times ordered. This will also allow staggering of the blood pressure medication and prevent the large swings of blood pressure that can occur if multiple anti-hypertensives are given at the same time.
15.2.2 Nitrogen
Nitrogen-based drugs react with oxyhemoglobin to produce nitrous oxide, which causes vasodilation, reducing systemic resistance and in turn reducing systolic blood pressure. In patients with suspected elevated ICP (e.g., hemorrhagic stroke, traumatic brain injury, or malignant cerebral edema) this class of antihypertensives should not be used due to its mechanism of action, vasodilation, which would also occur in the cranium. 3 According to the Monro–Kellie doctrine this increase in intravascular blood volume would cause an increasing ICP, thus decreasing CPP and leading to secondary injury. This class of drug also has the side effects of coronary steal syndrome, headache, hypotension, rebound hypertension, and methemoglobinemia, which can result in undesirable patient outcome. However, there may be a role for vasodilation during times of increased cardiac output.
Sodium Nitroprusside (Nipride)
Action: Reacts with oxyhemoglobin to form cyanide and nitric oxide (NO). NO stimulates cyclic guanosine monophosphate (cGMP) production, causing potent vasodilation (arterial > venous) and hepatic and renal metabolism. 1 , 4
Contraindications: Increased ICP, intracranial mass lesion (raises ICP), pregnancy. 1 , 3
Rx: Intravenous (IV) drip 0.25 to 8 μg/kg/min. To prepare: 50 mg in 500 mL dextrose 5% in water (D5W) = 100 μg/mL; can be double concentrated to reduce fluid or glucose load. 1 , 5
Side effects: “Cerebral and coronary steal” phenomenon due to preferential peripheral vasodilation before cerebral vasodilation. Thiocyanate/cyanide toxicity causes neurologic deterioration and hypotension (cover bottle with foil: light sensitive). Nausea, diuresis, platelet inhibition; may increase ICP. 1 , 3 , 4
Nitroglycerin (Tridil)
Action: Releases NO, resulting in guanylyl cyclase stimulation of cGMP synthesis. This medication acts predominantly on venous capacitance vessels, affecting arterial vascular smooth muscle at higher concentrations. Primarily venodilation without reflex tachycardia. 1 , 4
Contraindication: Increased ICP or decreased cerebral perfusion 1 , 2 , 3
Rx: IV drip 10 to 20 μg/min (increase by 5–10 μg/min every 5–10 min). 1 , 4 , 5
Side effects: Does not cause “coronary steal”; can cause transient increase in ICP, headache, hypotension, rebound hypertension, and methemoglobinemia. 1 , 2 , 3 , 4 , 5
Hydralazine (Apresoline)
Action: Direct arteriolar smooth muscle vasodilator; may act through NO or calcium. 1 , 4
Contraindication: Liver metabolism; slow acetylators should not receive > 200 mg/d—may induce lupus-like syndrome. 1 , 4
Rx: 10 to 20 mg every 15 to 20 minutes, maximum 40 mg; repeat as needed. 1 , 4 , 5
Side effects: Nausea/vomiting, headache, increased intracranial blood flow, reflex tachycardia. 1 , 4
15.2.3 Beta Blockers
Beta blockers are a first-line drug in traumatic brain injury and hemorrhagic stroke as they have been associated with a significant reduction in mortality.
Beta blockers should not be used in patients with a history of cocaine or methamphetamine abuse due to the potential of inciting drug-induced coronary artery vasoconstriction. 6 , 7 , 8 The combination of beta blockers and stimulants, such as cocaine and methamphetamines, can cause systemic vasoconstriction and paradoxical hypertension. This is due to the release of norepinephrine in excess (from stimulant use) compounded with blockade of β-adrenergic receptors (β2 causes vasodilation) causing unopposed α1-adrenergic receptor stimulation. The end result is vasoconstriction, which can exacerbate hemorrhagic stroke and cause increased ICP, cerebral ischemia, myocardial infarction, and death.
