Drugs Used For Pain and Inflammation (NSAIDs, Opioid Drugs, DMARDS) (trans 9) Flashcards
(166 cards)
1
Q
PAIN – “Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”
A
Ways of Classifying Pain Region of the body involved System with the dysfunction Duaration and pattern of occurrence Intensity and time since onset Etiology
2
Q
Nociceptive Pain
o Acute or Chronic
o Due to inflammation; usually with tissue damage and mobilization; infiltration of immune cells
A
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
3
Q
Pain Management
A
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)
4
Q
Pain - chemical mediators
A
Bradykinin and Hydroxytryptamine
Protaglandins/ Prostanoids
Leukotrienes
TNFa, IL1
5
Q
***Main mediator of Acute Inflammation: PROSTAGLANDIN
A
*Chronic Inflammation: T-LYMPHOCYTES and CYTOKINES
6
Q
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: -
A
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
7
Q
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
A
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
8
Q
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
A
Therapeutic Goals
Relief of signs and symptoms
Eliminate the cause
Prevent progression and complication
9
Q
NSAIDS - ROLE OF NSAIDs
A
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
10
Q
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
A
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
11
Q
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
A
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
12
Q
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
A
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
13
Q
NSAIDS - NSAIDS CLASSIFICATION
A. Non-selective COX Inhibitor
B. COX-2 Selective Inhibitors
C. Acetaminophen/Paracetamol
A
NSAIDS - NSAIDS CLASSIFICATION Non-selective COX Inhibitor 1. Aspirin 2. Indomethacin 3. Sulindac 4. Ibuprofen 5. Naproxen 6. Mefenamic Acid 7. Piroxicam 8. Ketorolac
14
Q
NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver
A
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).
15
Q
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
A
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
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Q
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
A
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
17
Q
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Sulindac
A
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
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Q
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Ibuprofen
A
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
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Q
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Naproxen
A
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
20
Q
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Mefenamic Acid
A
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
21
Q
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
A
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
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Q
NSAIDS - NSAIDS CLASSIFICATION
Non-selective COX Inhibitor: Ketorolac
A
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
23
Q
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
A
- Meloxicam
- Celecoxib
- Etoricoxib - Highly selective COX-2 inhibitor
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Q
NSAIDS - NSAIDS CLASSIFICATION
Nons-elective Inhibitors: Diclofenac
A
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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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.
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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.
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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)
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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
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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
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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.
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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.
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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
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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.
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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.
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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.
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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
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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)
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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
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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
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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
```
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OPIOID DRUGS
| RECEPTOR AGONISTS AND ANTAGONISTS: Kappa receptors (KOR) agonists
o Nalbuphine, butorphanol, pentazocine
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OPIOID DRUGS
| RECEPTOR AGONISTS AND ANTAGONISTS: Mu receptor (MOR) antagonists
o Naloxone, naltrexone, nalmefene, methylnaltrexone
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```
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)
```
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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
```
