Drugs Used For Pain and Inflammation (NSAIDs, Opioid Drugs, DMARDS) (trans 9) Flashcards
PAIN – “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”
Ways of Classifying Pain Region of the body involved System with the dysfunction Duaration and pattern of occurrence Intensity and time since onset Etiology
Nociceptive Pain
o Acute or Chronic
o Due to inflammation; usually with tissue damage and mobilization; infiltration of immune cells
Pathological Pain
o Usually Chronic
o Damage to Nervous Tissues
- Neuropathic pain like herpetic neuralgia, phantom pain, diabetic neuropathy
- Sometimes, there is no inflammation; it is damage to nervous tissues that causes the perception of pain. Not relieved by usual antiinflammatories and pain relievers
o Abnormal function
- Irritable bowel syndrome, tension headache
Pain Management
1) Acute Pain – acute inflammation (NSAIDs)
2) Chronic Pain – Cancer pain, trigeminal neuralgia, postherpetic neuralgia, chronic inflammation (NSAIDs, Opiods), psychogenic pain (Anti-depressants)
3) Severe pain – post operative pain (NSAIDs, Opiods)
Pain - chemical mediators
Bradykinin and Hydroxytryptamine
Protaglandins/ Prostanoids
Leukotrienes
TNFa, IL1
***Main mediator of Acute Inflammation: PROSTAGLANDIN
*Chronic Inflammation: T-LYMPHOCYTES and CYTOKINES
Mediators of Acute Inflammatory Response PRE-INFLAMMATORY Amines: Histamine, bradykinin Lipid Mediators: PGE2, PGI2, LTB4, LTC4 Complement: C3a, C5a Cyclic Nucleosides: cGMP Adhesion Molecules: E-selectin, PSelectin, ICAM1, VCAM1 Cytokines: TNF, IL-1B, IL-5 Chemokines: IL-8 (CCL8), GRO/KC, MIP1a (CCL3), MCP1 (CCL2) Steroid Hormones: -
ANTIINFLAMMATORY Amines: Adrenaline, Noradrenaline Lipid Mediators: PGI2, PGA2, lipoxins Complement: Clq receptor Cyclic Nucleosides: cAMP Adhesion Molecules: a2b2 integrin, TSP receptor, PS receptor Cytokines: TGF-B1, IL-10 Chemokines: - Steroid Hormones: Glucocorticoids
The Different Prostaglandins
PGD2: Vasodilation
PGE2:
EP1: Bronchoconstriction; GIT smooth ms. contraction
EP2: Bronchodilation; GIT smooth ms relaxation; vasolidation, pain
EP3: decrease gastric acid secretion; increase gastric mucus secretion; GIT smooth muscle contraction; uterine contraction; lipolysis inhibition; increase autonomic neurotransmitters, pyresis
PGF2A: Uterine contraction; brochoconstriction, decreased IOP
PGI2/Prostacyclin: Vasodilation; inhibit platelet aggregation; bronchodilation, salt excretion, renal blood flow
TXA2: Vasoconstriction; stimulate platelet aggregation, bronchoconstriction, decrease renal blood flow and salt excretion
PGs Functions
Constriction and dilation in vascular smooth muscle cells
Stimulate and inhibit platelet aggregation
Acts on parietal cells in the stomach to inhibit acid secretion
Acts on mesangial cells in the glomerulus to increase GFR
Induce labor
Decrease intraocular pressure
Regulates hormones
Control cell growth
Regulate inflammation
Sensitize spinal neurons to pain
Regulate calcium movement
Acts on thermoregulatory center in hypothalamus to produce fever
Therapeutic Goals
Relief of signs and symptoms
Eliminate the cause
Prevent progression and complication
NSAIDS - ROLE OF NSAIDs
Suppress signs and symptoms of inflammation
Exerts anti-pyretic and analgesic effects
o Treatment for fever
o Treatment for almost all kinds of acute pain and chronic inflammation
Inhibits COX and prostaglandin synthesis (antiinflammatory)
o Leads to numerous adverse reactions, especially on GIT, cardiovascular, and renal systems
NSAIDS - PHARMACOKINETICS
Absorption
All NSAIDs are weak organic acids EXCEPT Nabumetone
Most of the NSAIDs are rapidly absorbed
EXCEPT for Ketorolac – poorly absorbed, so that it is only available in parenteral and topical forms
Food delays absorption and may decrease bioavailability (as observed in Fenoprofen and Sulindac)
Distribution
Peak plasma level for most NSAIDs, especially for nonselective COX inhibitors, are reached in 2-3 hours; 1 hour for Etoricoxib
95 – 99% are protein-bound (albumin); if displaced from proteins, the effects of these NSAIDs can be increased in the presence of other drugs
All NSAIDs can be found in synovial fluid after repeated dosing. The amount of time NSAIDs remain in the joints is inversely proportional to their half-lives.