Labetalol (Normodyne)
Action: Blocks α1 selective, β nonselective; hepatic glucuronide conjugation; may lower ICP. 1 , 4 , 8
Contraindications: Asthma, pregnancy. 1
Rx: Give each dose by slow intravenous push (IVP) (over 2 minutes) every 10 minutes until desired blood pressure (BP) is achieved; dose sequence: 20, 40, 80, 80, then 80 mg (300 mg total). Once controlled, use=same total dose IVP every 8 hours. Alternative: IV drip: add 40 mL (200 mg) to 160 mL of intravenous fluids (IVF) (result 1 mg/mL). Run at 2 mL/minute (2 mg/min) until desired BP (usual effective dose 50–200 mg) or until 300 mg given, then titrate the rate. Bradycardia limits dose; increase slowly because the effect takes 10 to 20 minutes. Oral dose: start with 200 mg twice a day if converting from IV; otherwise, start 100 mg orally twice a day and increase 100 mg/dose every 2 days, maximum 2,400 mg/d. 1 , 2 , 4 , 5
Side effects: Fatigue, dizziness, orthostatic hypotension. 1 , 4
Esmolol (Brevibloc)
Action: Short-acting selective β1 antagonist; metabolized by red blood cell esterase, urinary excretion; may lower ICP. 1 , 4 , 8
Contraindication: Avoid in congestive heart failure (CHF). 1
Rx: Mix 5 g/500 mL normal saline (NS), give IV 500 μg/kg loading dose over 1 minute, follow with 4-minute infusion starting with 50 μg/kg/min. Repeat the loading dose and increment the infusion rate by 50 μg/kg/min every 5minutes. Rarely > 100 μg/kg/min is required. Doses > 200 μg/kg/min add little benefit. 1 , 2 , 5
Side effects: Dose-related hypotension; resolves within 30 minutes of discontinuation. Less bronchospasm than with other beta blockers. 1 , 2
15.2.4 Calcium Channel Blockers
Nimodipine has been identified as a standard of care in prevention and treatment of vasospasms in patients who have subarachnoid hemorrhage from ruptured aneurysm. Though the mechanism of action in preventing vasospasm is unclear, it was concluded from a double-blinded, randomized clinical trial that nimodipine significantly reduces the occurrence of cerebral arterial spasm.
Nimodipine (Nimotop)
Action: Inhibits calcium ion influx in vascular smooth muscle and neurons, resulting in increased collateral circulation and prevention of neuronal calcium overload. 1
Contraindications: Hypersensitivity to drug class, parenteral use, caution if there is hepatic disease. 1 , 4
Rx: 60 mg oral/nasogastric (NG) every 4 hours × 21 days. May dose at 30 mg oral/NG every 2 hours × 21 days if patient’s blood pressure is hypotensive and patient is not tolerating 60 mg dosing. 1
Side effects: Hypotension, rash, headache, flushing, gastrointestinal bleeding, thromboembolism, CHF, thrombocytopenia anemia, ileus, intestinal obstruction. 1 , 4
Diltiazem (Cardizem)
Action: Slow calcium-channel antagonist; relaxes vascular smooth muscle without reflex tachycardia. 1
Contraindications: Sick sinus syndrome, wide complex tachycardia, Wolff–Parkinson–White (WPW) syndrome, second-degree or greater atrioventricular (A-V) block and concurrent beta blockers. 1 , 4
Rx: 20 mg IV over 2 minutes; 0.25 mg/kg. May repeat 1 × in 15 minutes if response is inadequate. Not suggested as a drip for neurosurgical patients. 1
Side effects: Hepatitis, edema, blurred vision, flushing, injection site reaction. 1 , 4
Nifedipine (Procardia)
Action: Short-acting calcium-channel blocker. Decreases systemic vascular resistance; increases cardiac index, cerebral blood flow (by 10–20%), glomerular filtration rate, and Na+ retention. 1 , 4
Contraindications: Hypersensitivity, acute myocardial infarction. 1 , 4
Rx: Oral 10 to 20 mg, faster onset with sublingual/buccal administration (puncture capsule) or if chewed. If no response after 20 to 30 minutes, give additional 10 mg. 1 , 4 , 5
Side effects: Flushing, headache, palpitation, edema, reflex tachycardia. 1 , 4
Nicardipine (Cardene)
Action: The only second-generation IV dihydropyridine calcium channel blocker.