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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
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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
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OPIOID DRUGS - THEBAIN (paramorphine)
Natural form inactive; precursor for oxycodone, oxymorphone, nalbuphone, naloxone, naltrexone, buprenorphine, etorphine
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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)
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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
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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
62
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
63
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
64
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
65
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
66
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
67
OPIOID DRUGS: synthetic Mu agonists
| ALFENTANIL
1/3 duration of action compared to fentanyl; fast acting; observable marked respiratory depression; fewer CV events; IV; seldom used
68
OPIOID DRUGS: synthetic Mu agonists
| SULFENTANIL
Very potent analgesic and aesthetic; fast onset; IV, patch, intrathecal; marked respiratory depression
69
OPIOID DRUGS: synthetic Mu agonists
| SULFENTANIL
Very potent analgesic and aesthetic; fast onset; IV, patch, intrathecal; marked respiratory depression
70
OPIOID DRUGS: synthetic Mu agonists
| REMIFENTANIL
Potent analgesic, mild sedative; fast onset (faster than fentanyl and sulfentanil); short duration of action (predictable termination of effect); synergistic with other hypnotics
71
Other MOR and KOR agonists and their potency
Synthetic MOR an KOR Agonists: Potency
| Tramadol, Tapendtadol: Mild or moderate pain = morphine Severe or chronic
72
OPIOID DRUGS: Other MOR and KOR agonists
| TRAMADOL
Available over the counter combined with Paracetamol
Given for mild to moderate pain
Weak new receptor agonist
MAO inhibitor (NE reuptake inhibitor - NERI)
Derivative of codeine; or analog of codeine
May cause but with minimal risk of seizures
Less respiratory depression; may cause or reinitiate dependence
73
OPIOID DRUGS: Other MOR and KOR agonists
| TAPENTADOL
Similar to Tramadol but more potent
Weak serotonin reuptake inhibition (NERI)
Blocked by adrenergic blockers
74
OPIOID DRUGS: Other MOR and KOR agonists
| DIPHENOXYLATE, DIFENOXIN, LOPERAMIDE
Anti-diarrheal agent
Weak new receptor agonist
Acts peripherally and doesn’t cross the blood-brain barrier
Chronic use can cause dependence; loperamide very minimal risk of dependency and tolerance
Diphenoxylate/Difenoxin available in combo with atropine
Poor water solubility = less abuse
Loperamide has very minimal risk of dependency and tolerance
75
OPIOID DRUGS: Other MOR and KOR agonists
| DEXTROMETHORPHAN
Antitussive; NMDA antagonist
Codeine analog
Risk for tolerance and dependency
Low toxicity; potential for dependence if given chronically
Used for cough; similar potency to codeine
76
OPIOID DRUGS: Other MOR and KOR agonists
| BUPRENORPHINE
Highly lipophilic MOR partial agonist – it has a new MOR agonist effect but when given with a full agonist, it has antagonistic effect
Derived from thebaine
May be used in opioid addiction if requiring low maintenance dose of opioids
77
OPIOID DRUGS: Other MOR and KOR agonists
| METHADONE
Long acting MOR agonist
For severe chronic pain and neuropathic pain (good analgesia)
Used in opioid dependence/addiction
Same potency as morphine
Can produce opioid tolerance and dependency
78
OPIOID DRUGS: Other MOR and KOR agonists
| PROPOXYPHENE
Narrow therapeutic index = many adverse reactions
May produce liver and renal toxicity and toxic psychoses
Similar to morphine in analgesia
Mild analgesic effect limit use of drug
79
OPIOID DRUGS: COMPETITIVE MOR ANTAGONIST
1. NALOXONE
2. NALTREXONE
3. METHYLNALTREXONE
80
OPIOID DRUGS: COMPETITIVE MOR ANTAGONIST
| NALOXONE
Most commonly used on patients with acute opioid overdose
Competitive inhibitor of new receptor agonists
Short duration of action
May produce overshoot and withdrawal
81
OPIOID DRUGS: COMPETITIVE MOR ANTAGONIST
| NALTREXONE
Long acting competitive MOR antagonist
Used as maintenance drug for addicts in treatment programs and for alcohol dependence
Many adverse reactions and can produce “overshoot”
May produce withdrawal syndrome
82
OPIOID DRUGS: COMPETITIVE MOR ANTAGONIST
| METHYLNALTREXONE
Potency similar to naltroxene
Reverses peripheral opioid GI effects
Poor lipid solubility
Cannot pass BBB
83
OPIOID DRUGS: OTHER SYNTHETIC KOR AGONISTS
| NALBUPHINE, BUTORPHANOL, PENTAZOCINE
KOR agonist, MOR antagonist
Analgesic effect
Decreased risk for tolerance and dependency
Can be used in patients with opioid dependence since it is a KOR agonist
Nalbuphine – Post-operative analgesic drug
Butorphanol – Best for acute pain
84
CLINCAL USE AND EFFECTS OF OPIOIDS
| Postop analgesics
Morphine, Fentanyl, Remifentanil, Nalbuphine, Tramadol
85
CLINCAL USE AND EFFECTS OF OPIOIDS
| Severe/Chronic pain (cancer pain, renal cholic, fractures)
Morphine, Nalbuphine, Hydrocodone, Tramadol
86
CLINCAL USE AND EFFECTS OF OPIOIDS
| Anti-diarrhea
Loperamide, Diphenoxylate
87
CLINCAL USE AND EFFECTS OF OPIOIDS
| Anti-tussive
Dextromethorphan
88
CLINCAL USE AND EFFECTS OF OPIOIDS
| Opioid overdose
Naloxone
89
CLINCAL USE AND EFFECTS OF OPIOIDS
| Opioid dependence
Methadone, Buprenorphine, Antagonists
90
OPIOID TOLERANCE
A process characterized by neuroadaptations that result in reduced drug effects usually requiring higher doses of the same medication over time to achieve the same effect
Happens in 2-3 weeks of continued use and in large doses with short intervals
Ultra potent drugs can produce tolerance in hours
Toxicity and tolerance varies from person to person; cross tolerance (opioid rotation and opioid recoupling)
