opioids drugs

1.OPIOIDS Dr.Khalid Al-Jonaieh Demonstrator Anesthesia Department KKUH

Opiate:

used to refer to drugs derived from opium including morphine.

Narcotic:

not useful in a pharmacologic or clinical context.

Affinity:

the ability to bind a receptor to produce a stable complex and intrinsic activity.

Efficacy:

the range in magnitude of an effect produced by a drug receptor combination relative to the maximum possible effect.

Potency:

the relative dose required to achieve an effect which related to receptor affinity.

described by the dose-effect curve resulting from drug-receptor combination

All of the endogenous opioids are derived from three prohormones :

Proenkephalin

Prodynorphin

Pro-opiomelanocortin ( POMC )

All being with the pentapeptide sequences of {Leu} or {Met}-enkephalin

Widely distributed throughout the brain, spinal cord, and peripheral sites, particularly the adrenal medulla.

All begin with the[ Leu ]- enkephalin sequence and are widely distributed throughout the brain, spinal cord, and peripheral sites .

The common precursor of - endorphin, ACTH, and melanocyte - stimulating hormone.

The termendorphinis reserved for peptides of the POMC family.

The major site of POMC synthesis is the pituitary, but it is also found in the pancreas and placenta .

The initial classification by Martin of opioid receptors into the three types

Based on binding activity of the exogenous ligands

Morphinemu ()

Ketocyclazocinekappa ()

SKF10,047sigma( )

Other Opioid receptors identified :

Enkephalinsdelta( )

Endorphinepsilon ()

Very few endogenous opioids exhibit great selectivity for a single receptor type.

Naloxone, the most commonly used opioid antagonist, is not selective for opioid receptor type.

Naltrindole( a - opioid receptor antagonist )

Nor - binaltorphimine( a - opioid receptor antagonist ) .

Receptor binding initiates a series of physiologic functions resulting in cellular hyperpolarization and inhibition of neurotransmitter release, effects that are mediated by second messengers .

All opioid receptors appear to be coupled to G proteins, which regulate the activity of adenylate cyclase among other functions.

G protein interactions, in turn, affect ion channels.

Different ion may be involved at different opioid receptor types.

Pharmacokineticsdetermines the relationship between drug dose and its concentration at the effect site(s).

Pharmacodynamicvariables relate the concentration of a drug at its site of action, in this case opioid receptors in the brain and other tissues, and the intensity of its effects.

The processes of absorption, redistribution, biotransformation, and elimination .

Compartmental models describe the time course of change in plasma concentration.

Opioids used in anesthesia are characterized by two -or three - compartment models.

Distribution phase: The early rapid decline in plasma concentration after the peak.

Elimination phase: The subsequent slower decline.

Two main mechanisms are responsible for drug elimination

biotransformation

excretion

Opioids are biotransformed in the liver by two types of metabolic processes .

Phase I reactionsinclude oxidative and reductive reactions, such as those catalyzed by cytochrome P450 system, and hydrolytic reactions .

Phase II reactionsinvolve conjugation of a drug or its metabolite to an endogenous substrate, such as D - glucuronic acid .

Remifentanil is metabolized viaester hydrolysis , which is unique for an opioid .

With the exceptions of theN -dealkylated metabolite of meperidine and the 6- and possibly 3-glucuronides of morphine, opioid metabolites are generallyinactive .

Routes of opioid excretion:

Kidneys

The biliary system

To reach its effector sites in the central nervous system( CNS ) , an opioid must cross biologic membranes from the blood to receptors on neuronal cell membranes .

The ability of opioids to cross this bloodbrain barrier depends on such properties as

molecular size

ionization

lipid solubility

protein binding

Of these characteristics, lipid solubility and ionization assume major importance in determining the rate of penetration to the CNS .

Lipid solubility is measured as an octanol :water or octanol :buffer partition coefficient .

Drug ionization is also an important determinant of lipid solubility.

Nonionized drugs are 1,000 to 10,000 times more lipid - soluble than the ionized form .

The degree of ionization depends on the pKa of the opioid and the pH of the environment .

Plasma protein binding also affects opioid redistribution because only the unbound fraction is free to diffuse across cell membranes .

The major plasma proteins to which opioids bind are albumin and 1-acid glycoprotein.

Analgesia

Effect on MAC of Volatile anesthesia

CNS effects

Respiratory Depression

Cough Reflex

Muscle Rigidity

Nausea and Vomiting

GIT Motility and Secretion

Biliary Track

Genitourinary Effects

Histamine Release

Cardiovascular Effects

Disposition Kinetics

Active Metabolites

Morphine analgesia results from complex interactions at a number of discrete sites in the brain, spinal cord, and under certain conditions, peripheral tissues.

Involves both 1 and 2 opioid effects.

Act selectively on neurons that transmit and modulate nociception.

Leaving other sensory modalities and motor functions intact .

Presynaptically :

acts on primary afferent nociceptors to decrease the release of substance P.

Postsynaptically :

hyperpolarizes postsynaptic neurons in the substantia gelatinosa of the dorsal spinal cord to decrease afferent transmission of nociceptive impulses.

Spinal morphine analgesia is mediated by 2 - opioid receptors .

