LOCAL ANESTHETICS : AMIDES & ESTERS

IMPORTANT FACTORS THAT AFFECT DRUG METABOLISM IN THE ELDERLY DURING ANESTHESIA

🚨Hepato-portal blood flow and hepatic enzymatic activity decrease 

🚨Plasma albumin level is reduced as you age, and for plasma protein-bound drugs this will lead to an increased proportion of unbound, active drug.

🚨Glomerular filtration rate falls by approximately 1% per year beyond the age of 30

🚨Opioid receptors decrease in number and increase in affinity ( The importance of this factor is less than the above mentioned ones, in case of opioid toxicity in elderly)

🚨IMPORTANT: lean body mass, body fat and total body water all fall. The volume of distribution of most drugs is therefore reduced. B͎u͎t͎ t͎h͎e͎ T͎O͎T͎A͎L͎ B͎O͎D͎Y͎ W͎A͎T͎E͎R͎ ( and muscle mass) d͎e͎c͎r͎e͎a͎s͎e͎s t͎o͎ a͎ g͎r͎e͎a͎t͎e͎r͎ e͎x͎t͎e͎n͎t͎ t͎h͎a͎n͎ t͎h͎e͎ T͎O͎T͎A͎L͎ B͎O͎D͎Y͎ F͎A͎T͎. 

⚙So drugs that are water-soluble, are affected more

🚨Elderly patients may be particularly sensitive to remifentanil, as a large proportion of its metabolism is catalysed by muscle-based esterases.

#DrugToxicity , #geriatrics , #anesthesia , #pharmacology

ROLAPITANT

🔹Its a Neurokinin-1 receptor antagonist . NK-1 receptors are highly concentrated in the vomiting center of the brain and bind a neurokinin termed substance P; activation of NK-1 receptors by substance P plays a central role in eliciting chemotherapy-induced nausea and vomiting

Blocking the interaction of substance P at the NK-1 receptor, NK-1 receptor antagonists improve the management of nausea and vomiting

🔹Comes in Tablet form (90 mg)

🔹Indication: In combination with other antiemetic agents, to prevent nausea and vomiting associated with emetogenic cancer chemotherapy 

🔹Especially useful in preventing delayed phase chemotherapy induced nausea and vomiting

🔹Highly emetogenic chemotherapy

Day 1: Rolapitant 180 mg PO 1-2 hr before chemotherapy PLUS dexamethasone 20 mg PO 30 minutes before chemotherapy PLUS 5HT-3 antagonist

 

Days 2-4: Dexamethasone 8 mg PO BID

🔹Moderately emetogenic chemotherapy

Day 1: Rolapitant 180 mg PO 1-2 hr before chemotherapy PLUS dexamethasone 20 mg PO 30 minutes before chemotherapy PLUS 5HT-3 antagonist 

Days 2-4: 5HT-3 antagonist 

🔹Contraindicated with the use of thioridazine ( risk of arrhythmias due to increased thioridazine levels)

Safety not established for pediatric use and in pregnancy 

🔹SIDE EFFECTS 

Decreased appetite (9%), Neutropenia (7-9%)

Dizziness (6%)

🔹Rolapitant vs Aprepitant 

Rolapitant has been studied as a one-time dose on day 1 of chemotherapy, while aprepitant is recommended to be given on days 1 through 3. Rolapitant does not inhibit CYP 2C9 or 3A4 enzymes, whereas aprepitant induces CYP 2C9 and 3A4 and moderately inhibits 3A4.3,4 As a result, aprepitant can interfere with warfarin, hormonal contraceptives, and certain chemotherapy, among other drugs.

Ref: WHO DRUG INFORMATION, VOL 29, number 3, 2015

Medscape Reference , http://reference.medscape.com/drug/varubi-rolapitant

Don't run away; it's simple : PARALLEL Vs CROSS OVER DESIGNS IN RANDOMIZED CONTROLLED TRIALS

 CONTROLLED TRIALS 

⏸Parallel groups 

➖➖➖➖➖➖➖

(👳🏻🔷vs 👳▪️ ) Simple, head-to-head comparison of two or more treatments 

1️⃣Subjects are allocated at random to a single treatment or a single treatment programme for the duration of the trial 

🆓The groups are independent  of each other

 🔀Crossover trials 

➖➖➖➖➖➖➖

(💂🔷  ➡ ️vs  💂▪️)This involves a single group study, where each patient receives two more treatments in turn; i.e. Each patient acts as their own control and comparisons of treatments are made within patients 