91
OPIOID DEPENDENCE
| Physical Dependence
Physiological adaptation of the body to the presence of opioid
Development of withdrawal syndrome when a substance is discontinued (severe dysphoria, craving for another opiate dose, irritability, sweating, nausea, rhinorrhea, tremor, vomiting and myalgia)
92
OPIOID DEPENDENCE
| Opioid Addiction
Complex set of aberrant behaviors typically associated with misuse of certain drugs, developing over time and with higher drug dosages
93
Degrees of tolerance that may develop to some of the effects of the opioids
High: Analgesia. Euphoria, dysphoria, Mental clouding, Sedation, Respiratory, depression, Antidiuresis, Nausea and vomiting, Cough
suppression
Moderate: Bradycardia
Minimal or None: Miosis, Constipation, Convulsions
**Important! How will you check if a person is dependent on opioids or if they really need it for severe pain? Check for miosis (pupillary response)
94
APPROACH TO OPIOID DEPENDENCE AND ADDICTION
```
Slow tapering and removal of the drug
Medications:
o Long acting MOR agonists (Methadone)
o Partial agonists (Buprenorphine)
o MOR antagonists (Naloxone, Naltrexone)
```
95
GOUT
Metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage
Hyperuricemia is a prerequisite but does not always lead to gout
More common to under excreters than to overproducers (purine)
Inflammatory response activated by urate crystals in the joints
Uric acid, renal calculi, tophi and interstitial nephritis may also occur
Aims of treatment:
o Relieve acute gouty inflammatory attacks
o Prevent recurrent gouty episodes and urate lithiasis
o Reverse hyperuricemia
96
Xanthine oxidase inhibitor is used to decrease production of Uric Acid Risk factors for gout:
o High purine diet – meat, seafood, beans, beverages sweetened by fructose, beer
o Obesity
o Uncontrolled HPN, DM, metabolic syndrome, cardiac and renal disease
o Aspirin, Thiazides, Beta-blockers
o Male (30-50), menopausal women (>50)
o Trauma, Surgery
```
Goals
o Control of inflammation:
NSAIDs
Colchicine
Steroids
o Reverse hyperuricemia
Under excreters – Uricosuric agents
Over producers – Xanthine oxidase inhibitors
```
97
Pathway of how urate crystals can cause inflammation
Urate crystals are initially phagocytosed by synoviocytes => release prostaglandins, lysosomal enzymes, and interleukin-1 => neutrophils migrate into the joint space and amplify the ongoin inflammatory process => increased number of mononuclear phagocytes (macrophages) appear, ingest the urate crytals, and release more inflammatory mediators
98
Drugs Used for the Treatment of Gout:
| Anti-inflammatory Agents (to control inflammation) - NSAIDs - within 24 hours, 3-5 days; taper for 7-10 days
o Non-selective COX inhibitors
o COX 2 inhibitors
o Aspirin
99
Drugs Used for the Treatment of Gout:
| Anti-inflammatory Agents (to control inflammation) - NSAIDs - within 24 hours, 3-5 days; taper for 7-10 days
```
Non-selective COX inhibitors
Naproxen
Ibuprofen
Mefenamic Acid
Indomethacin
Sulindac
Aspirin
```
100
Drugs Used for the Treatment of Gout:
| Anti-inflammatory Agents (to control inflammation) - NSAIDs - within 24 hours, 3-5 days; taper for 7-10 days
```
COX 2 inhibitors
Celecoxib
Etoricoxib
Diclofenac
Meloxicam
```
101
Drugs Used for the Treatment of Gout:
| Anti-inflammatory Agents (to control inflammation) - NSAIDs - within 24 hours, 3-5 days; taper for 7-10 days
Aspirin
Low dose inhibit urate excretion, can cause renal calculi and inhibits uricosuric agents
Highly discouraged to give >5 grams per day
102
Drugs Used for the Treatment of Gout:
Anti-inflammatory Agents (to control inflammation) - Colchicine
o Only anti-inflammatory agent that is used for gout alone
o MOA: Anti mitotic effects on cells with rapid turnover (neutrophils, GI epithelium)
o Inhibits microtubule polymerization by binding to tubulin; often called mitotic poison
o Inhibits neutrophil motility and activity (more in musculoskeletal areas, joint areas)
o Oldest known therapy for gout
o Before, it is the first drug of choice for gout but because of ADRs, it became the second choice
**REMEMBER: Upon recurrence, use NSAIDs / Colchicine
Adverse reaction include:
Lowers body temp
Depresses respiration
GI stimulation and sympathetic stimulation
Neutropenia
Sympathetic stimulation
All may lead to HYPOVOLEMIC SHOCK and RENAL FAILURE
o Plant alkaloid
o Relieves the pain and inflammation and gouty arthritis in 12-24 hours without altering the metabolism or excretion of urates and without other analgesic effects
o 2 doses 1 hour apart; should be given within 24 hours of acute attack
o Dose 1.2 mg and 0.6 mg
o Narrow therapeutic window
o For prevention of recurrent attacks:
0.6 mg, 3-4 days / week if 1 attack per year
0.6 mg daily 2-3 times a day if with severe attacks
103
Drugs Used for the Treatment of Gout:
| Anti-inflammatory Agents (to control inflammation) - Steroids
o Delayed effect (2-3 days after)
o Prednisone – rapid relief within hours, high doses for 3 days and taper for 7-10 days
o Intra-articular steroids – avoids GI degradation and bone marrow depression
o Very narrow therapeutic index
104
Drugs Used for the Treatment of Gout: Xanthine Oxidase Inhibitors
to reverse hyperuricemia of over producers
> 800 mg in 24 hour urine
Allopurinol may cause hypoxanthine stones
Febuxostat is the best drug to give when there is renal and hepatic impairment (will NOT cause hypoxanthine stones)
Allopurinol and Febuxostat has equal uric acid lowering effect
It is highly encouraged to control inflammation first before hyperuricemia management because there will be a sudden rise in uric acid level during uncontrolled inflammation
105
Drugs Used for the Treatment of Gout: Uricosuric Agents
to reverse hyperuricemia of underexcreters
|
106
RHEUMATOID ARTHRITIS
Rheumatoid arthritis is an autoimmune disease that can
cause chronic inflammation of the joints and other areas
of the body.