Opioid analgesia originates in

the periaqueductal gray matter

the locus ceruleus

nuclei within the medulla

notably the nucleus raphe magnus

Primarily involves 1-opioid receptors

Microinjections of morphine into any of these regions activate the respective descending modulatory systems to produce profound analgesia

Coadministration at the level of the brain and spinal cord increases morphine's analgesic potency nearlytenfold , an effect mediated by 2 -opioid receptors

An action when acute inflammation is present.

By activating peripheral opioid receptors

Mediated by 3 - opioid receptors .

In chronic pain conditions such as neuropathic pain or chronic arthritis, spinal and peripheral receptors may be down - regulated, a state that can decrease morphine analgesia.

The minimum effective analgesic concentration( MEAC )of morphine

For postoperative pain relief is 10 to 15 ng / mL

For more severe pain, plasma morphine concentrations of 30 to 50 ng/mL are needed to achieve adequate analgesia

Decreases MAC of volatile anesthetics in a dose - dependent manner.

1 mg / kg administered with 60% nitrous oxide( N2O) blocks the adrenergic response to skin incision in 50% of patients, a characteristic calledMAC-BAR

Epidural morphine 4 mg given 90 minutes prior to incision reduces halothane MAC by nearly 30%.

Cognitive and fine motor impairment

Euphoria,dysphoria

Sleep disturbances including reduction in rapid eye movement and slow-wave sleep.

slowing of EEG, increased voltage and decreased frequency .

Pruritus appears to be a receptor-mediated effect produced at the level of the medullary dorsal horn.

Antipruritic effect mediated by receptors & not histamine-mediated.

Affect the release of several pituitary hormones, both directly and indirectly

Inhibition of corticotropin - releasing factor

Inhibition of gonadotropin - releasing hormone

Which decreases circulating concentrations of:

- endorphin

follicle - stimulating hormone

luteinizing hormone

Antidiuretic hormone release is inhibited

Prolactin and growth hormone concentrations may be increased by opioids.

Produce dose - dependent ventilatory depression.

Primarily by decreasing the responsivity of the medullary respiratory center to CO 2 .

Similar for young and elderly patients.

With increasing morphine doses, periodic breathing resemblingCheyne-Stokesbreathing, decreased hypoxic ventilatory drive, and apnea can occur.

Oxygen desaturation

Obstructive apnea

Paradoxic breathing

Slow respiratory rate

Have been reported in asleep patients receiving morphine infusions for postoperative analgesia.

Obesity

Depress by a direct effect on the medullary cough center .

Receptors mediating this effect appear to be less stereospecific and less sensitive to naloxone than those responsible for analgesia .

Ex. abdominal muscle rigidity and decrease thoracic compliance

Large doses of IV morphine (2 mg/kg infused at 10 mg/min)

Increased by the addition of 70% N 2 O

Mediated by receptors at supraspinal sites.

These effects are reduced or eliminated by :

naloxone

muscle relaxants

drugs that facilitate GABA agonist activity such as thiopental and diazepam

The incidence appears to be similar if you use it as premedication or intraoperative.

The incidence appears to be similar what ever the route of administration.

including oral, IV, intramuscular, subcutaneous, transmucosal, transdermal, intrathecal, and epidural .

Laboratory and clinical studies comparing the incidence or severity of nausea and vomiting have found no differences among opioids in equianalgesic doses.

including morphine, hydromorphone, meperidine, fentanyl, sufentanil, alfentanil, and remifentanil .

Receives input from the chemotactic trigger zone( CTZ ):

the area postrema of the medulla

pharynx

gastrointestinal tract

mediastinum

visual center

The CTZ is rich in opioid, dopamine, serotonin, histamine, and( muscarinic )acetylcholine receptors.

The CTZ receives input from the vestibular portion of the eighth cranial nerve .

At the level of the vomiting center:

High doses of morphine

Naloxone

Propofol

Benzodiazepines

Studies suggests that antiemetic effects of morphine are more short-lived than emetic effects.

Possible explanation for this observation is that the active metabolite morphine-6-glucuronide accumulates and worsens nausea.

Mediated by - , - , and - opioid receptors.

Inhibit gastric secretion

Decrease gastrointestinal motility and propulsion

Suppress diarrhea

Delayed gastric emptying

Decreases lower esophageal sphincter tone

Increase the tone of the common bile duct and sphincter of Oddi .

Symptoms vary from epigastric distress to typical biliary colic and may even mimic angina .

Possibly via histamine release.

Antagonism of morphine's biliary effects bydiphenhydraminesupports this hypothesis.

Reversed by :

Naloxone

Atropine

Nitroglycerine

Urinary retention.

Results in dyssynergia between the bladder detrusor muscle and the urethral sphincter because of a failure of sphincter relaxation .

Spinal morphine appears to causenaloxone - reversibleurinary retention via -and / or - , butnot - opioid receptors .

From circulating basophils.

From tissue mast cells in skin and lung.

Morphine - mediated histamine release is dose - dependent.

Not prevented by pretreatment with naloxone.

Suggesting that histamine release is not mediated by opioid receptors .

The decrease in peripheral vascular resistance seen with high - dose morphine( 1 mg / kg )correlates well with elevated plasma histamine concentration . Fentanyl

arteriolar and venous dilation.

decreased peripheral resistance.

inhibition of baroreceptor reflexes.

Lead to postural hypotension.

Mechanism:

histamine release.

morphine - mediated central sympatholytic activity.

direct action on vascular smooth muscle.