2️⃣Two or more treatments are given to each patient in random order 

✅useful for chronic conditions  such as pain relief in long-term illness or the control of high blood pressure where the outcome can be assessed relatively quickly

✴️It may not be feasible for treatments for short-term illnesses that once treated are cured, for example antibiotics for infections

😃Advantages of parallel group designs

➖➖➖➖➖➖➖➖➖➖➖➖➖➖

✔️The comparison of the treatments takes place concurrently 

✔️Can be used for any condition, especially an acute condition which is cured or self-limiting such as an infection 

✔️No problem of carry-over effects 

😬Disadvantages of parallel group designs 

➖➖➖➖➖➖➖➖➖➖➖➖➖➖➖

✖️The comparison is between patients and so usually needs a bigger sample size than the equivalent cross-over trial 

😃Advantages of crossover designs 

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✔️Treatments are compared within patients and so differences between patients are accounted for explicitly 

✔️Usually need fewer subjects than the equivalent parallel group trials 

✔️Can be used to test treatments for chronic conditions 

😬Disadvantages of crossover designs 

➖➖➖➖➖➖➖➖➖➖➖➖➖➖

✖️Cannot be used for many acute illnesses 

✖️Carry-over effects need to be controlled 

✖️Likely to take longer than the equivalent parallel designs 

✖️Statistical analysis is more complicated if subjects do not complete all periods

ѦԀԀIṬIȎṄѦʟ IṄҒȎ➕ 

〰〰〰〰〰〰〰

🏃🏾In cross over trials, it is important to avoid the 'carry-over effect' of one treatment into the period in which the next treatment is allocated. 

↔️This is usually achieved by having a gap or 'washout period'  between treatments

#

TRAMADOL AND ONDANSETRON: THEY ARE NOT A GOOD PAIR ! ; WHY FORCING THEM TO LIVE TOGETHER ?

Tramadol- highlights 

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✔️both opioid and non-opioid modes of action. . 

(1) inhibition of noradrenaline re-uptake 

(2)increased release and decreased re-uptake of serotonin in the spinal cord, and 

(3)a weak effect on mu opioid receptors

✔️The weak, opioid effect is mediated by an active metabolite, (+)-M1 (O-desmethyltramadol), formed via the genetically polymorphic P450 CYP2D6 iso-enzyme system. The biological activity of this system is variable, and individuals may be classified as extensive or poor metabolisers of tramadol. 

✔️Tramadol’s affinity for opioid receptors is about 6000 times weaker than morphine, but the (+)-M1 metabolite has an affinity about 200 times greater than tramadol. Poulsen et al. report much higher concentrations of the (+)-M1 metabolite and greater analgesic efficacy of tramadol in extensive metabolisers compared to poor metabolisers. Also noted was a reduction of nausea, vomiting and tiredness amongst poor metabolisers

Ondansetron-highlights

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✔️Ondansetron competitively antagonises serotonin, subtype 3 (5-HT3) receptors in the CTZ and enteric neurones. 

✔️ Peripheral 5-HT3 receptors are also involved in nociceptive pathways and ondansetron may alter 5-HT3 nociceptive responses at the level of dorsal horn neurones

✔️ Ondansetron can block sodium channels in a similar fashion to local anaesthetic agents, and exhibit agonist activity at mu opioid receptors, thus resulting in a peripheral anti-nociceptive effect.

Tramadol + Ondansetron 

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✔️PONV due to Tramadol is often managed with a competitive serotonin antagonist, ondansetron

✔️ There is evidence that the concurrent use of these two drugs results in a mutual reduction of effect—tramadol is a less potent analgesic and ondansetron is a less effective as an antiemetic. 

✔️ But the effect of ondansetron on tramadol consumption diminished with time. 

✔️ De Witte et al. found a significant (50%) increase in cumulative tramadol consumption during the first post-operative hour when patients were given ondansetron along with Tramadol.

✔️ Ondansetron is, in part, metabolised by the CYP2D6 iso-enzyme system—an iso-enzyme system responsible for formation of an active tramadol metabolite that has analgesic effect . Competition for this metabolic pathway may result in a reduction in formation of the (+)-M1 metabolite of tramadol and a consequent reduction in analgesic efficacy.

DO YOU KNOW❓😳 additional points➕

✔️ There is animal and human evidence that both tramadol and ondansetron have local anaesthetic type properties.

✔️ Ondansetron was approximately fifteen times more potent than lignocaine and may well be a prototype molecule for the development of a new group of local anaesthetic agents. 

✔️ These findings are further supported in a human clinical study by Memis et al.which showed that tramadol and ondansetron both significantly reduced the pain associated with the injection of the neuromuscular blocking drug, rocuronium.