While inflammation of the tissue around the joints and inflammatory arthritis are characteristic features of rheumatoid arthritis, the disease can also cause inflammation and injury in other organs in the body. Because it can affect multiple other organs of the body, rheumatoid arthritis is referred to as a systemic illness and is sometimes called rheumatoid disease. Rheumatoid arthritis that begins in people under 16 years of age is referred to as juvenile idiopathic arthritis (formerly juvenile rheumatoid arthritis).
Can affect 1% of the population.
Goals in treatment:
o Symptomatic relief (COX2 inhibitors)
o Retard the progression of arthritic tissue destruction (steroids, cytotoxic agents, biologicals).
107
RHEUMATOID ARTHRITIS - DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS)
Disease-modifying antirheumatic drugs (DMARDs) are a group of medications commonly used in patients with rheumatoid arthritis. They work to decrease pain and inflammation, to reduce or prevent joint damage, and to preserve the structure and function of the joints. Some of these drugs are also used in treating other conditions such as ankylosing spondylitis, psoriatic arthritis, and systemic lupus erythematosus.
Immunosuppressives and cytotoxic agents
Acts on T cell, B cell, and TNF
Used against cancers, autoimmune conditions, antimicrobials and chronic inflammation
Conventional synthetic, biologicals
The effects of disease-modifying therapies may take 6 weeks to 6 months to become clinically evident, although some biologics are effective within 2 weeks or less.
This drug must be used together with NSAIDs. NSAIDs mainly offer symptomatic relief, reduce inflammation and the pain it causes, and often preserve function
Generally slow-acting as compared to NSAIDs
**How DMARDs affect DNA and protein synthesis. Purine metabolism is interrupted my Methotrexate. Pyrimidine metabolism is interrupted by Leflunomide. DNA may be converted but it produces impaired products that may lead to tumors.
108
RHEUMATOID ARTHRITIS: DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS) - BIOLOGIC
1. ABATACEPT
| 2. RITUXIMAB
109
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
BIOLOGIC - ABATACEPT
MECHANISM OF ACTION:
Stimulation modulator biologic that inhibits the activation of T cells
After a T cell has engaged an antigenpresenting cell (APC), a second signal is produced by CD28 on the T cell that interacts with CD80 or CD86 on the APC leading to T-cell activation.
Abatacept (which contains the endogenous ligand CTLA-4) blocks activation of T‐cells by binding to CD80 or CD86, thereby inhibiting the binding to CD28 and preventing the activation of T‐cells.
CTLA‐4: a co‐stimulatory molecule found on T cells that binds to CD80 and CD86 on antigen presenting cells
110
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
BIOLOGIC - ABATACEPT
DOSAGE & PHARMACOKINETICS:
Intravenous infusion in three initial doses (day 0, week 2, and week 4) followed by monthly infusions
Dose is based on body weight:
- 100kg receives1000mg
- Dosing regimens in any adult group can be increased if needed.
Terminal serum half‐life is 13‐16 days
Co-administreation with methotrexate, NSAIDs, and corticosteroids does not influence Abatacept clearance.
111
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
BIOLOGIC - ABATACEPT
INDICATIONS
Approved for patients with severe rheumatoid arthritis who have failed other disease modifying antirheumatic drugs
Reduces the signs and symptoms of rheumatoid arthritis, including slowing of radiographic progression.
112
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
BIOLOGIC - ABATACEPT
ADVERSE EFFECTS:
Should not take other TNF-α antagonist drugs while taking abatacept due to increased incidence of serious infections
Slightly increased risk of infection (as with other biologic DMARDs), predominantly of the upper respiratory tract
Rarely: infusion-related reactions and hypersensitivity reactions (including anaphylaxis)
113
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
BIOLOGIC - RITUXIMAB
MECHANISM OF ACTION:
Chimeric monoclonal antibody biologic agent that targets CD20 B-lymphocytes through cell-mediated and complementdependent cytotoxicity and stimulation of cell apoptosis.
