Tag Archives: pharmacology

Tumescent Solution (for burn surgery and liposuction and other things too)

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Tumescent solution is also called “Klein’s Solution” after the physician who characterized the recipe and the use of it.

It’s called “tumescent” because it makes things tumescent, which is a fancy word for swollen. Tumescent is a dilute solution of lidocaine, epinephrine, and sodium bicarbonate that is injected in the subcutaneous tissue (fat). The epinephrine is the most important ingredient as it causes vasoconstriction, this means that the blood loss that could be a big problem for large procedures like burn surgery and liposuction becomes much less of a big deal.

The other interesting thing is that since fat is relatively avascular compared to other tissues, the “safe amount” of tumescent is much higher than what is normally stated for injections of lidocaine or epinephrine.

For example, it was reported by Klein that the toxic dose of lidocaine for tumescent solution is 35 mg/kg of body weight.

There are a few different recipes for tumescent anesthesia, the one presented in the doodle is the one first outlined by Klein, some use more or less lidocaine or epinephrine.

References

  1. Kucera IJ1, Lambert TJ, Klein JA, Watkins RG, Hoover JM, Kaye AD. Liposuction: contemporary issues for the anesthesiologist. J Clin Anesth. 2006, 18(5): 379-87.
  2. Klein JA. The tumescent technique. Anesthesia and modified liposuction technique. Dermatol Clin. 1990, 8(3): 425-37.
  3. Klein JA. Tumescent technique for local anesthesia improves safety in large-volume liposuction. Plast Reconstr Surg. 1993, 92: 1085-100.

Side Effects of Atypical Antipsychotics

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antipsychotics

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Atypical (a.k.a., “second-generation”) antipsychotics are commonly used in the treatment of psychotic disorders, and mood disorders as well. Compared to typical (first-generation) antipsychotics, the atypical antipsychotics have lower affinity for dopamine D2 receptors, and they also act at serotonin (5-HT) receptors (they are antagonists for these receptors). Other neurotransmitter receptors are affected as well, and each atypical antipsychotic preferentially antagonizes different receptors.

When atypical antipsychotics were first introduced, it was hoped that they would be more effective than typical antipsychotics and have fewer extrapyramidal side effects (see below). While these expectations may have been somewhat overblown and atypicals are not markedly superior in decreasing psychosis symptoms, most atypicals certainly have a lower risk of developing extrapyramidal side effects. However, they do come with their own array of side effects.

Extrapyramidal side effects (EPSE): These are movement-related side effects caused by dopamine antagonism. These include acute dystonia (torticollis, an uncomfortable muscular spasm of the neck; as well as spasms of the eyes, tongue, jaw), akathisia (motor restlessness and a need to remain in motion), tardive dyskinesia (repetitive, involuntary movements usually involving facial muscles), parkinsonian symptoms (resting tremor, rigidity, slowed movements), and neuroleptic malignant syndrome (potentially fatal!).
Elevated prolactin (PRL): This can lead to gynecomastia (breast growth) and galactorrhea (milk-production), which can be very distressing for male patients! Can also cause infertility and sexual dysfunction. It also happens with typical antipsychotics.
Weight gain: This can be very a troublesome symptom, and may lead to diabetes in some patients.
Sedation: This may prevent patients from engaging in their usual activities and work.
Orthostatic hypotension: Drop in blood pressure after standing from sitting position.

Some antipsychotics have especially severe side effects. Clozapine, for example, is extremely effective in treating psychosis but can lead to fatal agranulocytosis (drop in white blood cells), as well as tremendous weight gain and sedation. Ziprasidone use can lead to QTc prolongation and increase the risk for serious cardiac arrhythmia.

The above chart shows the relative side effect profiles of eight atypical antipsychotics (aripiprazole, clozapine, lurasidone, olanzepine, paliperidone, quetiapine, risperidone, ziprasidon) versus two typical antipsychotics (chlorpromazine, haloperidone).

  • Haddad PM, Sharma SG. 2007. Adverse effects of atypical antipsychotics: Differential risk and clinical  implications. CNS drugs; 21:911.
  • Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lassig B, Salanti G, Davis JM. 2013. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple treatments meta-analysis. Lancet; 382:951.
  • Meltzer HY. 2013. Update on typical and atypical antipsychotic drugs. Annual Review of Medicine: 64:393.
  • Sadock BJ, Sadock VA (Eds.). 2007. Serotonin-dopamine antagonists: Atypical antipsychotics. In: Kaplan & Sadock’s Synopsis of Psychiatry. Lippincott Williams & Wilkins, Philadelphia PA.