o Half-life: NSAIDs can reach their half-life from 1 hour to 50 hours; 75 hours in the elderly
Biotransformation
NSAIDs taken orally also undergo first pass Excretion
NSAIDs undergo hepatic biotransformation and excreted in the kidneys
NSAIDS - PHARMACODYNAMICS
NSAID anti-inflammatory activity is mediated chiefly through inhibition of prostaglandin biosynthesis
o Mechanism of action of various NSAIDs include: inhibition of chemotaxis, down-regulation of interleukin-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events
NSAIDs are classified based on their selectivity for inhibition, which is either non-selective or COX-2 selective
o COX-2 inhibitors do not affect platelet function at their usual doses
o GIT safety is also improved with COX-2 inhibitors as compared to older NSAIDs
o COX-2 inhibitors may however also increase the incidence of edema, hypertension, and some cardiovascular thrombotic events
NSAIDs decrease the sensitivity of vessels to bradykinin and histamine, affect lymphokine production from Tlymphocytes, and reverse the vasodilation of inflammation
All newer NSAIDs are analgesic, anti-inflammatory, antipyretic, and inhibitors of platelet aggregation (EXCEPT COX-2 Selective NSAIDs)
All are gastric irritants, though newer groups cause less GIT irritation than aspirin
Nephrotoxicity and hepatoxicity can also occur with any NSAID
NSAIDS - ADVERSE REACTIONS BY NSAIDS
CNS: headaches, tinnitus, dizziness
CVS: fluid retention, hypertension, edema, myocardial infarction, congestive heart failure
GIT: abdominal pain, dysplasia, nausea, vomiting, ulcers or bleeding
Hematologic: rare thrombocytopenia, neutropenia, aplastic anemia
Hepatic: abnormal liver function tests and rare liver failure
Pulmonary: asthma
Renal: salt and fluid retention, hypertension, interstitial nephritis, acute renal failure, acute tubular necrosis, analgesic nephropathy
Skin: rashes, pruritus
Others: Hypersensitivity reactions (because of synthetic NSAIDs), erectile dysfunction, abortion, premature labor, Stevens Johnson syndrome
NSAIDS - NSAIDS CLASSIFICATION
A. Non-selective COX Inhibitor
B. COX-2 Selective Inhibitors
C. Acetaminophen/Paracetamol
NSAIDS - NSAIDS CLASSIFICATION Non-selective COX Inhibitor 1. Aspirin 2. Indomethacin 3. Sulindac 4. Ibuprofen 5. Naproxen 6. Mefenamic Acid 7. Piroxicam 8. Ketorolac
NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver
Most of the NSAIDs are highly protein-bound (∼ 98%), usually to albumin. Most of the NSAIDs (eg, ibuprofen, ketoprofen) are racemic mixtures, while one, naproxen, is provided as a single enantiomer and a few have no chiral center (eg, diclofenac).