Contraindications: Can often cause neurologic worsening in patients with stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Nicardipine IV drip is the relative large volume of fluid needed (up to 150 mL/h). This calcium channel blocker has been shown to increase ICP in some limited animal and human studies.
Rx: Nicardipine drip 25 mg/250 mL in 250 mL NS, on a pump for a concentration of 0.1 mg/mL induction at a rate of 0.2 μg/kg/min, or 5 mg/h (50 mL/h), and may be increased in increments of 2.5 mg/h every 5 to 15 minutes, depending on the need to rapidly or gradually control blood pressure, to a maximum of 15 mg/h (150 mL/h). Once the desired level is achieved decrease the rate to 3 mg/h (30 mL/h). Nicardipine drip is not compatible with sodium bicarbonate injection or lactated Ringer’s solution.
Side effects: Dizziness, fainting, unusual weakness, lightheadedness, headache, flushing, nausea, vomiting, tiredness, swelling of the ankles/feet, frequent urination, shortness of breath, irregular heartbeat, joint/muscle pain, tingling of the hands/feet, mood changes, ringing in the ears.
15.2.5 Angiotensin II Receptor Blockers
Angiotensin II receptor blockers (ARBs) are medications that block the action of angiotensin II by preventing it from binding to its receptors on the smooth muscles on blood vessels. As a result, blood vessels dilate, reducing blood pressure. Examples of ARBs include candesartan cilexetil, eprosartan, irbesartan, losartan, mesylate, olmesartan, telmisartan, valsartan.
Action: Allow blood vessel wall relaxation and dilation, reducing blood pressure and increasing release of sodium and water into urine.
Contraindications: Hypersensitivity, pregnancy.
Rx: The oral dosage depends on the specific medication used.
Side effects: Headache and dizziness. Other side effects may be diarrhea, stomach problems, muscle cramps, back and leg pain, insomnia, nasal congestion, cough, sinus problems, and upper respiratory infection. This class of drug is less likely to cause a cough when compared to angiotensin–converting enzyme blockers.
15.2.6 Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors are used as first-line drugs in the treatment of hypertension because they have been proven to reduce the risk of primary stroke beyond their blood pressure lowering capacity. It is believed that their effects on the renin–angiotensin–aldosterone system are their primary mechanism of action in the reduction of stroke risk. In addition, early use of ACE inhibitors immediately after stroke has been associated with improved cerebral perfusion. 9 , 10 This is thought to be a result of their effect on improving vascular compliance by reducing proliferation of vascular smooth muscle, enhancing endogenous fibrinolysis, and inhibiting plaque rupture and vascular occlusion. ACE inhibitors are also used in the treatment of traumatic brain injury because they have no deleterious effect on ICP.
Enalaprilat (Vasotec)
Action: ACE inhibitor; may lower ICP. 1 , 4 , 9 , 10
Contraindication: Pregnancy. 1
Rx: Titrate to effect, starting with IV 1.25 mg slowly over 5 minutes, followed by 1.25 to 5 mg IV every six hours depending on response within 15 minutes; may repeat 0.625 mg IV in one hour if response is inadequate, but maximum 6 hour dose should not exceed 5 mg. 1 , 4 , 5
Side effects: Hyperkalemia ~ 1%; can cause renal insufficiency, angioedema, agranulocytosis. 1 , 4
15.2.7 Alpha Agonist
In treating hypertension, clonidine is the most widely used α-adrenergic receptor agonist. It is a centrally acting presynaptic α2-adrenergic receptor agonist that causes a decrease in peripheral vascular resistance and a decrease in sympathetic tone. This gives clonidine its antihypertensive and sedative properties. In the neurosurgical intensive care unit (NICU), clonidine is effective in treating patients with cocaine and methamphetamine abuse as its mechanism of action is antagonistic to these stimulants by decreasing presynaptic calcium levels, thus inhibiting the release of norepinephrine. This reduces hypertension created by systemic vasoconstriction and agitation created by overstimulation.