Caution : morphine's effect on vascular resistance is greater under conditions of high sympathetic tone .

Carefull with Severe Trauma & Cardiac Patients.

Does not suppress myocardial contractility.

Produce dose - dependent bradycardia.

In clinical anesthesia practice, opioids are often used to prevent tachycardia and reduce myocardial oxygen demand .

Patients undergoing cardiovascular surgery who received 1 to 2 mg / kg of morphine experienced minimal changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance .

Cautiously in spontaneously breathing patients with head injury or other conditions associated with elevated intracranial pressure.

After IV administration morphine undergoes rapid redistribution

Mean redistribution half - time between 1.5 and 4.4 min.

pKa: 7.9Nonionized 23%

Clearance: 1050 ml/min

Terminal elimination half - life between 1.7 and 3.3 hours.

35% protein bound, mostly to albumin .

Its steady - state volume of distribution is large, the range of 3 to 4 L / kg in normal adults .

The MEAC is 10-15 ng / mL.

Morphine's major metabolic pathway is hepatic phase II conjugation, to form morphine-3-glucuronide( M3G )and morphine-6 - glucuronide( M6G ).

The rate of hepatic clearance of morphine is high, with a hepatic extraction ratio of 0.7

Extrahepatic sites such as kidney, intestine, and lung.

Unchanged morphine in the urine accounts for only about 10% of the dose .

A single IV dose, 40% of the dose are excreted in the urine as M3G and and 10% as M6G.

M6G possesses significant receptor affinity and potent antinociceptive activity .

Because morphine glucuronides are eliminated by the kidney, morphine should be administered cautiously to patients with renal failure .

Used mainly as a premedicant and for postoperative analgesia.

For adults range from 0.01 to 0.20 mg / kg .

When used in a balanced anesthetic technique with N2O, morphine can be given in total doses of up to 3 mg/kg.

When combined with other inhalation agents, it should not exceed more than 1 to 2 mg / kg.

The morphine dose associated with apparent cardioprotective effect is a single dose of 40 mg, given before cardioplegia and cardiopulmonary bypass .

Because of its hydrophilicity, morphine crosses the bloodbrain barrier relatively slowly.

Its onset can be observed within 5 minutes

peak effects may be delayed for 10 to 40 minutes .

This delay makes morphine more difficult to titrate as an anesthetic supplement than the more rapidly acting opioids .

A phenylpiperidine derivative.

Was the first totally synthetic opioid .

It was initially studied as an anticholinergic agent.

Last comment about this opioid was

Bad-Drug. 3 rdinternational anesthesia conference .

Potency is about one - tenth that of morphine's.

Mediated by - opioid receptor activation mostly.

Also has moderate affinity for -and - opioid receptors.

The MEAC of meperidine is 200 ng / mL

A dose - dependent reduction in the MAC of halothane .

Well - recognized weak local anesthetic properties .

Alters nerve conduction and produces analgesia .

Neuraxial meperidine may also produce sensory and motor blockade as well as sympatholytic effects thatare not seen with other opioids .

Therapeutic doses can produce:

sedation, pupillary constriction, and euphoria.

Very high doses produce CNS excitement and seizures.

In equianalgesic doses produce :

respiratory depression

nausea & vomiting

dizziness

delay in gastric emptying

increase common bile duct pressure

Not associated with hemodynamic instability.

1 mg / kg in patients withcardiac diseasedecreased heart rate, cardiac index, and ratepressure product.

High dose depress contractility and significantly more hemodynamic instability than morphine or fentanyl, partially related to histamine release .

Causes :

general and epidural anesthesia

hypothermia

transfusion reactions

administration of amphotericin B

Eliminates visible shiveringprevent the increase of O2 consumption.

Equianalgesic doses of fentanyl (25 g) and morphine (2.5 mg) did not reduce postoperative shivering

Not mediated by - opioid receptors .

Butorphanol effectively reduces postoperative shivering in a dose of 1 mg

Mediated by - opioid receptors .

Low doses of naloxone, sufficient to block receptors, did not reverse the antishivering effect of meperidine.

High - dose naloxone, designed to block both andreceptors, did reverse the antishivering effect.

1-adrenergic agonists (clonidine 1.5 g/kg), serotonin antagonists, and propofol, can reduce postoperative shivering.

Suggests that a nonopioid mechanism may be involved.

Physostigmine 0.04 mg / kg can also prevent postoperative shivering.

Suggesting a role for the cholinergic system .

Following IV administration, plasma concentration falls rapidly.

Redistribution half - life is 4 to 16 minutes.

Its terminal elimination half - life is between 3 and 5 hours.

pKa : 8.5nonionized 7%

Moderately lipid soluble.

40 to 70% protein bound mostly to albumin and 1-acid glycoprotein.

Large large Vd ss , range of 3.5 to 5 L/kg in adults.

High hepatic extraction ratio.

The high clearance rate :10 mL / kg / min.

It isN -demethylated in the liver to form normeperidine.

Also hydrolyzed to meperidinic acid.

Both metabolites may then be conjugated and excreted renally.

Normeperidine is pharmacologically active and potentially toxic.

Normeperidine : pharmacological active.

Produce signs of CNS excitation.

Mood alterations such as apprehension and restlessness.

Neurotoxic effects such as tremors, myoclonus, and seizures.