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Aspirin
Irreversible COX inhibitor
o Blocks the enzyme cycloxygenase (COX) which catalyzes the conversion of arachidonic acid to endoperoxide compounds
o This means that the effect of Aspirin remains permanent until new prostaglandins are produced in other tissues to replace the inactivated enzyme
o Aspirin is the only irreversible COX inhibitor
Standard for comparison when studying newer NSAIDs
Rapidly absorbed in the stomach and intestine
Used as an anti-thrombotic drug because of its bleeding tendency
Has a uricosuric effect but NOT used as a uricosuric drug
o Uricosuric: increases the excretion of uric acid in the urine, thus reducing the concentration of uric acid in the blood plasma
o Not used as a uricosuric drug because aspirin produces a uricosuric effect of >5grams/dose which is already toxic to the patient
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Indomethacin
More potent than aspirin
An indole derivative
Inhibits phospholipase A and C, reduce neutrophil migration, and decrease T-cell and B-cell proliferation
Previously used to treat patent ductus arteriosus (PDA) in preterm infants, as with Ibuprofen
o Surgery is used nowadays to treat PDA because the dose required to close PDA is harmful for infants
Not commonly used in treatment because of high rate of intolerance due to observed 50% GIT adverse reaction, as with Naproxen
o However, Indomethacin still has a more severe adverse reaction than Naproxen
Adverse drug reactions include: pancreatitis, hepatitis, neutropenia, aplastic anemia
Interactions with other drugs:
o Probenecid – increases effect of Indomethacin
o Furosemide, Thiazides, a and b blockers, ACE inhibitor – inhibited by Indomethacin
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Sulindac
Indications for rheumatic heart disease, familial intestinal polyposis, and inhibition of development of colon, breast, and prostate cancer in humans
Do not alter renal prostaglandins
Has observed 20% GIT adverse reaction
Observed adverse reaction also includes: Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, and agranulocytosis
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Ibuprofen
Most common NSAIDs drug today
A phenylpropionic acid derivative
Interferes with anti-platelet effect of aspirin
Mixed with other drugs, usually with Paracetamol or some opioids
Oral Ibuprofen prescribed in lower doses has an analgesic but not anti-inflammatory effect
Previously used to treat patent ductus arteriosus in preterm infants, as with Indomethacin
Has less adverse drug effect than aspirin and indomethacin, which makes it better tolerated
o 5 – 15% GIT adverse reaction
Prep: 20 mg capsule, 100mg/5ml suspension
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Naproxen
Has most FDA approved indications
A naphthylpropionic acid derivative
Usually for rheumatologic indications
Potency of Naproxen is almost the same with Indomethacin, but Naproxen has fewer adverse reactions than Indomethacin
Less severe adverse reactions, but is observed 35-50% of the time
o Adverse reactions in Indomethacin are not seen in Naproxen
Prep: 500 mg and 550 mg tab
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Mefenamic Acid
Has more adverse drug effects than Ibuprofen
o This is a possible cause why Ibuprofen is more common in the Philippines now than Mefenamic Acid
Has no clear advantage compare to other NSAIDs
Prep: 500 mg and 250 mg tablets, 250 mg/5ml liquid
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Piroxicam
In high concentrations, Piroxicam inhibits PMN leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function
Used in post-operative analgesia because of its increased half-life
o Can be used as a once-a-day drug
Not used in acute pain because it has a delayed effect
o In post-op, other NSAIDs, such as Ketorolac, must be given first before administering Piroxicam because of its delayed effect.