Clonidine (Catapres)
Action: Inhibits sympathetic outflow by acting on cardiovascular control receptors in the medulla oblongata. 1 , 4
Contraindication: Hypersensitivity. 1
Rx: Rapid control: 0.2 mg orally, then 0.1 mg orally every hour; stop at 0.8 mg total or if orthostatic. Maintenance dose: 0.1 mg orally two or three times a day; increase slowly to maximum 2.4 mg/d (usual 0.2–0.8 mg/d). Patch 0.1 mg, 0.2 mg, 0.3 mg/wk titrate to desired effect; maximum 0.6 mg/wk. 1 , 4 , 5
Side effects: Tachycardia rare; mild confusion/sedation; fluid retention, dry mouth, constipation, rebound hypertension. 1
15.2.8 Hypotension
It is important to prevent hypotensive episodes in the neurologically compromised patient because it is associated with an increase in morbidity and mortality. The first step in treating hypotension is identifying the cause, such as volume loss, heart failure, infection, or shock. Treatment of the underlying cause will correct the hypotension; however, symptomatic treatment must be initiated with volume resuscitation and vasopressor support.
Dopamine (Intropin)
Action: Primarily a vasoconstrictor; 25% of dopamine given is rapidly converted to norepinephrine. At doses > 10 μg/kg/min, α, β, and dopaminergic effect (essentially giving norepinephrine). At 2 to 10 μg/kg/min, primarily β1, positive inotrope. At 0.5 to 2.0 μg/kg/min, primarily dopaminergic, vasodilating renal, mesenteric, coronary, and cerebral vessels, positive inotrope. 1 , 4
Contraindication: Pregnancy class C. 1 , 4
Rx: Mix 800 mg/250 mL NS, central line. Start with 2 to 5 μg/kg/min and titrate for response; maximum 20 μg/kg/min. 1 , 2 , 4 , 5
Side effects: Tachycardia, peripheral vasoconstriction, arrhythmias, hyperglycemia. 1 , 4
Dobutamine (Dobutrex)
Action: Racemic mixture: L-isomer is alpha agonist, D-isomer nonspecific; beta agonist comparable to dopamine and nitroprusside. 1 , 4
Contraindication: Hypertrophic cardiomyopathy. 1
Rx: Mix 500 mg/250 mL NS. Usual range 2.5 to 10.0 μg/kg/min; rarely, doses up to 40 μg used. To prepare: Put 50 mg in 250 mL D5 W to yield 200 μg/mL. 1 , 2 , 4 , 5
Side effects: Tachycardia, possibly platelet function inhibition. 1 , 4
Norepinephrine (Levophed)
Action: β1– and α1-adrenergic receptor agonist. 1
Contraindications: Hypertrophic obstructive cardiomyopathy, tetralogy of Fallot (right ventricular outflow tract obstruction). 1 , 4
Rx: Mix 4 mg/250 mL NS. Initial rate 0.5 to 1.0 μg/min. Average 4 to 16 μg/min; maximum 30 to 47 μg/min. 1 , 4
Side effects: Vasoconstriction (splanchnic and renal), arrhythmias. 1
Phenylephrine (Neo-Synephrine)
Action: Pure alpha vasoconstrictor; causes reflex increase in parasympathetic tone with resultant slowing of pulse. Useful in hypotension associated with tachycardia. 1 , 4
Contraindication: Spinal cord injuries.