1. Chimeric murine human monoclonal IgG1 (human Fc) binds to the CD20 molecule on normal malignant B lymphocytes
2. Rapidly depletes peripheral B cells
3. Reduction of inflammation by decreasing the presentation of antigens to T lymphocytes and inhibiting secretion of proinflammatory cytokines
Shown benefit in the treatment of rheumatoid arthritis refractory to anti-TNF agents Approved for the treatment of active rheumatoid arthritis when combined with methotrexate
114
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
BIOLOGIC - RITUXIMAB
DOSAGE & PHARMACOKINETICS:
Two intravenous infusions of 1000 mg, separated by 2 weeks
May be repeated every 6-9 months as needed (repeated courses remain effective)
Pretreatment with intravenous glucocorticoids given 20 mins prior to infusion decreases incidence and severity of infusion reactions.
115
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
BIOLOGIC - RITUXIMAB
ADVERSE EFFECTS:
Rashes with the first 1000 mg treatment, decreases to about 10% w/ the second infusion and progressively decreases therafter
Infections may occur due to decreased IgG and IgM
116
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
BIOLOGIC - RITUXIMAB
INDICATIONS
Treatment of moderately to severely active rheumatoidarthritis in combination with methotrexate in patients with inadequate response to one or more TNF-α antagonists.
Reduced levels of C‐reactive protein, erythrocytesedimentation rate, serum IL‐6 and matrix metalloproteinases MMP‐1 and MMP‐3 were observed
117
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
| SYNTHETIC
1. METHOTREXATE
2. SULFASALAZINE
3. AZATHIOPRINE
4. CYCLOPHOSPHAMIDE
118
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
SYNTHETIC - METHOTREXATE
MECHANISM OF ACTION:
Synthetic antimetabolite
First line DMARDs and is used in 50-70% of patient
Principal MOA: At low doses, this drug
inhibits aminoimidazolecarboxamideribonucleotide (AICAR) transformylase and thymidiylate synthase
1. AICAR which accumulates intracellularly, inhibits AMP deaminase
2. AMP accumulation
3. AMP is released and converted to adenosine (potent inhibitor of inflammation)
4. Macrophages, neutrophils and lymphocytes are suppressed.
Secondary effects: Polymorphonuclear chemotaxis
Direct inhibitory effects on proliferation, i.e. stimulates apoptosis, in immuneinflammatory cells
Some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function
Inhibition of proinflammatory cytokines
119
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
SYNTHETIC - METHOTREXATE
DOSAGE & PHARMACOKINETICS:
15-25 mg weekly, increased effect up to 30-35 mg weekly
Approximately 70% absorbed after oral administration
Metabolized to a less active hydroxylated metabolite
Both the parent compound and the metabolite are polyglutamated within cells, where they stay for prolonged periods
Half-life: 6-9 hoursbut 24 hours in some individuals
Increased in the presence of hydroxychloroquine, which can reduce the clearance or increase the tubular reabsorption of methotextrate
Excreted principally in the urine, 30% excreted in the bile
120
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
SYNTHETIC - METHOTREXATE
INDICATIONS
```
Decreases the rate of appearance of new erosions
Juvenile chronic arthritis
Psoriasis
Psoriatic arthritis
Ankylosing spondylitis
Polymyositis
Dermatomyositis
Wegner’s granulomatosis
Giant cell arthritis
Systemic lupus erythematosus
Vasculitis
```
121
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
SYNTHETIC - METHOTREXATE
ADVERSE EFFECTS
Most common: nausea and mucosal ulcers
Result of inhibiting cellular proliferation: leukopenia, anemia, stomatitis, GI ulcerations, alopecia
Dose-related hepatotoxicity (frequently in the form of enzyme elevation); occurs frequently but cirrhosis is rare
Rarely: hypersensitivity-like lung reaction with acute shortness of breath, pseudolymphomatous reactions
Contraindicated in pregnancy
122
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
SYNTHETIC - SULFASALAZINE
MECHANISM OF ACTION
Metabolized to sulfapyridine and 5‐aminosalicylic acid, and it is thought that the sulfapyridine is probably the active part when treating rheumatoid arthritis
In vitro, inhibits the release of inflammatory cytokines, including those produced by monocytes or macrophages, e.g. IL‐1,‐6, and ‐12 and TNF-α
123
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
SYNTHETIC - SULFASALAZINE
DOSAGE & PHARMACOKINETICS
The usual regimen is 2‐3 g/d.