The elimination half - life of the metabolite normeperidine( 14 to 21 hours ) .

Mean plasma normeperidine concentration of 0.81 g / mLdeveloped seizures even with patients without renal dysfunction.

A single IV dose is approximately one - tenth as potent as morphine.

IV : a shorter duration of action.

IV analgesic doses for adults range from 0.1 to 1 mg / kg.

IV doses of 12.5 to 50 mg are effective in reducing postoperative shivering .

The total daily dose should not exceed 1,000 mg in 24 hours .

Primarily a agonist.

Pharmacologic properties that are similar to morphine .

Chemical structure is very different from that of morphine.

Pseudopiperidine ring for opioid activity.

Because of its long elimination half-life, mostly used for :

Long - term pain management

Treatment of opioid abstinence syndromes .

The onset of analgesia is rapid, within 10 to 20 minutes.

After single doses of up to 10 mg, the duration of analgesia is similar to morphine.

Large or repeated parenteral doses, can reach up to 20 hours.

Similar in magnitude and frequency to those of morphine .

Did not appear to have clinically significant respiratory depression .

About 50% experienced nausea or vomiting, which was easily treated with standard antiemetic therapy.

Decreases intestinal propulsive activity

Biliary spasm.

Mean redistribution half - time is 6 min.

Mean terminal elimination T 1/2is 34 hrs.

Well absorbed after an oral dose with bioavailability 90%, and peak plasma concentration at 4 hours.

90% plasma protein.

Extensive metabolism in the liver, mostlyN -demethylation and cyclization to form pyrrolidines and pyrroline.

To achieve prolonged postoperative analgesia

20 mg provide analgesia without significant post-OP respiratory depression.

Important note: that these long-acting opioids are not currently approved for prophylaxis of postoperative pain.

Structurally related to phenylpiperidines.

Clinical potency ratio 50 to 100 times that of morphine .

Progressive EEG changes (slow) with a lag of 3 to 5 minutes.

Resolution of EEG changes lagged by 10 to 20 minutes after stop of fentanyl infusion.

A - opioid receptor agonist.

Dose - dependent analgesia.

Ventilatory depression.

Sedation.

High doses produce unconsciousness.

In post-OP patients, the mean fentanyl dose requirement was 55.8 g/hr.

Mean plasma fentanyl concentration of 1.3 ng / mL reduced experimental pain intensity ratings by 50%.

Reduces the MAC of volatile anesthetics in dose - dependent fashion.

A single IV bolus dose of fentanyl 3 g / kg, given25 to 30 minprior to incision, reduced both isoflurane and desflurane MAC by 50% .

3 ng / mL provides a 59% reduction of sevoflurane MAC.

Combining with propofol is a technique for providing general anesthesia, (TIVA).

The potency index for TIVA is described as the plasma concentration required to prevent a response in 50%( CP 50 ) or 95% (CP 95 ) of patients to various surgical stimuli.

Fentanyl reduces requirements for both volatile agents and propofol by a similar proportion .

Spontaneous ventilation returned when the fentanyl concentration dropped to 1.5 to 2 ng / mL .

Fentanyl has been used as the sole agent for anesthesia, a technique that requires a large initial dose of 50 to 150 g / kg.

Significantly blunt the stress response that is, hemodynamic and hormonal responses to surgical stimuliwhile producing only minimal cardiovascular depression .

Disadvantages :

early extubation

fast - track techniques because of prolonged respiratory depression

intraoperative awareness and recall

muscle rigidity

Increase middle cerebral artery flow.

Elevation in ICP.

Hypercarbia from fentanyl-induced respiratory depression influence fentanyl ionization and cerebral blood flow and hence the delivery brain tissue.

Muscle rigidity.

Instructed to deep - breathe during fentanyl induction may experience less rigidity.

Seizurelike movements represent as myoclonus.

Can activate epileptiform EEG activity in patients having surgery for intractable temporal lobe epilepsy.

Pruritus typically presents as facial itching.

Respiratory depression expressed as

elevation in end-tidal CO 2

a decrease in the slope of the CO 2response curve

decrease minute ventilation at an end-tidal CO 2of 50 mm Hg (VE 50 )

Greatly increased when it is given in combination with midazolam.

Blunts the hypoxic ventilatory drive to a greater extent than the hypercarbic ventilatory drive .

Expiration, panting, and coughing decreased, the duration of laryngospasm shortened, in a dose - dependent fashion .

These protective reflexes return to baseline rapidly after emergence.

Concentration - dependent negative inotropic effects.

A very high concentration reduced contractility by 50%.

In clinical practice up to 75 g / kg is associated with hemodynamic stability.

7 g / kg at induction had a slight decrease in heart rate, but no change in mean arterial pressure.

20 g / kg, decreases 15% in heart rate, MAP, systemic and PVR seen in patients with CAD .

Does not prevent the inflammatory effects associated with cardiopulmonary bypass.

Does not produce the apparent cardioprotective effects.

Hypertension in response to sternotomy is the most common hemodynamic disturbance during high - dose fentanyl anesthesia and occurs in 40 and 100% in patients receiving 50 to 100 g / kg .

Unlike morphine and meperidine, which induce hypotension, at least in part because of histamine release.

The combination of fentanyl and diazepam produces significant cardiovascular depression, increased central venous pressure significantly.