Monitoring Neuromuscular Blockade

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As mentioned in a previous post, neuromuscular blocking drugs are used in anesthesia to ensure paralysis during surgery. The degree of neuromuscular block is assessed using nerve stimulation, where two electrodes impose a pulse of current on a peripheral nerve (e.g., ulnar n., facial n., posterior tibial n.) and induce muscle twitches which can then be monitored through the surgery. There are a few different ways to do nerve stimulation :

Tetany: A sustained stimulation (5 s)
Train-of-four (TOF): Four pulses in rapid succession
Double-burst stimulation (DBS): A series of 3 pulses followed after a pause by 2 or 3 pulses.
Post-tetanic potentiation: When a pulse is sent after a tetanic stimulation, it will bring on a stronger twitch than at first.

With non-depolarizing muscle blockers, there is a fade phenomenon where twitch amplitude decreases from the first stimulation. For instance, in a TOF each twitch is weaker than the last; the last twitch is the first to disappear with non-depolarizing blockade, while the first twitch is the last to disappear. This non-depolarizing fade is also seen in DBS and tetany, though there is still post-tetanic potentiation.

With a depolarizing muscle blockade, no fade will be seen. Instead, all twitches in response to stimulation will be uniformly decreased, and there is no post-tetanic potentiation. This pattern is known as a Phase I block. But, if there is a ton of succinylcholine or the blockade is of a long duration, the pattern of response will look like a non-depolarizing block. This would be a Phase II block.

Recovery of neuromuscular function
Throughout a surgery, the TOF ratio is often mentioned as a means of assessing neuromuscular blockade on an ongoing basis. This means dividing the amplitude of the fourth (and most influenced  by neuromuscular blockers) twitch in a TOF by the amplitude of the first (which is the least affected). In normal people, the 4:1 amplitude is the same, for a TOF ratio of 1. In a Phase I depolarizing block, the TOF ratio is also 1. The TOF ratio will be less than 1 in a non-depolarizing block (remember the fade?). It is commonly mentioned that a TOF ratio of 0.7 represents an full recovery of neuromuscular function, but these days it is thought that a TOF ratio of at least 0.9 is needed before extubation.

It is very hard to tell what the TOF ratio is by sight or feel alone! DBS ratio is more sensitive than TOF ratio for assessing neuromuscular block, and it’s easier to gauge by tactile evaluation than the TOF ratio. So, quantitative monitoring by electomyography (EMG), mechanomyography (MMG), or accelerometry is ideal!

  • Fuchs-Buder T. 2010. Neuromuscular monitoring in clinical practice and research. Springer.
  • McGrath CD, Hunter JM. 2006. Monitoring of neuromuscular block. Continuing Education in Anesthesia, Critical Care & Pain; 6:7.
  • Neuromuscular blocking agents. 2006. In: Clinical Anesthesiology (Eds: Morgan GE, Mikhail MS, Murray MJ). Lange.
  • Viby-Mogensen J. 2005. Neuromuscular monitoring. In: Miller’s Anesthesia (Eds: Miller RD, Erikkson LI, Fleisher LA, Wiener-Kronish JP, Young WL). Elsevier.

Induction Agents in Anesthesia

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General anesthesia has a bunch of different steps:

  1. Pre-oxygenation/Pre-induction (some people don’t count this as a step)
  2. Induction (putting them “to sleep”)
  3. Maintenance (keeping them asleep)
  4. Emergence (waking them up)

In North America, many physicians like to use a combination of an analgesic and a sedative followed by the induction agent propofol. Sometimes other agents are used for induction such as etomidate or ketamine, particularly if there is a worry about hemodynamic instability as propofol not uncommonly can cause bradycardia and/or hypotension.

If the patient is going to be intubated, a paralytic (muscle relaxant) is also used to relax the vocal cords to prevent unnecessary trauma as the tube is passed through them. Competitive acetyl choline (ACh) receptor antagonists such as rocuronium or succinylcholine are used for this. The main difference between the two is that succinylcholine is a depolarizing agent – meaning that when it first binds to the ACh receptor, it causes a contraction, whereas rocuronium is non-depolarizing – so when it binds nothing happens. So with this pesky contraction thing why would any one choose succinylcholine? The nice thing is that the half-life is much much shorter than rocuronium, so if things don’t work out quite the way you want them to, or you just want something fast, you don’t need to continue to help the patient breath.

Serotonin Syndrome

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Serotonin syndrome is a serious and life-threatening reaction caused by excess serotonin in the CNS.

The classic triad

  1. Mental status changes (anxiety, restlessness, delirium, easy to startle)
  2. Autonomic hyperactivity (hyperthermia, hypertension, tachycardia, diaphoresis, vomiting, diarrhea)
  3. Neuromuscular abnormalities (hyperreflexia, myoclonus, tremor, muscle rigidity, and bilateral Babinski sign) – more pronounced in lower extremities
Serotonin Syndrome Neuroleptic Malignant Syndrome
Onset <24 H Days to weeks (not
Neuromuscular Hyperreactivity (tremor, clonus) Severe muscle rigidity, hyporeactivity (bradyreflexia)
Cause SSRIs, TCAs, MAOIs, other serotonergic drugs Dopamine antagonists (antipsychotics)
Lab findings None Elevated CK
Treatment STOP AGENT! Benzodiazepines +/- Propranolol STOP AGENT! + Bromocriptine +/- Dantrolene
Resolution Within 24h Days to week

 

 

Anticholinergic Mnemonic

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The way to remember the effects of anticholinergic medications is using the mnemonic Hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter.

