Category Archives: Drugs and Pharmacology

ANTIDEPRESSANTS; AS ANALGESIC Vs AS ANTIDEPRESSANT

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The tricyclic antidepressants prevent the reuptake of monoamines, including serotonin and noradrenaline, as both pathways are important in the pain propagation. So the mixed reuptake drugs work better than more selective drugs like SSRIs

But serotonin-noradrenaline reuptake inhibitor antidepressants (SNRIs), for example, venlafaxine & duloxetine and the atypical antidepressant group, such as bupropion and mirtazapine are also effective for some chronic pain conditions and are increasingly used because of their improved tolerability

The superiority of tricyclics, particularly clomipramine and amitriptyline, in the management of pain may also be explained by their additional action on sodium channels blockade ( which is an action that SNRIs do not exhibit.)

The dose of amitriptyline to treat pain is much lower when compared to that needed to treat depression

The analgesic action has a faster onset, whereas antidepressant action takes weeks to start

The sedative action of tricyclic antidepressants are helpful in treating the sleep disturbances associated with neuropathic syndromes. Nortriptyline is less sedative than amitriptyline.

#antidepressants , #analgesics , #PainManagement , #ChronicPain

Reference: Medscape, Pharmacogenetics and Analgesic Effects of Antidepressants in Chronic Pain Management, Frédérique Rodieux; Valérie Piguet; Patricia Berney; Jules Desmeules; Marie Besson, Personalized Medicine. 2015;12(2):163-175.
Ryder S A, Stannard C F. Treatment of chronic pain: antidepressant, antiepileptic and antiarrhythmic drugs. Contin Educ Anaesth Crit Care Pain 2005; 5: 18–20 .

Succinylcholine aka Suxamethonium

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Two molecules of acetyl choline joined together by the acetyl group forms Succinylcholine

It can be presented as chloride, bromide or iodide salt

When presented as the chloride salt, it’s a solution with concentration 50 mg/ mL

When presented as bromide or iodide salts, they are powders, with more stability, shell life and suited for warm climates; but has to be reconstituted before use

pH of the solution is around 4

So they are destroyed by mixing it with alkaline solutions (e.g. Thiopentone )

#anesthesiology , #anaesthesia , #pharmacology

Reference: Kestin I. Suxamethonium. Update in Anaesthesia 1992; 1: article 7. Peck T, Hill S, Williams M. Pharmacology for Anaesthesia and Intensive Care, 3rd edn. Cambridge: Cambridge University Press, 2008; pp. 179–84 .

HOW METABOLISM AFFECTS THE JOURNEY OF DRUGS TO THE TARGET SITE?

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Oral administration –> cross the gut mucosa –> enter portal circulation –> pass through the liver –> enter the systemic circulation.

Only un-ionised molecules can cross the mucosal barrier

Weakly acidic drugs (e.g. aspirin) begin to be absorbed in the acidic environment of the stomach

Weakly basic drugs only begin to be absorbed in the small intestine.

Drugs that are permanently ionised (e.g. the NDMR) are not absorbed from the gut at all.

Metabolism occurring in the liver is called ‘first-pass’ metabolism. The metabolism which happens in gut wall as in case of NTG is also first-pass metabolism. First-pass metabolism reduces the amount of drug that reaches its target site.

If liver is having a high metabolic capacity, in case of a particular drug, any drug entering the hepatocyte is quickly broken down. This maintains a concentration gradient favouring the dissociation of the drug from protein binding sites, and thus the overall hepatic metabolism is mainly related to hepatic blood flow. E.g. Propranolol

In case of drugs with lower hepatic metabolic capacity, drug remains bound to protein and so, the degree of protein binding influences entry to the hepatocyte than the hepatic blood flow

Sublingual and nasal routes have the advantage of rapid onset and bypassing of the portal circulation and hence the intake through these routes avoid first-pass metabolism.

Rectal route also avoids first-pass metabolism, but absorption is slow and can be incomplete.

DESFLURANE & ITS VAPORIZER

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#Desflurane has a saturated vapour pressure of 664 mm of Hg @ 20 degree C and a boiling point of 22.6 degree C

This is less than other agents; thus it requires a specific vaporizer

The Tec Mk 6 vaporizer is a plenum vaporizer and is designed for desflurane.

It operates at 39 °C and 2 atmospheres (All other vaporizers operate at atmospheric pressure and temperature).

It takes 5–10 minutes to warm up to the correct temperature.

It will not operate until the vaporisation chamber has reached 39 °C.

It needs an external power supply, and it has a 9 V battery as a backup in case of mains failure.

Unlike other plenum vaporisers, the Tec Mk 6 vaporizer is designed so that the fresh gas flow does not enter the chamber. The desflurane vapour is added to the fresh gas flow as it leaves the vaporiser.