Adding 60% N2O to high-dose fentanyl produced a significant decrease in cardiac output and increases in systemic and pulmonary vascular resistance.

High - dose fentanyl( 100 g / kg ) prevented increases the stress response during surgery

plasma epinephrine

Cortisol

glucose

free fatty acids

growth hormone

but a lower dose of fentanyl did not .

( 5 g / kg followed by an infusion of 3 g / kg / h )

Fentanyl, significantly increases common bile duct pressure (the highest)

Nausea and vomiting

Delay gastric emptying

Intestinal transit

Fentanyl's extreme lipid solubility.

Rapid crossing of biologic membranes.

Rapid uptake by highly perfused tissue groups, including the brain, heart, and lung.

Thus, after a single bolus dose, the onset of effects is rapid and the duration brief.

pKa 8.4Nonionized 8.5%

The onset within10 secondsand correlated with a rapid increase inbrain tissuefentanyl concentration, which equilibrated withplasmaby1.5 min .

Recovery from fentanyl effects started within5 minand was complete by60 min .

Peak muscle concentration was seen at5 min .

Fat concentration reached a maximum30 min , because of the limited blood supply to that tissue .

With prolonged administration of fentanyl, fat can act as a reservoir of drug .

The terminal elimination half - time ranged from 3.1 to 6.6 hours.

Significantly bound to red blood cells: 40%.

Blood: plasma partition coefficient of 1.

Highly protein bound, 79 to 87%. mostly1-acid glycoproteinwhich is pH-dependent.

Decrease in pH will increase the proportion of fentanyl that is unbound.

Thus, a patient with respiratory acidosis will have a higher proportion of unbound( active )fentanyl, which could exacerbate respiratory depression .

Clearance of fentanyl is primarily by rapid and extensive metabolism in the liver .

Indicate a high hepatic extraction ratio.

Which dependent on liver blood flow .

Metabolism is primarily byN -dealkylation to norfentanyl.

By hydroxylation of both the parent and norfentanyl.

6% is excreted unchanged in the urine.

Single bolus doseshort - acting opioid.

Very large doses and multiple doses prolonged respiratory depression and delayed recovery could occur.

useful as a sedative / analgesic premedication : 25 to 50 g IV.

A transmucosal delivery system is effective premedicant for pediatric and adult patients as well as an effective treatment for breakthrough pain in chronic pain patients, should be administered in a monitored environment .

Fentanyl blunt the hemodynamic response to laryngoscopy and tracheal intubation, which can be particularly severe in patients with hypertension or cardiovascular disease .

doses of 1.5 to 5 g / kg

Should be complete approximately3 minprior to laryngoscopy to maximally blunt hemodynamic responses to tracheal intubation .

Administration of up to3 to 5 g / kg / hrwill allow recovery of spontaneous ventilation at the end of surgery . 0.5 to 2.5 g / kg every 30 minutes .

Prevents hemodynamic changes in response to noxious stimuli, can be achieved with:

a loading dose of 50 g/kg,

followed by a continuous infusion of 30 g/kg/hr.

A thienyl derivative of fentanyl.

Has a clinical potency ratio 2,000 to 4,000 times that of morphine.

Has a clinical potency ratio 10 to 15 times that of fentanyl .

EEG changes lagged behind plasma concentration changes by2 to 3 min , after 4-min sufentanil infusion.

Resolution of the EEG changes lagged behind plasma concentration changes by20 to 30 min .

Highly selective - opioid receptor agonist.

IV infusion rate to adequate postoperative analgesia, mean rate of 8 to 17 g / hr was required during the first 48 hours .

Decreases the MAC of volatile anesthetics in a dose - dependent manner 70 to 90%.

In cardiac surgery, high doses( 10 to 30 g / kg ) with oxygen and muscle relaxants are needed.

When used as the sole anesthetic agent, even high dosesmay notcompletely block the hemodynamic responses to noxious stimuli.

Equianalgesic doses of sufentanil and fentanyl produce similar changes in the EEG.

With 15 g / kg,activity became prominent within a few seconds, and within 3 min, the EEG consisted almost entirely of slowactivity .

1 to 2 g / kg, Rigidity and myoclonic activity reported during induction, and on emergence.

0.5 g / kg was not associated with changes in cerebral blood flow.

1 g / kg was associated with an elevation in spinal cerebrospinal pressure, a decrease in cerebral perfusion pressure and arterial pressure had dropped significantly.

In spontaneously breathing patients anesthetized with 1.5% halothane and N2O, 2.5 g reduced mean minute ventilation by 50%, and 4 g reduced mean respiratory rate by 50%.

Comparing with fentanyl:

Changes in end - tidal CO2 were the same for fentanyl and sufentanil

the slope of the ventilatory response to CO2 was depressed to a greater extent by fentanyl.

Produces vasodilation by :

A sympatholytic mechanism.

A direct smooth muscle effect .

15 g/kg, decrease in MAP which is used for induction of anesthesia.

Combining vecuronium and sufentanil can cause a decrease in MAP during inductionand significant bradycardia and sinus arrest, but not with pancuronium.

Sufentanil, like fentanyl, reduces the endocrine and metabolic responses to surgery .

However, even a large induction dose( 20 g / kg )did not prevent increases in cortisol, catecholamines, glucose, and free fatty acids during and after cardiopulmonary bypass .