Available in oral and topical forms
o Topical form is more advantageous as it causes fewer adverse reactions
o Oral forms cause increased incidence of peptic ulcer and bleeding in dosages higher than 20mg/d
Prep: 20 mg capsule, 20 mg Flash tablet
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Ketorolac
Non-selective but a highly COX 1 inhibitor
A potent analgesic but less anti-inflammatory
Poorly absorbed, available in parenteral form
Good for acute severe pain
Rapid onset in a short duration
o Causes fewer adverse reactions
Prep: 30 mg/ml ampule
NSAIDS - NSAIDS CLASSIFICATION
COX-2 Selective Inhibitors
Also known as “coxibs”
NSAIDs under this category selectively bind to and block the active site of the COX-2 enzyme
Same effects similar to non-selective COX inhibitors but has halving of GI adverse effects
Have no effect on platelet aggregation, which is mediated by thromboxane produced by COX-1
Causes higher incidence of renal toxicity and cardiovascular thrombotic events
- Meloxicam
- Celecoxib
- Etoricoxib - Highly selective COX-2 inhibitor
NSAIDS - NSAIDS CLASSIFICATION
Nons-elective Inhibitors: Diclofenac
Preferentially selective COX-2 inhibitor
A phenylacetic acid derivative
Does not interfere with the anti-platelet action of aspirin (can be given together with aspirin)
GI ulceration and bleeding occur less frequently than with other NSAIDs
Adverse reactions:
o Elevated hepatic transaminase
o Fluid retention due to renal impairment
NSAIDS - NSAIDS CLASSIFICATION
COX-2 Selective Inhibitors: Meloxicam
Preferentially selective COX-2 inhibitor
Increases COX-2 selectivity
Inhibits synthesis of thromboxane A2
Adverse reactions: increased thrombotic effects
Dose: 7.5 – 15 mg OD for osteoarthritis
Prep: 7.5 – 15 mg tablet
NSAIDS - NSAIDS CLASSIFICATION
Non-selective Inhibitors: Etodolac
Has the same degree of COX 2 selectivity with the “coxibs”
A racemic acetic acid derivative with an intermediate halflife
GIT irritation and ulceration occur less frequently because of the relatively limited effect on the production of PGE2 in gastric mucosa
NSAIDS - NSAIDS CLASSIFICATION
COX-2 Selective Inhibitors: Celecoxib
Has a faster onset because of an increased peak plasma concentration in an hour than Etoricoxib
Indications for: osteoarthritis, acute pain, and primary dysmenorrhea
Can be used as a once-a-day drug
Dose: osteoarthritis: 12.5 – 25 mg once a day, acute pain/dysmenorrhea: 25 – 50 mg once a day
**It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9
NSAIDS - NSAIDS CLASSIFICATION
Acetaminophen/Paracetamol
More of an analgesic and anti-pyretic drug, but not an antiinflammatory drug
Has a poor COX inhibition due to the high levels of peroxides in the site of inflammation
Has a good absorption and bioavailability
Protein-binding is less than the other NSAIDs
Has a mild risk of GIT adverse reactions and hypersensitivity reactions
Well tolerated
In paracetamol intoxication that reaches to >7.5 grams/dose, most will be converted to NAPQI (N-acetyl-pbenzoquinone imine, a toxic byproduct).
o Hepatic necrosis , hypoglycemia, and renal tubular necrosis may be observed in 2-4 days
OPIOID DRUGS
Very potent analgesics
Mostly centrally acting (on the CNS)
Stimulates opioid receptors
Used for severe pain; chronic pain
Opium, the source of morphine, is obtained from the poppy, Papaver somniferum and P album.
After incision, the poppy seedpod exudes a white substance that turns into a brown gum that is crude opium.
Opium contains many alkaloids, the principal one being morphine, which is present in a concentration of about 10%. Codeine is synthesized commercially from morphine.
Opioid describes all compounds that work at opioid receptors; it refers to SYNTHETIC substances.
Opiate specifically describes the NATURALLY occuring alkaloids: morphine, codeine, thebaine, and papaverine.
Opiods include full agonists, partial agonists, and antagonists - measures of intrinsic activity or efficacy.
Their effects will depend on their receptor binding affinity.