#anesthesia , #anaesthesia , #anesthetist

Reference: Al-Shaikh B, Stacey S. Essentials of Anaesthetic Equipment, 2nd edn. Edinburgh: Churchill Livingstone, 2002

VITAMIN K

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Vitamin K is so named as it was originally called Koagulationsvitamin.

The body stores about 1 week’s supply of vitamin K.

Vitamin K is a fat-soluble vitamin

Vitamin K is required for the synthesis of six factors in the clotting cascade : factors II, VII, IX, X and the anticoagulants protein C and protein S.

γ -Carboxylation of these factors is carried out by the vitamin K-dependent carboxylase. This reaction subsequently allows calcium binding and the conformational change required to become active. The reaction involves the oxidation of vitamin K. Warfarin works by stopping the reversal of this oxidation.

Bile is required for absorption of vitamin K in the gut.

Menadiol, a synthesized form of vitamin K (K3), is water-soluble and therefore can be absorbed in conditions in which bile secretion is low. But, it is not recommended for use in neonates as it may produce haemolysis.

Haemorrhagic disease of the newborn is caused by a relative vitamin K deficiency.

Prophylaxis against haemorrhagic disease of the newborn is usually given at birth as an injection of the naturally occurring fat-soluble phytomenadione.

STEROID EQUIVALENT DOSES

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CLINICAL GUIDELINES FOR #Opioid ROUTE CONVERSION AND ROTATION

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Rotation of an opioid, secondary to uncontrolled pain requires equianalgesic doses.

If you are rotating an opioid secondary to toxicity, it requires a dose 30-50% lower than the equivalent dose of the second opioid. This is because of incomplete analgesic cross-tolerance.

Thirty percent of patients who are on opioids need an alternative route, as in severe nausea or mucositis.

Once toxicity occurs, before doing rotation, consider treating side effects, lowering the dose of the current opioid(if pain is controlled), and use of adjuvant analgesics.

Whenever we start or titrate opioid dose, always consider the pharmacokinetic alterations due to age, comorbid conditions, gender, other simultaneously administered medications, and organ failure etc

Opioids that are partial agonists have less analgesia per dose increment at higher doses than full agonists or opioids with high intrinsic efficacy (e.g., methadone); therefore, equianalgesic ratios will change with dose.

Rotating to a new opioid before reaching steady-state of the first opioid is pharmacologically meaningless.

Rotation in the setting of organ dysfunction is dangerous even if we use the recommended doses from equianalgesic tables.

Note that, opioids may worsen intestinal colic. Dexamethasone, glycopyrrolate, or octreotide are better options for such pains.

Opioid-induced toxicity takes some time to resolve. If symptoms related to toxicity are persisting after rotation, it can be because of slow clearance of the first opioid and not the new opioid.

Be cautious while rotating between short and long-acting opioids and do it in a careful way, so as to avoid withdrawal or overdosing.

Reference: Opioid Equianalgesic Tables: Are They All Equally Dangerous? Philip E. Shaheen, Declan Walsh, Wael Lasheen, Mellar P. Davis and Ruth L. Lagman (Journal of Pain and Symptom Management, Vol. 38 No. 3 September 2009)

 

PHARMACOLOGICAL TREATMENT OF ACUTE SEVERE ASTHMA ( BASED ON 2014 BTS GUIDELINES)

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Supplementary oxygen to all hypoxaemic patients with acute severe asthma to maintain an SpO2 level of 94-98%

Nebulisers for giving nebulised β2 agonist bronchodilators should preferably be driven by oxygen. A flow rate of 6 l/min is required to drive most nebulisers

High-dose inhaled β2 agonists as first line agents in patients with acute asthma. Repeat doses of β2 agonists at 15–30 minute intervals or give continuous nebulisation of salbutamol at 5–10 mg/hour (requires appropriate nebuliser) if there is an inadequate response to initial treatment. Higher bolus doses, for example 10 mg of salbutamol, are unlikely to be more effective (2.5–5 mg salbutamol in children >2 years).

There is no evidence for any difference in efficacy between salbutamol and terbutaline. Nebulised adrenaline (epinephrine), a non-selective β2 agonist, does not have significant benefit over salbutamol or terbutaline.

Add nebulised ipratropium bromide (0.5 mg 4-6 hourly) to β2 agonist treatment for patients with acute severe or life-threatening asthma or those with a poor initial response to β2 agonist therapy. ( 250 micrograms/dose in children >2 years).

Consider giving a single dose of IV magnesium sulphate (1.2-2 g IV infusion over 20 minutes) to patients with acute severe asthma who have not had a good initial response to inhaled bronchodilator therapy.

Nebulised magnesium is not recommended for treatment in adults with acute asthma. Consider adding 150 mg magnesium sulphate to each nebulised salbutamol and ipratropium in the first hour in children >2 years with a short duration of acute severe asthma symptoms presenting with an oxygen saturation less than 92%.

Routine prescription of antibiotics is not indicated for patients with acute asthma.