10‐20% of orally administered drug is absorbed although a fraction undergoes enterohepatic recirculation into the bowel where bacteria reduce it and liberate sulfapyridine and 5‐aminosalicylic acid
Sulfapyridine is well absorbed while 5‐aminosalicylic acid is unabsorbed.
Some sulfasalazine is excreted in the urine.
Sulfasalazine has a half‐life of 6‐17 hours.
124
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
SYNTHETIC - SULFASALAZINE
INDICATIONS
Effective in rheumatoid arthritis and reduces radiologic disease progression in juvenile chronic arthritis, and in ankylosing spondylitis with its associated uveitis
125
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SYNTHETIC - SULFASALAZINE
ADVERSE EFFECTS
Nausea, vomiting, headache, and rash
Rarely: hemolytic anemia and methemoglobinemia also occur
Pulmonary toxicity and positive doublestranded DNA (dsDNA) are occasionally seen
Reversible infertility in men
30% of patients discontinue the drug because of toxicity.
126
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SYNTHETIC - AZATHIOPRINE
MECHANISM OF ACTION
Acts through its major metabolite: 6-thioguanine
Its metabolite:
- Suppresses inosinic acid synthesis, B cell and T cell function, immunoglobulin production, Interleukin-2 secretion
- Xanthine oxidase splits much of the active material to 6-thiouric acid prior to excretion in the urine
127
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SYNTHETIC - AZATHIOPRINE
DOSAGE & PHARMACOKINETICS
Approved for use in rheumatoid arthritis: 2 mg/kg/day
Bimodal metabolism: some are rapid metabolizers (4x faster) and slow metabolizers
Production of 6-thioguanine is dependent on thiopurinemethyltransferase (TPMT)
Patients with low or absent TPMT activity (0.3% of the population) are at particularly high risk of myelosuppression by excess concentrations of the parent drug if dose is not adjusted.
128
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SYNTHETIC - AZATHIOPRINE
INDICATIONS
Prodrug of mercaptopurine and functions as an antimetabolite
Rheumatoid arthritis
Showed efficacy in psoriatic arthritis, reactive arthritis, polymyositis, systemic lupus, erythematosus, Bechet’s disease
129
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SYNTHETIC - AZATHIOPRINE
ADVERSE EFFECTS
Bone marrow suppression
Gastrointestinal disturbances
Infection risk
Rarely: lymphoma risk, fever and rash, hepatotoxicity signal acute allergic reaction
130
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SYNTHETIC - CYCLOPHOSPHAMIDE
MECHANISM OF ACTION
One of the most efficacious immunosuppressive drugs
Major active metabolite: phosphoramide mustard
Its metabolite:
- Cross-links DNA to prevent cell replication
- Suppresses T-cll and B-cell function by 30- 40%
T cell suppression correlates with clinical response in rheumatoid disease
Destroys proliferating lymphoid cells and also appears to alkylate some resting cells
131
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SYNTHETIC - CYCLOPHOSPHAMIDE
DOSAGE & PHARMACOKINETICS
Active against rheumatoid arthritis: 2 mg/kg/day given orally
Different dosage when given intravenously
132
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SYNTHETIC - CYCLOPHOSPHAMIDE
INDICATIONS
Wegner’s granulomatosis
Systemic lupus erythematosus
Vasculitis
Other severe rheumatic diseases
133
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SYNTHETIC - CYCLOPHOSPHAMIDE
ADVERSE EFFECTS
Significant dose-related infertility in both men and women
Bone marrow suppression
Alopecia
Pancytopenia
Hemorrhagic cystitis
GI disturbances like nausea, vomiting, cardiac toxicity and electrolyte disturbances
Rarely bladder carcinoma
134
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SEMI-SYNTHETIC - MYCOPHENOLATE MOFETIL
MECHANISM OF ACTION
Active form of the drug: mycophenolic acid
Its metabolite:
- Inhibits cytosine monophosphate dehydrogenase leading to suppression of T- and B-lymphocyte proliferation
- Suppression of T‐lymphocyte responses to mitogens,decreased leukocyte chemotaxis, stabilization oflysosomal enzymes, inhibition of DNA and RNAsynthesis, and the trapping of free radicals
- Interferes with leukocyte adhesion to endothelial cells through inhibition of Eselectin, P-selectin and intracellular adhesion molecule 1
135
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SEMI-SYNTHETIC - MYCOPHENOLATE MOFETIL
DOSAGE & PHARMACOKINETICS
Treatment of rheumatoid arthritis: 2 g/d
| There is no well-controlled data regarding efficacy
136
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SEMI-SYNTHETIC - MYCOPHENOLATE MOFETIL
INDICATIONS
Treatment of renal disease due to systemic lupus erythematosus
Vasculitis
Wegner’s granulomatosis
137
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): SEMI-SYNTHETIC - MYCOPHENOLATE MOFETIL
ADVERSE EFFECTS
Gastrointestinal disturbance (nausea, vomiting, diarrhea, dyspepsia and abdominal pain)
Can cause hepatotoxicity, leucopenia, thrombocytopenia and anemia
Headache
Hypertension
Reversible myelosuppression (primarily neutropenia)
138
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC
1. CYCLOSPORINE
2. CHLOROQUINE &HYDROXYCHLOROQUINE
3. LEFLUNOMIDE
139
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - CYCLOSPORINE
MECHANISM OF ACTION
Peptide antibiotic but is considered a nonbiologic DMARD
Through regulation of gene transcription, inhibits IL-1 and IL-2 receptor production andsecondarily inhibits macrophage T‐cell interaction andT‐cell responsiveness
T-cell dependent B-cell function is also affected.