(Ref: J.H. Ye, W.C. Mui, J. Ren, T.E. Hunt, W.H. Wu, V.K. Zbuzek Ondansetron exhibits the properties of a local anesthetic. Anesth. Analg., 85 (1997), pp. 1116–1121)

✔️Tropisetron and granisetron are able to reverse an acetaminophen-mediated analgesia completely.

 

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References:

Anaesthesia. 2015 Feb;70(2):209-18. doi: 10.1111/anae.12948. Epub 2014 Dec 10.

The effect of ondansetron on the efficacy of postoperative tramadol: a systematic review and meta-analysis of a drug interaction.

Stevens AJ1, Woodman RJ, Owen H.

Ondansetron Inhibits the Analgesic Effects of Tramadol: A Possible 5-HT3 Spinal Receptor Involvement in Acute Pain in Humans

Arcioni, Roberto MD*,; della Rocca, Marco MD*,; Romanò, Sarah MD*,; Romano, Rocco MD†,; Pietropaoli, Paolo MD*, and; Gasparetto, Alessandro MD*

ScienceDirect Review

Aspects of tramadol and ondansetron interactions Bruce Hammonds, David A. Sidebotham, Brian J. Anderson,

BASICS: POTENCY, DURATION AND ONSET OF ACTION OF LOCAL ANESTHETICS⚙

🗡POTENCY: 

👉🏿is affected by several factors including:

🔹Hydrogen ion balance

🔹Fiber size, type, and myelination

🔹Vasodilator/vasoconstrictor properties (affects rate of vascular uptake)

🔹Frequency of nerve stimulation

🔹pH (acidic environment will antagonize the block)

🔹Electrolyte concentrations (hypokalemia and hypercalcemia antagonizes blockade)

↔️Duration of action 

🔹is associated with lipid solubility. 

🔹Highly lipid soluble local anesthetics have a longer duration of action due to decreased clearance by localized blood flow and increased protein binding.

⏱ONSET OF ACTION

🔹Local anesthetics are weak bases and contain a higher ratio of ionized medication compared to non- ionized. 

🔹Increasing the concentration of non-ionized local anesthetic will speed onset. 

🔹In general, local anesthetics with a pKa that approximates physiologic pH have a higher concentration of non- ionized base resulting in a faster onset. 

🔹On the other hand, a local anesthetic with a pKa that is different from physiologic pH will have more ionized medication which slows onset. 

🔹For example, the pKa for lidocaine is 7.8 and 8.1 for bupivacaine. Lidocaine is closer to physiologic pH than bupivacaine. Lidocaine has a greater concentration on non-ionized local anesthetic than bupivacaine which results in a faster onset. 

🔹 Non-ionized and ionized portions of local anesthetic solution exert distinct actions. 

🔹 Lipid soluble, non-ionized form of the local anesthetic penetrates the neural sheath and membrane. 

🔹 In the cell, the non-ionized and ionized forms equilibrate. 

🔹 The ionized form of the local anesthetic binds with the sodium channel. Once “bound” to the sodium channel, impulses are not propagated along the nerve.

🔹 Clinically, onset of action is not the same for all local anesthetics with the same pKa. This is due to the intrinsic ability of the local anesthetic to diffuse through connective tissue. 

🔹 Local anesthetics with a pKa closest to the physiological pH generally have a higher concentration of non-ionized molecules and a more rapid onset. 

🔹 Two notable exceptions are chloroprocaine and benzocaine. Chloroprocaine has a high pKa and rapid onset. Benzocaine does not exist in an ionized form and exerts its effects by alternate mechanisms.

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#LocalAnesthetics, #RegionalAnesthesia , #Pharmacology , #anaesthesia

References

Heavner, J.E. (2008). Pharmacology of local anesthetics. In D.E. Longnecker et al (eds) Anesthesiology. 

Joyce, J.A. (2002). A pathway toward safer anesthesia: stereochemical advances. AANA Journal, 70, 63-67.

Katzung, B.G. (1992). Section 1: basic principles. In B.G. Katzung Basic & clinical pharmacology, 5th edition. Norwalk, Connecticut: Appleton and Lange.

Morgan, G.E., Mikhail, M.S., Murray, M.J. (2006). Local Anesthetics. In G.E. Morgan et al Clinical Anesthesiology, 4th edition. 

Stoelting, R.K. & Hillier, S.C. (2006). Pharmacology and pharmacodynamics of injected and inhaled drugs. In R.K. Stoelting & S.C. Hillier (eds) Pharmacology & Physiology in Anesthetic Practice, 4th edition. 