  • Hot as a hare: increased body temperature
  • Blind as a bat: mydriasis (dilated pupils)
  • Dry as a bone: dry mouth, dry eyes, decreased sweat
  • Red as a beet: flushed face
  • Mad as a hatter: delirium

Common anticholinergic medications are dimenhydrinate (Gravol) and low-potency antipsychotics, benztropine, atropine and antihistamines.

Don’t forget about the other toxidromes!

 

Toxidromes

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toxidromes

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A toxidrome is a syndrome (set of symptoms) caused by specific medications or toxins.

There are 5 big ones to know:

  1. Anticholinergic: low potency antipsychotics, oxybutynin, ACh receptor antagonists (ipratropium, atropine, scopolamine)
  2. Cholinergic: ACh recptor agonists (pilocarpine), AChEIs (organophosphates, phyostigmine)
  3. Opioid: Morphine, heroin, hydromorphone, etc
  4. Sympathomimetic: epinephrine, cocaine, amphetamine (Aderol), methylphenidate (Ritalin)
  5. Sedative-Hypnotic: Benzodiazepines, barbituates, “Z-drugs” (zopiclone, zolpidem), antihistamines

Alcohol and Benzodiazepine Withdrawal

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The thing to remember with both alcohol and benzodiazepine withdrawal is that THEY CAN KILL YOU!

What to watch out for

Withdrawal seizures and alcoholic hallucinosis (hallucinations that develop within 12 – 24 h and resolve within 24 – 48 h)

Delirium Tremens (DTs): hallucinations, disorientation, tachycardia, hypertension, fever, agitation, and diaphoresis. Symptoms can persist for up to 7d

Wernicke’s Encephalopathy: Happens in hours to days, it has a classic triad

  1. Encephalopathy: profound disorientation, indifference and inattentiveness
  2. Oculomotor dysfunction: nystagmus, lateral rectus palsy, conjugate gaze palsies (affecting the CN III, VI and VIII nuclei)
  3. Gait ataxia: affecting the vermis of the cerebellum

How it works

Since alcohol and benzodiazepines both work on the GABA receptor (potentiating the effect of GABA by increasing the frequency of channel opening) they are cross-reactive. This means that you can treat alcohol withdrawal with a tapering dose of benzos (and you can treat benzo withdrawal also with a tapering dose of more benzos).

The thing to watch out for with someone who has chronically used benzodiazepines and has suddenly stopped is that the onset of symptoms will depend on the half-life of that particular drug.

  • Alprazolam (Xanax): 10 – 20 h
  • Lorazepam (Ativan): 10 – 25 h
  • Clonazepam (Rivotril): 20 – 50 h
  • Diazepam (Valium): 30 – 200 h

To minimize benzodiazepine withdrawal symptoms if someone has extended use (>3 months): taper by 1-20% over 6 or more weeks and/or switch to longer-acting agents.

 

Where diuretics work in the nephron

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The nephron is composed of distinct areas that are specific to regulating different electrolytes.

An overview of nephron anatomy

Loop diuretics: blocks the sodium/potassium/chloride transporter in the ascending loop of Henle, potassium-wasting
Thiazide diuretics: blocks the sodium/chloride transporter in the distal tubule, potassium-wasting
Amiloride: directly blocks sodium channels in the collecting duct, potassium-sparing
Spironolactone: blocks the aldosterone receptors in the cortical collecting duct. This causes a decrease in sodium and water reabsorption and decreases potassium secreting (therefore is potassium-sparing)

Determinants of Glomerular Filtration Rate (GFR)

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GFR should be ~100 mL/min

Calculating GFR
(140 – age) x lean body weight (kg) / sCr (umol/L)

What determines GFR

  1. Renal blood flow: effective circulating volume, cardiac output
  2. Resistance to flow: vascular tone of afferent and efferent arterioles
  3. Permeability of glomerular basement membrane

Drugs that increase GFR

  • Prostaglandin: vasodilator (afferent > efferent)
  • Angiotensin II: vasoconstrictor (efferent > afferent)
  • Norepinephrine: vasoconstrictor, increases blood pressure
  • ANP: afferent vasodilator, efferent vasoconstrictor

Drugs that decrease GFR

  • NSAIDs: afferent vasoconstriction
  • ACE Inhibitors: decrease efferent vasoconstriction
  • Angiotensin Receptor Blockers (ARBs): decrease efferent vasoconstriction