Extremely lipophilic.

pKa 8nonionized 20%.

Smaller degree of ionization at physiologic Ph.

Protein Binding 93% mostly to 1-acid glycoprotein.

Vd ss smaller than fentanyl : 1.9 Kg/L.

Elimination half - life shorter than that of fentanyl : 2.7 hrs.

Plasma concentration drops very rapidly after an IV bolus dose.

98% of the drug is cleared from plasma within 30 minutes after IV bolus dose.

Less red cell bound than fentanyl( 22 compared with 40% ).

Clearance is rapid.

As fentanyl high hepatic extraction ratio.

Metabolism in the liver is by :

N -dealkylation

O -demethylation

Study show clearance and elimination half - life in patients with cirrhosis are similar to controls.

Loss of consciousness is seen with total doses between 1.3 and 2.8 g / kg .

Doses in the range of 0.3 to 1.0 g / kg given 1 to 3 minutes prior to laryngoscopy can be expected to blunt hemodynamic responses to intubation

Balanced anesthesia is maintained with (A)intermittent bolus doses or (B)a continuous infusion

A:0.1 to 0.5 g / kg, mean maintenance requirements of 0.35 g / kg / hr

B:initial bolus of 0.5 g / kg followed by an infusion of 0.5 g / kg / hr

Can be used as the sole agent.

Much higher bolus doses( 10 g / kg )and / or infusion rates( 0.15 g / kg / min ) .

A tetrazole derivative of fentanyl.

Alfentanil is a -opioid receptor agonist and produces typical naloxone-reversible analgesia and side effectssuch assedation, nausea, and respiratory depression.

Its clinical potency is 10 times that of morphine.

Its clinical potency one - fourth to one - tenth that of fentanyl.

Peak effect of EEG lagged behind peak plasma concentration by 1.0 g / kgproduce brief increases in systolic BP( 5 to 20 torr ) and heart rate( 10 to 25 beats / min ).

In patients anesthetized, remifentanil( up to 5 g / kg )produces dose - dependent decreases in systolic BP and heart rate around 20% .

Attenuated by premedication with glycopyrrolate 0.3 to 0.4 mg and reversed with ephedrine or phenylephrine.

These hemodynamic effects were not mediated by histamine release

Transient and easily treated with fluids and downward titration of propofol .

A study show :

Hypotension:12% with remifentanil 4% with fentanyl

Bradycardia : 2% with remifentanil 1% with fentanyl

In a comparison of high - dose remifentanil( 2 g / kg / min ) and remifentanil0.5 g / kg / minplus propofol.

Both techniques produced similar changes:

30% drop in mean arterial pressure

25% drop in cardiac index.

30% drop in myocardial blood flow

40% drop in oxygen consumption

Rapid injection of remifentanil 1 g / kg followed by a continuous infusion at 0.1 to 0.2 g / kg / min on induction

Bradycardia( heart rate 2 g / kg can drop arterial pressure 20 to 30%.

Hemodynamic changes in cardiac patients receiving high - dose infusion are similar to remifentanil plus propofol .

Combined with a potent inhalation agent, a loading dose of1 g / kggiven slowly( over 60 seconds ) can provide adequate intubating conditions with hemodynamic stability.

The most commonly reported remifentanil - based regimen for anesthetic induction and laryngoscopy consists of remifentanil0.5 to 1 g / kggiven over 60 seconds plus propofol1 to 2 mg / kg , followed by remifentanil infusion of0.25 to 0.5 g / kg / min .

In combination with 70% N2O in O2, remifentanil 0.6 g/kg/min is generally adequate.

A lower infusion rate( 0.2 to 0.25 g / kg / min ) is needed when remifentanil is combined with inhalation agents.

For TIVA, maintenance infusion rates for remifentanil and propofol are0.25 to 0.5 g / kg / minand75 to 100 g / kg / min , respectively .

If N2O is added, remifentanil infusion rates as low as0.125 g/kg/minand propofol infusion of 50 to75 g/kg/mincan be used.

For elderly patients or those with cardiac disease, a reduction in propofol by about 25% is recommended .

Children require higher remifentanil doses to block responses to skin incision.

For high - dose opioid anesthesia for cardiac surgery, the remifentanil infusion is maintained at 1 to 3 g / kg / min and should be adjusted downward for hypothermia.

Adding a low - dose propofol infusion of50 g / kg / minto this high infusion rate effectively suppressed responses to skin incision, sternotomy, and aortic cannulation .

Related to its short duration of action.

Patients may experience substantial pain on emergence from anesthesia .

If moderate - to - severe postoperative pain is anticipated, continuing the remifentanil infusion between0.05and0.15 g / kg / min .

The use of local and regional anesthetic techniques is also effective .

Mild postoperative pain is anticipated, intraoperative administration of a NSAID 30 to 60 minutes before the end of surgery.

Used for conscious sedation / analgesia.

Used an adjunct for sedation or analgesia during regional anesthesia, or for block placement.

During colonoscopy, a continuous remifentanil infusion of0.2 to 0.25 g/kg/min , supplemented with small(10-mg)doses of propofol provided good analgesia but mild respiratory depression was common.

Patients who received low - dose( 12.5 to 25 g ) intermittent bolus injection of remifentanil with or without infusion at0.05 g / kg / minreported better analgesia than continuous infusion of0.1 g / kg / minalone .