Rx: Mix 40 mg/500 mL NS to yield 80 μg/mL; rate of 8 mL/h = 10 μg/min. Vasopressor range: Initial 100 to 180 μg/min; maintenance 40 to 60 μg/min. 1 , 4
Side effects: Cardiac output and renal blood flow may decrease. 1
Inamrinone (Inocor)
Action: Inotropevasodilator; inhibits phosphodiesterase III; resembles dobutamine hemodynamically with less tachyphylaxis. 1 , 4
Contraindication: Thrombocytopenia. 1 , 4
Rx: 0.75 mg/kg IV slow bolus over 2 to 3 minutes, then 5 to 30 μg/kg/min infusion. May rebolus 0.75 mg/kg IV slow 30 minutes after starting therapy. 1 , 4 , 5
Side effects: Vasodilation hypotension, 2% thrombocytopenia, and hepatotoxicity. 1 , 4
Epinephrine (Adrenaline)
Action: Nonspecific adrenergic agonist has β2 activity unlike norepinephrine and twice as potent ionotrope. 1 , 4
Contraindications: Hypertrophic obstructive cardiomyopathy, tetralogy of Fallot (right ventricular outflow tract obstruction). 1 , 4
Rx: 0.5 to 1.0 mg of 1:10,000 solution IVP; may repeat every 5 minutes (may bolus per endotracheal tube). Drip: Start at 1 μg/min; titrate up to 8 μg/min (to prepare: put 1 mg in 100 mL NS). 1 , 4 , 5
Side effects: Vasoconstriction (splanchnic and renal), arrhythmias. 1
Isoproterenol (Isuprel)
Action: Nonselective β-adrenergic receptor agonist, potent inotrope (β1), and peripheral vasodilator (β2); second-line agent after dopamine for bradycardia unresponsive to atropine. 1 , 4
Contraindications: Digitalis bradycardia, angina. 1
Rx: Mix 1 mg/500 mL NS = 2 μg/mL; start at 2 μg/min, titrate up to 10 μg/min. 1 , 5
Side effects: Tachycardia, vasodilation, increased myocardial oxygen demand. 1 , 4
15.3 Electrolytes/Intravenous Fluids
The optimal fluid status in patients with neurologic disease is euvolemia. Electrolytes function within a narrow therapeutic range to promote health and ameliorate disease. Increasing amounts of electrolytes are needed at times of stress but still less than would cause further harm.
15.3.1 Sodium and Intravenous Fluids Phosphorus
Hyper: Phos-Lo (calcium acetate) 2 tablets NG/oral three times a day with meals. 1 , 4
Action: Combines with dietary phosphate to form insoluble calcium phosphate. 1
Contraindications: Hypersensitivity to components, hypercalcemia, renal calculi. 1
Side effects: Hypercalcemia. 1
Hypo: Potassium phosphate 1 to 2 g three times a day divided NG/IV three times a day. 1 , 5
Action: Elevates serum phosphorus and serum potassium levels. 1
Contraindications: Hyperphosphatemia, hyperkalemia, hypocalcemia, hypomagnesemia, renal failure. 1
Side effects: Diarrhea, nausea, stomach pain. 1
Calcium
Hyper: Treat aggressively with 0.9 NS infusion to correct volume deficit. Follow with loop diuretic (i.e., furosemide 20–40 mg IV/oral every 2–4 hours). May use zoledronate 4 mg IV over 15 minutes four times a day if unresponsive to loop diuretic. 1 , 5
Hyper: Calcium gluconate 2.25 to 14 mEq slow IVP or 500 to 2000 mg orally two or three times a day. Calcium chloride 500 to 1,000 mg slow IVP every 1 to 3 days. 1 , 5
Action: Elevation of serum calcium. 1 , 4
Contraindications: Hypersensitivity, hypercalcemia. 1 , 4
Magnesium
Hypo: Magnesium sulfate 1 g of 20% solution intramuscularly (IM) every 6 hours × 4 doses or 2 g IVP over 1 hour (note: monitor for hypertension); 1 g will raise serum magnesium 0.4 mEq/dL. 1 , 5
Action: Elevation of serum magnesium. 1
Contraindications: Heart block, serious renal impairment, myocardial damage, hepatitis, Addison’s disease. 1
Side effects: Hypotension, asystole, CNS depression, diarrhea, decreased neuromuscular transmission. 1
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