Strichartz, G.R. & Berde, C.B. (2005). Local Anesthetics. In R.D. Miller Miller’s Anesthesia, 6th edition

ANESTHESIA INFO FROM THE LAY MEDICAL MAN- Facebook Page

XENON-THE STRANGER🌪

🍭colorless, odourless, tasteless gas

🍭four times denser than air. 

🍭density and viscosity are substantially higher than those of other inhalational anaesthetics. 

🍭occurs in extremely low concentrations (0.0875 ppm) in the atmosphere, hence its name from the Greek ‘xenos’ meaning ‘stranger’. 

🍭Xenon has been used experimentally as an anaesthetic for more than 50 years 

🍭Recently there has been a renewed interest in xenon as a safe, effective and more environmentally friendly substitute for nitrous oxide (Sanders et al. 2003). 

🍭manufactured by fractional distillation of liquefied air, currently at a cost of US $10 per litre (i.e. about 2,000 times the cost of producing N2O). This high cost is the major factor limiting its more widespread use, even when used in low-flow delivery systems. 

🍭Xenon has many of the properties of an ideal anaesthetic. 

🍭Its blood/gas partition coefficient (0.12) is lower than that of any other anaesthetic, giving rapid induction and emergence. 

🍭It is unlikely to be involved in any biochemical events in the body, and is not metabolised. 

🍭Xenon causes no significant changes in myocardial contractility, blood pressure or systemic vascular resistance, even in the presence of severe cardiac disease (Sanders et al. 2005). 

🍭The unique combination of analgesia, hypnosis, and lack of haemodynamic depression in one agent would make xenon a very attractive choice for patients with limited cardiovascular reserve 

🍭In contrast to other inhaled anaesthetic agents, xenon slows the respiratory rate and increases the tidal volume, thereby maintaining minute ventilation constant. 

🍭Airway pressure is increased during xenon anaesthesia, due to its higher density and viscosity rather than direct changes in airway resistance (Baumert et al 2002). 

🍭Because of its high cost xenon must be used in low-flow closed circuits. Crucial to this method of administration is accurate measurement of the concentration of xenon in the circuit. This measurement is generally difficult as xenon is  diamagnetic and does not absorb infrared radiation (commonly used to measure the  concentrations of other agents), and its low reactivity precludes the use of specific fuel cell or electrode-type devices. 

🍭Xenon conducts heat better than other gases, and a technique based on thermal conductivity has proved to be effective (Luginbuhl et al 2002). 

🍭Because xenon is heavier than air, the speed of sound is slower in xenon than that in air, and this difference has been also been used to measure xenon concentration. 

🍭Because xenon is a normal constituent of the atmosphere, it does not add to atmospheric pollution when emitted from the anaesthesia circuit. This is in contrast to the other inhalational anaesthetics, which have ozone-depleting potential and pollute the atmosphere when released from the anaesthesia system (Marx et al. 2001). 

🍭On a molecular basis, N2O is 230 times more potent as a greenhouse gas than carbon dioxide. N2O released as a waste anaesthetic contributes roughly 0.1% of total global warming. The lifetime of N2O in the atmosphere is long—approximately 120 years. 

🍭The anaesthetic actions of xenon are thought to result primarily from noncompetitive inhibition of  NMDA receptors (De Sousa et al. 2000), a property it shares with nitrous oxide. 

🍭In common with other NMDA receptor antagonists, xenon appears to have neuroprotective properties (Sanders et al. 2003). 

🍭Xenon is also an excellent analgesic, an action mediated by NMDA receptors (De Sousa et al. 2000). 

🍭Xenon also inhibits the plasma membrane Ca 2+   pump, altering neuronal excitability and inhibiting the nociceptive responsiveness of spinal dorsal horn neurones. 

(Reference : Jürgen Schüttler •  Helmut Schwilden Modern Anesthetics ,Handbook of Experimental Pharmacology, vol 182)

RESPIRATORY STIMULANTS AND DEPRESSANTS

🏀Drugs that act as Respiratory stimulants 

⤴️Acetazolamide 

⤴️Aminophyllines 

⤴️Doxapram  

⤴️Progesterone 

⤴️Salicylates

🏀Drugs that act as Respiratory depressants 

⤵️Alcohol 

⤵️Anaesthetics 

⤵️Anticholinergics 

⤵️Antihistamines 

⤵️Barbiturates 

⤵️Benzodiazepines 

⤵️Opioids

#pharmacology , #pulmonology , #icu , #sedation , #anesthesia , #anaesthesia , #criticalcare