OPIOID DRUGS - RECEPTOR SUBTYPES
(mu)
Functions:
Endogenous Opioid Peptide Affinity:
OPIOID DRUGS - RECEPTOR SUBTYPES
(mu)
Functions: Supraspinal and spinal analgesia; Sedation; Inhibition of respiration; Slowed GI transit; Modulation of hormone and neurotransmitter release
Endogenous Opioid Peptide Affinity: Endorphins >
enkephalins > dynorphins
OPIOID DRUGS - RECEPTOR SUBTYPES
(delta)
Functions:
Endogenous Opioid Peptide Affinity:
OPIOID DRUGS - RECEPTOR SUBTYPES
(delta)
Functions: Supraspinal and spinal analgesia; Modulation of hormone and neurotransmitter release
Endogenous Opioid Peptide Affinity: Enkephalins > endorphins and dynorphins
OPIOID DRUGS - RECEPTOR SUBTYPES
(kappa)
Functions:
Endogenous Opioid Peptide Affinity:
OPIOID DRUGS - RECEPTOR SUBTYPES
(kappa)
Functions: Supraspinal and spinal analgesia Psychotomimetic effects Slowed GI transit
Endogenous Opioid Peptide Affinity: Dynorphins >
endorphins and enkephalins
OPIOID DRUGS - RECEPTOR SUBTYPES
(mu) Receptor
Very important opioid receptor because it mainly controls the pain
Distributed all over the body including parts of the brain (cerebral cortex, amygdala, medulla), spinal cord, skin, and gastrointestinal tract
When there is overstimulation of μ receptors, there is itching/pruritus in those who take morphine regularly
Can cause analgesia, seizures, respiratory depression, slowed intestinal transit, and dependency
Morphine is a full agonist at the (mu)-opioid receptor, the major analgesic opioid receptor
OPIOID DRUGS - RECEPTOR SUBTYPES
(delta) Receptor
Almost the same to μ receptors; adjunct to μ receptors to increase the level of analgesia
Found in parts of the brain (cerebral cortex, amygdala, medulla), spinal cord
Can cause analgesia, seizures, respiratory depression, slowed intestinal transit, and dependency
OPIOID DRUGS - RECEPTOR SUBTYPES
(kappa) Receptor
Difference with μ and δ receptors: there is less of the tolerance when κ receptors are stimulated but almost the same analgesic effect if all 3 receptors are stimulated
Found in parts of the brain (hypothalamus, periaqueductal gray, and claustrum), spinal cord (substantia gelatinosa), and in pain neurons
Produce dissociative delirium and hallucinogenic effects
May antagonize μ receptor effects
Role in treatment of addiction and diuresis
OPIOID DRUGS - Endogenous Opioid Peptides:
Natural substances found in the body with opioid-like pharmacologic properties and include:
o Endorphins the pentapeptide
o Enkephalins (methionine-enkephalin and leucineenkephalin), and
o Dynorphins.
These three families of EOP have overlapping affinities for opioid receptors.
They are derived from three precursor proteins: preproopiomelanocortin (POMC), preproenkephalin (proenkephalin A), and preprodynorphin (proenkephalin B). POMC contains the met-enkephalin sequence, beta-endorphin, and several nonopiod peptides, including adrenocorticotropic hormone, beta-lipotropin, and melanocyte-stimulating hormone.
Preprodynorphin yields several active opioid peptides that contain the leu-enkephalin sequence. These are dynorphin A, B, and alpha and beta neoendorphins.
Painful stimuli can evoke relase of endogenous opioid peptides under the stress associated with pain or the anticipation of pain, and they diminish the perception of pain.
The receptor for this system is the G protein coupled orphanin opioid-receptor-like subtype 1 (ORL1). Its endogenous ligand has been termed nociceptin by one group of investigators and orphanin FQ by another group.
This ligand-receptor system is currently known as the N/OFQ system. This system is widely expressed in the CNS and periphery; it has been implicated in both pro- and antinociceptive activity as well as in the modulation of drug reward, learning, mood, anxiety, and cough processes, and of parkinsonism.
OPIOID DRUGS - PHARMACOKINETICS
Absorption:
Variable; high first pass effect (parenteral, oral) except codeine and hydrocodone (parenteral, nasal sprays, transdermal patches, lozenges);
o Most are well absorbed when given by subcutaneous, IM, and oral routes. First pass effect in oral doses elicits a therapeutic effect that may need to be higher than the parenteral dose. This causes a considerable interpatient variability in first-pass opioid metabolism and makes prediction of an effective oral dose difficult.