140
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - CYCLOSPORINE
DOSAGE & PHARMACOKINETICS
3‐5mg/kg/d divided into 2 doses
Absorption is incomplete and somewhat erratic: 20‐30% bioavailability
Grapefruit juice increases cyclosporine bioavailabilityby as much as 62%
Metabolized by CYP3A and is subject to a largenumber of drug interactions
141
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - CYCLOSPORINE
INDICATIONS
Rheumatoid arthritis and retards the appearance of new bony erosions
Used for systemic lupus erythematosus, polymyositisand dermatomyositis, Wegener's granulomatosis, and juvenile chronic arthritis
142
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - CYCLOSPORINE
ADVERSE EFFECTS
Leucopenia, thrombocytopenia and to a lesser extent, anemia
High doses can be cardiotoxic and sterility may occur after chronic dosing at antirheumatic doses especially in women.
Rarely: Bladder CA
143
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - CHLOROQUINE & HYDROXYCHLOROQUINE
MECHANISM OF ACTION
Mainly used in malaria and in the rheumatic diseases
Unclear anti-inflammatory action of these drugs in rheumatic diseases
Suggested mechanisms:
- Suppression of T lymphocyte responses to mitogens
- Decreased leukocyte chemotaxis
- Stabilization of lysosomal enzymes
- Inhibition of DNA and RNA synthesis
- Trapping of free radicals
144
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - CHLOROQUINE & HYDROXYCHLOROQUINE
DOSAGE & PHARMACOKINETICS
Chloroquine: 200 mg/daily
Hydroxycloroquine: Up to 6.4 mg/kg/daily
Usually takes 3-6 months to obtain response
Rapidly absorbed but only 50% are proteinbound in the plasma
Very extensively tissue-bound, particularly melanin-containing tissues such as eyes
Deaminated in the liver
Blood elimination half-life: up to 45 days
145
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - CHLOROQUINE & HYDROXYCHLOROQUINE
INDICATIONS
Approved for rheumatoid arthritis but not considered very efficacious DMARDs
Dose-loading may increase rate of response
Often used for the treatment of:
- Skin manifestations
- Serositis
- Joint pains of systemic lupus erythematous
- Sjogren’s syndrome
146
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - CHLOROQUINE & HYDROXYCHLOROQUINE
ADVERSE EFFECTS
Ocular toxicity at doses:
- Greater than 250 mg/daily for chloroquine
- Greater than 6.4 mg/kg/daily for hydroxychloroquine
- Ophthalmologic monitoring every 12 months is advised
Dyspepsia, nausea, vomiting, abdominal pain, rashes and nightmares
Relatively safe in pregnancy
147
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - LEFLUNOMIDE
MECHANISM OF ACTION
Undergoes rapid conversion, both in the intestine and in the plasma, to its active metabolite:A77‐1726
The metabolite inhibits dihydroorotate dehydrogenase, leading to a decrease in ribonucleotide synthesis and the arrest of stimulated cells in the G1 phase of cell growth.
Consequently, it inhibits T‐cell proliferation and production of antibodies by B‐cells.
Secondary effects: increases of IL-10 receptor mRNA, decreased IL-8 receptor type A mRNA and decreased TNF- α-dependent nuclear factor kappa B (NF-kB) activation
148
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - LEFLUNOMIDE
DOSAGE & PHARMACOKINETICS
Completely absorbed
Mean plasma half-life: 19 days
Orally active
The active metabolite has approximately the same half-life and is subject to enterohepatic recirculation.
Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%
Should be started with a loading dose, but it can be taken once daily after reaching steady state.