SECOND LINE TREATMENT OF ACUTE ASTHMA

Consider early addition of a single bolus dose of intravenous salbutamol (15 micrograms/kg over 10 minutes) in a severe asthma attack where the patient has not responded to initial inhaled therapy.

Consider aminophylline for children >2 years with severe or life-threatening asthma unresponsive to maximal doses of bronchodilators and steroids. A 5 mg/kg loading dose should be given over 20 minutes with ECG monitoring (omit in those receiving maintenance oral theophyllines) followed by a continuous infusion at 1 mg/kg/hour. Measure serum theophylline levels in patients already receiving oral treatment and in those receiving prolonged treatment.

NOTE:

Give steroids in adequate doses in all cases of acute asthma attack.

Prednisolone 40–50 mg daily or parenteral hydrocortisone 400 mg daily (100 mg six-hourly in adults and 4 mg/kg repeated four hourly in children >2 years ) are as effective as higher doses. Continue prednisolone 40–50 mg daily for at least five days or until recovery. ( In children >2 years, treatment for up to three days is usually sufficient).

Following recovery from the acute asthma attack steroids can be stopped abruptly. Doses do not need tapering provided the patient receives Inhaled Corticosteroids

In adults with an acute asthma attack, i.v. aminophylline is not likely to result in any additional bronchodilation compared to standard care with inhaled bronchodilators and steroids. Side effects such as arrhythmias and vomiting are increased if Iv aminophylline is used

Heliox is not recommended for use in patients with acute asthma outside a clinical trial setting

Although theoretically furosemide may produce bronchodilation, a review of three small trials failed to show any significant benefit of treatment with nebulised furosemide compared to β 2 agonists

NICE guidelines for treatment of hypertension: really NICE

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NICE published guidelines in 2006, revised in 2011.

Step 1 : Choose either an ACE inhibitor, a thiazide diuretic or a calcium channel antagonist (A, D and C).

An ACE inhibitor is more effective as first-line therapy in younger patients (< 55 years ) and Caucasians.

Diuretics or calcium channel blockers are better in older patients and African / Caribbean patients of any age.

This trial of step 1 is run on for 4 weeks, and if blood pressure is not controlled, the opposite agent is added in:

Step 2 : An ACE inhibitor is added to a diuretic (A + D) or calcium channel antagonist (A + C), or vice versa.

Step 3 : Ongoing poor control is then managed by the addition of the third agent (A + C + D).

Step 4 : If a patient is established on triple therapy, and still not well controlled, they are probably aldosterone sensitive, so spironalactone would be a wise option.

National Institute for Health and Clinical Excellence. Hypertension: Clinical Management of Primary Hypertension in Adults. NICE Clinical Guideline 127, August 2011.

LEARN THE CONCEPT OF CRITICAL & PSEUDOCRITICAL TEMPERATURE WITH THE EXAMPLE OF ENTONOX

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Entonox is Nitrous oxide mixed 50:50 with oxygen

It provides analgesia with maintenance of consciousness.

Usually administered via a demand valve for self administration.

Takes 30 seconds to act and continues for approx. 60 sec after inhalation has stopped

For optimum effect inhalation should start when the contraction tightens. This will co-ordinate the maximal effect with the central painful part of the contraction.

20% N20 is equivalent to 15 mg of subcutaneous morphine.

The optimal analgesic concentration was found to be 70% but some mothers lost consciousness at this concentration

50% N20 in oxygen is safer and this has become standard now

Entonox is the BOC trade name for this gas mixture.

Poynting effect

The Poynting effect involves the dissolution of gaseous O2 when bubbled through liquid N2O, with vaporisation of the liquid to form a gaseous O2/N2O mixture.

Critical & Pseudocritical temperature

The critical temperature of a gas is the maximum temperature at which compression can cause liquefaction. Or it is the temperature above which a substance cannot be liquefied however much pressure is applied. Mixing gases may change their critical temperature.

The pseudocritical temperature applies to a mixture of gases, such as Entonox, and is the temperature at which gas mixtures separate into their component parts.

The Poynting effect produces a 50:50 mixture which reduces the crtical temperature of N20 so Entonox has a pseudocritical temperature of -6 degree.

Entonox

Highest -5.5°C @117 bar
Cylinder -7°C @137 bar
Pipeline -30°C @4 bar

In cylinders it is supplied at a pressure of 137 bar and must be stored above its pseudocritical temperature of -6°C.

Below this temperature the N2O liquefies in a process called lamination. If this occurs a high concentration of O2 will be delivered first with little analgesic effect, but as the cylinder empties the mixture will become progressively more potent and hypoxic as it approaches 100% N2O.

If a cylinder has been exposed to cold below -6 degree C it should be warmed for 5 minutes in a 37 degree C water bath or for 2 hours in a room at 15 degree C. It should then be inverted three times before use.

When delivered via a pipeline at 4.1 bar the pseudocritical temperature is less than -30°C.

Altitude per se has no effect on Entonox.

Reference: www.frca.uk