OPIOID DRUGS - PHARMACOKINETICS
Distribution:
Variable bioavailability after oral administration (25% morphine); 1/3 plasma bound
o Bind to plasma proteins with varying affinity, but drugs can rapidly leave blood compartment and localize in highest concentrations in highly perfused tissues such as the brain, lungs, liver, kidneys, and spleen. Blood flow to fatty tissue is much lower than the highly perfused tissues, but accumulation can be very important in frequent high-dose administration or continuous infusion of highly lipophilic opioids that are slowly metabolized (e.g. fentanyl)
OPIOID DRUGS - PHARMACOKINETICS
Metabolism:
Active polar metabolites through glucuronidation (they are converted to polar metabolites – mainly glucuronides)
o Morphine and hydromorphone can be converted to active metabolites
o Esters (heroin and remifentanil) are rapidly hydrolysed
o Meperidine, fentanyl, alfentanil, and sufentanil undergo hepatic oxidative metabolism
o Codeine, hydrocodone, and oxycodone are metabolized by CYP2D6
OPIOID DRUGS - PHARMACOKINETICS
Excretion:
readily excreted in kidneys when converted to polar metabolites, though small amounts of unchanged drug and also be found in the urine
OPIOID DRUGS - PHARMACODYNAMICS
Opiod agonists produce analgesia by binding to specific G protein-coupled receptors located in the brain and spinal cord regions involved in the transmission and modulation of pain.
Some effects may be mediated by opioid receptors in peripheral sensory nerve endings.
OPIOID DRUGS - PHARMACODYNAMICS
Potential receptor mechanism of analgesic drugs:
The afferent neuron originates in the periphery and carries pain signals to the dorsal horn of the spinal cord, where it synapses via glutamate and neuropeptide transmitters with the secondary neuron. Pain stimuli can be attenuated in the periphery by opioids acting at mu-opioid receptors (MOR) or blocked in the afferent axon by local anesthetics. Opioids also inhibit the postsynaptic neuron, as do neuropeptide antagonists acting at tachykinin (NK1) and other neuropeptide receptors.
OPIOID DRUGS - Factors affecting PD
Cellular actions
Two well-established direct effects on neurons: (1) They close the voltage gated Ca2+ channels on presynaptic nerve terminals and thereby reducing transmitter release, and (2) they open K+ channels and hyperpolarize and thus inhibit postsynaptic neurons
OPIOID DRUGS - Factors affecting PD
Relation of physiologic effects to receptor type
The majority of currently available opioid analgesics act primarily at the mu-opioid receptor, though morphine does act at kappa and delta receptor sites, it is unclear to what extent this contributes to its analgesic action. Endogenous opioid peptides differ from most of the alkaloids in their affinity for the delta and kappa receptors.
OPIOID DRUGS - Factors affecting PD
Receptor distribution and neural mechanisms of analgesia
All three major receptors are present in high concentrations in the dorsal horn of the spinal cord. Receptors are present both on SC pain transmission neurons and on the primary afferents that relay the pain message to them. Opioid agonists directly inhibit dorsal horn pain transmission neurons and also inhibit the release of excitatory transmitters from the primary afferents. The extent of differential expression of the mu and delta receptors in the DRG is characteristic of neurons throughout CNS remains to be determined.
OPIOID DRUGS - Factors affecting PD
Tolerance and dependence. Concepts include:
tolerance, receptor cycling, and receptor uncoupling
Opioid induced hyperalgesia: an increase in the
sensation of pain; can be produced by several opioids including morphine, fentanyl, and remifentanil.