149
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - LEFLUNOMIDE
INDICATIONS
Approved for the treatment of rheumatoid
| arthritis including inhibition of bony damage
150
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS): NON-BIOLOGIC - LEFLUNOMIDE
ADVERSE EFFECTS
```
Diarrhea (25% of patients)
Risk of liver damage (elevation of liver enzymes)
Mild alopecia
Weight gain
Increased blood pressure
Renal impairment
Teratogenic effects
Contraindicated in pregnancy
```
151
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS
- TNF-α affects cellular function via activation of specific membrane bound TNF receptors
1. ADALIMUMAB
| 2. INFLIXIMAB
152
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - ADALIMUMAB
MECHANISM OF ACTION
An IgG1 anti-TNF monoclonal antibody: complexes with soluble TNF-α and prevents interaction with p55 and p75 cell surface receptors. This results in down regulation of macrophages and T cell function.
Fully human
153
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - ADALIMUMAB
DOSAGE & PHARMACOKINETICS
40 mg every other week
Given subcutaneously
Increased by 29-44% in patients who are also taking methotrexate
The following happen, in the presence of methotrexate:
- Decreased clearance by more than 40% in the presence of methotrexate
- Decreased formation of human antimonoclonal antibody
In psoriasis, 80 mg is given at week 0, 40 mg at week 1, and then 40 mg every other week thereafter. Half-life: 10-20 days
154
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - ADALIMUMAB
INDICATIONS
```
Rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Juvenile idiopathic arthritis
Plaque psoriasis
Crohn’s disease
Decreases the rate of formation of new erosions
```
155
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - ADALIMUMAB
ADVERSE EFFECTS
Bacterial infections
Increased macrophage-dependent infection (including tuberculosis and other opportunistic infections)
Rarely: clinical lupus, leucopenia, vasculitis
156
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - INFLIXIMAB
MECHANISM OF ACTION
An IgG1 anti-TNF monoclonal antibody: complexes with soluble TNF-α and prevents interaction with p55 and p75 cell surface receptors.
- A chimeric (25% mouse, 25% human) IgG1 monoclonal antibody that binds with high affinity to soluble and possible membrane bound TNF- α
157
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - INFLIXIMAB
DOSAGE & PHARMACOKINETICS
Intravenous infusion at doses of 3-10 mg/kg although the usual dose is 3-5 mg/kg every 8 weeks
Given as intravenous infusion with “induction” at 0, 2, and 6 weeks and maintenance every 8 weeks thereafter
Half life: 9-12 days without accumulation after repeated dosing at the recommended dosage interval of 8 weeks
Concurrent infliximab therapy with methotrexate also decreases the prevalence of human anthichimeric antibodies
158
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - INFLIXIMAB
INDICATIONS
```
Rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Juvenile idiopathic arthritis
Plaque psoriasis
Crohn’s disease
```
159
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - INFLIXIMAB
ADVERSE EFFECTS
Bacterial infections
| Increased macrophage-dependent infection (including tuberculosis and other opportunistic infections)
160
REMEMBER
TREATMENT OF RHEUMATOID ARTHRITIS
Short term control of inflammation:
o NSAIDs / Steroids
Long term treatment:
o Methotrexate alone
o Moderate to severe: combination of non-biologicals
o Biologicals: Reserved only for severe disease with failure of treatment from other DMARDs
161
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - INFLIXIMAB
DOSAGE & PHARMACOKINETICS
Intravenous infusion at doses of 3-10 mg/kg although the usual dose is 3-5 mg/kg every 8 weeks
Given as intravenous infusion with “induction” at 0, 2, and 6 weeks and maintenance every 8 weeks thereafter
Half life: 9-12 days without accumulation after repeated dosing at the recommended dosage interval of 8 weeks
Concurrent infliximab therapy with methotrexate also decreases the prevalence of human anthichimeric antibodies
162
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - INFLIXIMAB
INDICATIONS
```
Rheumatoid arthritis
Ankylosing spondylitis
Psoriatic arthritis
Juvenile idiopathic arthritis
Plaque psoriasis
Crohn’s disease
```
163
MODIFYING ANTIRHEUMATIC DRUGS (DMARDS):
TNF α BLOCKING AGENTS - INFLIXIMAB
ADVERSE EFFECTS
Bacterial infections
| Increased macrophage-dependent infection (including tuberculosis and other opportunistic infections)
164
REMEMBER
TREATMENT OF RHEUMATOID ARTHRITIS
Short term control of inflammation:
o NSAIDs / Steroids
Long term treatment:
o Methotrexate alone
o Moderate to severe: combination of non-biologicals
o Biologicals: Reserved only for severe disease with failure of treatment from other DMARDs
165
ASPIRIN - pharmacokinetics
The salicylates are rapidly absorbed from the stomach and upper small intestine yielding a peak plasma salicylate level within 1–2 hours. Aspirin is absorbed as such and is rapidly hydrolyzed (serum halflife 15 minutes) to acetic acid and salicylate by esterases in tissue and blood
166
ASPIRIN - metabolism
1. conjugation with glucoronic acid = ester and ether glucoronides
2. conjugation with glycine = salycyluric acid
3. oxidation = gentisic acid