Remifentanil 1 g / kg with or without a subsequent infusion of 0.2 g / kg / min administered 90 seconds prior to placement of ophthalmologic block resulted in excellent analgesia.

14% of patients who received an infusion experienced respiratory depression.

When used as an adjunct to local or regional anesthesia, a much lower maintenance infusion rate,0.05to0.1 g / kg / min , provides adequate sedation and analgesia .

Finally, the dose requirement of remifentanil for sedation / analgesia is reduced 50% when combined with midazolam or propofol .

When 1 to 2 mg of midazolam premedication is given,0.01to0.07 g / kg / minremifentanil provides good sedation / analgesia.

Structurally related to morphine .

Characterized by binding activity at multiple opioid receptors and their differential effects( agonist, partial agonist, or antagonist ) .

The clinical effect of a partial agonist at the - opioid receptor is complex.

Administered alone, a partial agonist has a flatter dose - response curve and a lower maximal effect than a full agonist.

The observed effect of the combination of A and B is expressed as a fraction of the maximal effect of the full agonist .As the concentration of the partial agonist increases, the effect of the combination converges on the maximum effect of the partial agonist .When added to a low concentration( e . g . ,[ A ] =0.25 )of agonist, the partial agonist increases the response; but when added to a large concentration of the agonist, the response decreasesthat is, B acts like an antagonist .

Combined with a low concentration of a full agonist, the effects of the partial agonist are additive up to the maximum effect of the partial agonist .

Combined with increasing concentrations([ A ] =0.67 to 256 )of full agonist, the partial agonist will act as an antagonist .

These drugs mediate their clinical effects via and - opioid receptors.

Nalbuphine and butorphanol have been reported to be antagonists at the opioid receptor, they do cause respiratory depression, which is not a function ofagonists .Thus, they appear to have at least partial agonist activity at the - opioid receptor .

RECEPTOR:

Nalbuphine

Butorphanol

Buprenorphine

RECEPTOR:

Nalbuphine

Butorphanol

To be in the provision of postoperative analgesia.

Used for intraoperative sedation, as adjuncts during general anesthesia.

To antagonize some effects of full opioid agonists .

Is a phenanthrene opioid derivative .

Classified as aagonist and antagonist.

It is more accurately described as a partial agonist at bothand receptors .

0.5 mg / kg dose reduced enflurane MAC by 8%.

This modest MAC reduction, compared with 65% for morphine, suggests nalbuphine may not be a useful adjunct for general anesthesia .

Combined with diazepam 0.4 mg / kg and 50% N2O in oxygen, a loading dose of 3 mg/kg was followed by additional doses of 0.25 mg/kg as needed throughout surgery.

No significant increases in blood pressure, stress hormones, or histamine were seen.

Emergence from anesthesia was uncomplicated.

The most common side effect was drowsiness .

Respiratory depression.

Can precipitate withdrawal symptoms in patients who are physically dependent on opioids .

Fentanyl was found to better attenuate hypertensive responses to intubation and surgical stimulation .

Significant respiratory depression was seen in 8 of 30 patients who received fentanyl; compared with no respiratory depression in the nalbuphine group.

Analgesia was similar.

Postoperative sedation was common in the nalbuphine group.

The respiratory depression mediated by - opioid receptors.

Has a ceiling effect equivalent to that produced by ~0.4 mg / kg morphine .

Analgesia is mediated by bothand receptors .

Antagonize the respiratory depressant effects of full agonists while still providing analgesic effects .

Have ceiling analgesic and respiratory depressant effects.

Can be as effective as full agonists in providing postoperative analgesia .

Nalbuphine 5 to 10 mg has also been used to antagonize pruritus induced by epidural and intrathecal morphine .

The usual adult dose of nalbuphine is 10 mg as often as every 3 hours .

A morphinan congener.

Has partial agonist activity at -and - opioid receptors.

Produced dose - dependent sedation which mediated byreceptors .

Decreases enflurane MAC,11%, at 0.1 mg/kg. Increasing the butorphanol dose 40-fold does not produce a further reduction.

Butorphanol and morphine provided equally satisfactory anesthesia .

Produces respiratory depression with a ceiling effect below that of full agonists .

3 mg produces respiratory depression approximately equal to that of 10 mg morphine .

Its effectiveness in reversing fentanyl - induced respiratory depression (5 g / kg followed by an infusion of 3 g/kg/hr) by butorphanol 1 mg only.

Does not produce significant elevation in intrabiliary pressure.

Effective in the treatment of postoperative shivering.

Antipruritic effect that is blocked by a selectiveantagonist .

Reduce morphine - induced pruritus without completely blocking its analgesic effect .

Lower incidence of opioid - induced ileus compared with - selective opioids.

Use as a sedative as low as 0.5 mg.

Treatment of moderate postoperative pain .

Single analgesic doses range from0.5 to 2 mg.

Administered as patient - controlled analgesia.

Can be administered epidurally and transnasally .

Highly lipophilic thebaine derivative.

A partial opioid agonist .

At small - to - moderate doses it is 25 to 50 times more potent than morphine .

Does not appear to have agonist activity at the - opioid receptor.

Its slow dissociation from receptors, which can lead to prolonged effects not easily antagonized by naloxone .

Bell - shaped dose - response curve such that, at very high doses, it produces progressively less analgesia .