OPIOID DRUGS - Organ System Effects
CNS: Analgesia, sedation (as anesthetic prior to surgery), euphoria, respiratory depression, cough suppression, miosis (pupillary constriction which can be a sign of drug tolerance/dependency), truncal rigidity, nausea and vomiting (uncontrollable nausea and vomiting are the number one symptoms of withdrawal), temperature regulation
CVS: Bradycardia (BUT tachycardia in meperidine)
GIT: Constipation, biliary colic
Renal: Decrease in urine output, decrease in renal blood flow, salt retention
Uterus: Prolong labor, decrease uterine tone
Endocrine: Stimulates release of ADH & prolactin but inhibits release of LH
OPIOID DRUGS - ADVERSE EFFECTS
Behavioral restlessness, tremulousness, hyperactivity, (in dysphoric reactions)
Respiratory depression
Nausea and vomiting
Increased intracranial pressure
Postural hypotension accentuated by hypovolemia
Constipation
Urinary retention
Itching around nose, urticaria (more frequent with parenteral and spinal administration)
OPIOID DRUGS - DRUG INTERACTIONS
Sedative hypnotics
o Increased CNS depression, particularly respiratory depression (e.g. benzodiazepines)
Antipsychotic agents / Tranquilizers
o Increased sedation. Variable effects on respiratory depression. Accentuation of cardiovascular effects (antimuscarinic and alpha-blocking actions)
Monoamine oxidase inhibitors
o Relative contraindication to all opioid analgesics because of the high incidence of hyperpyrexic coma; hypertension has also been reported
OPIOID DRUGS - CONTRAINDICATIONS
Use of pure agonist with weak partial agonists
o Risk of diminishing analgesia or even inducing a state of withdrawal
Use in patients with head injuries
o You won’t be able observe the patient’s status well; carbon dioxide retention caused by respiratory depression results in cerebral vasodilation and caused elevated ICP – leading to lethal alterations in brain function
Use in pregnancy
o Fetus may become physically dependent in utero and manifest withdrawal symptoms in early postpartum period. A daily dose as small as 6 mg of heroin taken by the mother can result in a mild withdrawal syndrome in the infant (severe signs and symptoms include: irritability, shrill crying, diarrhea, or even seizures)
Use in patients with impaired pulmonary function
o May lead to acute respiratory failure
Use in patients with impaired hepatic or renal function
o Morphine and its congeners are metabolized primarily in the liver; half-life is prolonged in patients with impaired renal function, and morphine and its active glucuronide metabolite may accumulate
Use in patients with endocrine disease
o Those with adrenal insufficiency (Addison’s disease) and those with hypothyroidism (myxedema) may have prolonged exaggerated responses to opioids
OPIOID DRUGS
RECEPTOR AGONISTS AND ANTAGONISTS: Mu receptors (MOR) agonists
o Morphine and its congeners o Codeine and its congeners o Meperidine and its congeners o Methadone and propoxyphene o Tramadol and tamentadol o Partial agonists: buprenorphine
OPIOID DRUGS
RECEPTOR AGONISTS AND ANTAGONISTS: Kappa receptors (KOR) agonists
o Nalbuphine, butorphanol, pentazocine
OPIOID DRUGS
RECEPTOR AGONISTS AND ANTAGONISTS: Mu receptor (MOR) antagonists
o Naloxone, naltrexone, nalmefene, methylnaltrexone
CLASSIFICATION OF OPIOIDS Strong Agonists o Phenanthrenes Morphine Hydromorphone (Dilauidid) Oxymorphone Heroin o Phenylheptylamines Methadone (Dolophine) Tramadol (Tramal) o Phenylpiperidines Meperidine/Pethidine (Demerol) Alphaprodine (Nisentil) Fentanyl (Sublimaze) Sulfentanil (Sufenta) Alfentanil Remifentanil o Morphinans Levorphanol (Levo-Dromoran)
Mild to Moderate Agonists o Phenanthrenes Codeine Oxycodone (Percodan) Hydrocodone (Hycodan) o Phenylheptylamines Propoxyphene (Darvon) o Phenylpiperidines Diphenoxylate Mixed Agonist-Antagonists o Phenanthrenes Nalbuphine (Nubain) Buprenorphine (Temagesic) o Morphinans Butorphanol (Stadol) o Benzomorphans Pentazocine (Talwin) Antagonists o Phenanthrenes Naloxone (Narcan) Nalorphine (Nalline) Naltrexone o Morphinans Levallorphan (Lorfan)
Mu agonists and their potency
Mu Agonists: Potency Heroine (Diamorphine): 2-4x Thebaine (Paramorphine): Synthetic form - same as morphine Hydromorphone (Dihydromorphinone): 8-10x Oxymorphone: 6-8x Levorphanol: Same as morphine Codeine: 1/20 than morphine Hydrocodone: 1/10 than morphine Oxycodone: 1/2 than morphine
OPIOID DRUGS - MORPHINE
Natural alkaloid from the opium poppy
Prototype for morphinans, phenlypiperidines
Standard for comparison of the analgesic effects of the new opioids
Used for moderate to severe pain
OPIOID DRUGS - HEROIN (Diamorphine)
Semi-synthetic; fast onset; high risk for physical dependency; commonly used for recreation; medical use for heroin addiction; through insufflation, ingestion, suppository
More potent than morphine; used only recreationally; high risk of dependency and addiction which is why it is given in small amounts
OPIOID DRUGS - THEBAIN (paramorphine)
Natural form inactive; precursor for oxycodone, oxymorphone, nalbuphone, naloxone, naltrexone, buprenorphine, etorphine
OPIOID DRUGS - HYDROMORPHONE (Dihydromorphinone)
Semi-synthetic; hydrophilic (poor bioavailability; no oral forms)
Most potent in this group
Metabolite can cause neurotoxic effects (myoclonus, hyperalgesia, restlessness)
OPIOID DRUGS - OXYMORPHONE
Semi-synthetic; analgesia; no anti-tussive; onset 3-4 hours (oral), 5-10 minutes (IV, rectal);
Derivative of the weaker opioid oxycodone; faster onset and short acting
High risk of dependency with this drug
OPIOID DRUGS - LEVORPHANOL:
Synthetic; analgesic effects similar to morphine
Useful for severe chronic and neuropathic pain.
Acts on MOR, KOR, DOR, NMDA antagonist, MAO inhibitor
Long duration of action (15 hours); lack cross tolerance with morphine
OPIOID DRUGS - CODEINE:
Natural; anti-tussive, anti-diarrhea; prototype for weak
opioids; oral, IV, IM, SQ; converts to morphine by CYP2D6
Prototype of weak to mid-range opioids; mild to moderate pain and cough suppression; can be metabolized to morphine in liver.
Previously available in the market but is now already regulated
One of its derivatives is dextromethorphan, which can cause tolerance and dependency
OPIOID DRUGS - OXYCODONE:
Semi-synthetic; precursor is thebaine from poppy seed; useful for acute moderate pain; metabolized in the liver to oxymorphone
Difference with hydrocodone is that this is more potent
Analgesic; fair to good bioavailability; converted to oxymorphone (more potent); available in combination with naloxone
OPIOID DRUGS - HYDROCODONE
Semi-synthetic; analgesic/anti-tussive; poor bioavailability; onset: 30 mins; lasts 4-8 hours
CYP2D6 converts to hydromorphone (more potent); may lead to ototoxicity
Brand name includes Vicodin; derived from codeine; for moderate pain and as anti-tussive; converts to hydromorphone in the liver
OPIOID DRUGS: synthetic Mu agonists
MEPERIDINE (Pethidine)
Prototype of synthetic new receptor agonist
Analgesic (Biliary and renal colic), anticholinergic, antitussive (suppression of cough)
Used for postanesthetic shivering; not for constipation or diarrhea; it has same risks as morphine
Metabolite norpethidine – can cause serotonin syndrome
Onset 15 mins; t1/2 3hrs; 60% protein bound; not used >48 hrs
OPIOID DRUGS: synthetic Mu agonists
FENTANYL
Semi-synthetic opioid
Analgesic anesthetic and for breakthrough pain
High risk for physical dependency, commonly used for recreation and medical use for heroin addiction through insufflation, ingestion, suppository, lozenge, patch
Main characteristic: Fast onset, fast/short duration of action
Fentanyl derivatives: Alfentanil, Sulfentanil, Remifentanil