10 or 20 g / kg buprenorphine during surgery were pain - free postoperatively.

30 or 40 g / kg had significant postoperative pain .

Have a ceiling effect to its respiratory depressant dose - response curve .

Buprenorphine - induced respiratory depression can be prevented by prior naloxone administration.

Not easily reversed by naloxone once the effects have been produced .Which require around 5 to 10 mg to antagonize it which maximum occur after 3 hours.

A dose of 0.3 mg buprenorphine reduces CO 2responsiveness to about 50% of control values.

Did not antagonize fentanyl - induced respiratory depression, and appears to increase respiratory rate without antagonizing analgesic effects in slowly administered doses up to 0.5 mg .

Effective in treatment of moderate - to - severe pain.

Slow onset.

Analgesic duration can be >6 hours .

A single dose of 0.3 to 0.4 mg appears to produce analgesia equivalent to 10 mg morphine .

They are competitive inhibitors of the opioid agonists.

Effect profile depends on:

The type of agonist administered

Dose of agonist administered

The degree to which physical dependence on the opioid agonist

The most widely used opioid antagonist.

Structurally related to morphine and oxymorphone.

It is a pure antagonist at - , - , and - opioid receptors .

Administered to antagonize opioid - induced respiratory depression and sedation .

Long - acting oral agent.

Relatively pure antagonist activity .

Mediated by endogenous opioids:

reverse stress analgesia.

antagonize analgesia produced by low-frequency stimulation with acupuncture needles.

reverse analgesia produced by placebo medications.

Trials in prevention of treatment of opioid - mediated gastrointestinal dysfunction.

Producing sudden, severe pain in postoperative patients.

Severe hypertension.

Tachycardia and ventricular dysrhythmias.

Precipitate opioid withdrawal symptoms in opioid-dependent individuals.

Acute, sometimes fatal, pulmonary edema even in healthy young patients who have received relatively small doses( 80 to 500 g ) .

The mechanism for this phenomenon is thought to be centrally mediated catecholamine release, which causes acute pulmonary hypertension.

It is also essential to monitor vital signs and oxygenation closely after naloxone is administered to detect occurrence of any of these potentially serious complications.

Very fast onset of action = easy to titrated.

Peak effects occur within 1 to 2 minutes.

Duration is dose - dependent.

Total doses of0.4 to 0.8 mglast 1 to 4 hours.

Suggested incremental doses for IV titration are20 to 40 ggiven every few mins until the patient's ventilation improves, but analgesia is not completely reversed.

Because naloxone has a short duration of action, respiratory depression may recur if large doses and / or long - acting opioid agonists have been administered .

When prolonged ventilatory depression is anticipated, an initial loading dose followed by a naloxone infusion can be used .

Infusion rates between 3 and 10 g / hr have been effective in antagonizing respiratory depression from systemic and epidural opioids .

The goal of opioid premedication is to provide moderate sedation, anxiolysis, and analgesia while maintaining hemodynamic stability .

Potential risks of opioid premedication include:

Oversedation.

Respiratory depression.

Nausea and Vomiting .

Opioids are often used to blunt or prevent the hemodynamic responses to tracheal intubation .

Opioids with rapid onset of action, such as fentanyl and its derivatives, are appropriate for this use .

Opioid dosage is titrated to the desired effect based on :

the surgical stimulus.

individual patient characteristics, such as

volume status.

neurologic status.

liver dysfunction.

other systemic disease states .

Important pharmacokinetic differences among these opioids include volumes of distribution and intercompartmental (distributional) and central (elimination) clearances.

A smaller distribution volume tends to shorten recovery time.

A reduction in clearance tends to increase recovery time .

The major pharmacodynamic differences among these opioids are potency and the equilibration times between the plasma and the site of drug effect .

Equilibration half - times between plasma and effect site are 5 to 6 minutes for fentanyl and sufentanil.

Equilibration half - times between plasma and effect site are 1.3 to 1.5 minutes for alfentanil and remifentanil .

The rate of recovery after a continuous infusion will depend on the duration of the infusion as well as the magnitude of decline that is required .

If only a 20% drop in effect site concentration is required, recovery from all three opioids will be rapid, although recovery time increases for fentanyl after 3 hours of drug infusion .

If a 50% decrease is required, recovery from sufentanil will be fastest for infusions 8 hours .

Defined as the time required for the drug concentration in the central compartment to decrease by 50%, and demonstrated how this half - time changes as drug infusion duration increases .

During an infusion, the peripheral( fast and slow )compartments begin to fill up . After the infusion is stopped, drug will be eliminated, but will also continue to be redistributed as long as the concentration in a peripheral compartment is lower than that in the central compartment .This leads to a rapid drop in central compartment drug concentration .

When central compartment( plasma )concentration drops below that of the peripheral compartment ( s ) , the direction of drug redistribution will reverse and will slow the decline in plasma concentration .

The degree to which redistribution will affect the rate of drug elimination depends on the ratio of the distributional to elimination time constants .Thus, a drug that can rapidly redistribute will have a correspondingly larger contribution from the peripheral compartment ( s ) , and plasma concentration will drop progressively more slowly as infusion duration continues .

opioids drugs

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opioid receptor antagonist

opioid antagonist

opioid redistribution

opioid metabolites

martin of opioid receptors

case opioid receptors

drugreceptor combination

endogenous opioids