Drugs Used For Pain and Inflammation (NSAIDs, Opioid Drugs, DMARDS) (trans 9) Flashcards

Question 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”

Answer

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

Question 2

Q

Nociceptive Pain
o Acute or Chronic
o Due to inflammation; usually with tissue damage and mobilization; infiltration of immune cells

Answer

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

Question 3

Q

Pain Management

Answer

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)

Question 4

Q

Pain - chemical mediators

Answer

A

 Bradykinin and Hydroxytryptamine
 Protaglandins/ Prostanoids
 Leukotrienes
 TNFa, IL1

Question 5

Q

***Main mediator of Acute Inflammation: PROSTAGLANDIN

Answer

A

*Chronic Inflammation: T-LYMPHOCYTES and CYTOKINES

Question 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: -

Answer

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

Question 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

Answer

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

Question 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

Answer

A

Therapeutic Goals
 Relief of signs and symptoms
 Eliminate the cause
 Prevent progression and complication

Question 9

Q

NSAIDS - ROLE OF NSAIDs

Answer

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

Question 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

Answer

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

Question 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

Answer

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

Question 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

Answer

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

Question 13

Q

NSAIDS - NSAIDS CLASSIFICATION
A. Non-selective COX Inhibitor
B. COX-2 Selective Inhibitors
C. Acetaminophen/Paracetamol

Answer

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

Question 14

Q

NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver

Answer

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).

Question 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

Answer

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

Question 16

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

Answer

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

Question 17

Q

NSAIDS - NSAIDS CLASSIFICATION

Non-selective COX Inhibitor: Sulindac

Answer

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

Question 18

Q

NSAIDS - NSAIDS CLASSIFICATION

Non-selective COX Inhibitor: Ibuprofen

Answer

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

Question 19

Q

NSAIDS - NSAIDS CLASSIFICATION

Non-selective COX Inhibitor: Naproxen

Answer

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

Question 20

Q

NSAIDS - NSAIDS CLASSIFICATION

Non-selective COX Inhibitor: Mefenamic Acid

Answer

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

Question 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

Answer

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

Question 22

Q

NSAIDS - NSAIDS CLASSIFICATION

Non-selective COX Inhibitor: Ketorolac

Answer

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

Question 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

Answer

A

Meloxicam
Celecoxib
Etoricoxib - Highly selective COX-2 inhibitor

Question 24

Q

NSAIDS - NSAIDS CLASSIFICATION

Nons-elective Inhibitors: Diclofenac

Answer

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

Question 25

Q

NSAIDS - NSAIDS CLASSIFICATION

COX-2 Selective Inhibitors: Meloxicam

Answer

A

 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

Question 26

Q

NSAIDS - NSAIDS CLASSIFICATION

Non-selective Inhibitors: Etodolac

Answer

A

 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

Question 27

Q

NSAIDS - NSAIDS CLASSIFICATION

COX-2 Selective Inhibitors: Celecoxib

Answer

A

 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

Question 28

Q

NSAIDS - NSAIDS CLASSIFICATION

Acetaminophen/Paracetamol

Answer

A

 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

Question 29

Q

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.

Answer

A

 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.

Question 30

Q

OPIOID DRUGS - RECEPTOR SUBTYPES
(mu)
Functions:
Endogenous Opioid Peptide Affinity:

Answer

A

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

Question 31

Q

OPIOID DRUGS - RECEPTOR SUBTYPES
(delta)
Functions:
Endogenous Opioid Peptide Affinity:

Answer

A

OPIOID DRUGS - RECEPTOR SUBTYPES
(delta)
Functions: Supraspinal and spinal analgesia; Modulation of hormone and neurotransmitter release
Endogenous Opioid Peptide Affinity: Enkephalins > endorphins and dynorphins

Question 32

Q

OPIOID DRUGS - RECEPTOR SUBTYPES
(kappa)
Functions:
Endogenous Opioid Peptide Affinity:

Answer

A

OPIOID DRUGS - RECEPTOR SUBTYPES
(kappa)
Functions: Supraspinal and spinal analgesia Psychotomimetic effects Slowed GI transit
Endogenous Opioid Peptide Affinity: Dynorphins >
endorphins and enkephalins

Question 33

Q

OPIOID DRUGS - RECEPTOR SUBTYPES

(mu) Receptor

Answer

A

 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

Question 34

Q

OPIOID DRUGS - RECEPTOR SUBTYPES

(delta) Receptor

Answer

A

 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

Question 35

Q

OPIOID DRUGS - RECEPTOR SUBTYPES

(kappa) Receptor

Answer

A

 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

Question 36

Q

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.

Answer

A

 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.

Question 37

Q

OPIOID DRUGS - PHARMACOKINETICS

Absorption:

Answer

A

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.

Question 38

Q

OPIOID DRUGS - PHARMACOKINETICS

Distribution:

Answer

A

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)

Question 39

Q

OPIOID DRUGS - PHARMACOKINETICS

Metabolism:

Answer

A

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

Question 40

Q

OPIOID DRUGS - PHARMACOKINETICS

Excretion:

Answer

A

readily excreted in kidneys when converted to polar metabolites, though small amounts of unchanged drug and also be found in the urine

Question 41

Q

OPIOID DRUGS - PHARMACODYNAMICS

Answer

A

 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.

Question 42

Q

OPIOID DRUGS - PHARMACODYNAMICS

Potential receptor mechanism of analgesic drugs:

Answer

A

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.

Question 43

Q

OPIOID DRUGS - Factors affecting PD

Cellular actions

Answer

A

 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

Question 44

Q

OPIOID DRUGS - Factors affecting PD

Relation of physiologic effects to receptor type

Answer

A

 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.

Question 45

Q

OPIOID DRUGS - Factors affecting PD

Receptor distribution and neural mechanisms of analgesia

Answer

A

 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.

Question 46

Q

OPIOID DRUGS - Factors affecting PD
Tolerance and dependence. Concepts include:
tolerance, receptor cycling, and receptor uncoupling

Answer

A

Opioid induced hyperalgesia: an increase in the

sensation of pain; can be produced by several opioids including morphine, fentanyl, and remifentanil.

Question 47

Q

OPIOID DRUGS - Organ System Effects

Answer

A

 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

Question 48

Q

OPIOID DRUGS - ADVERSE EFFECTS

Answer

A

 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)

Question 49

Q

OPIOID DRUGS - DRUG INTERACTIONS

Answer

A

 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

Question 50

Q

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)

Answer

A

 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

Question 51

Q

OPIOID DRUGS

RECEPTOR AGONISTS AND ANTAGONISTS: Mu receptors (MOR) agonists

Answer

A

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

Question 52

Q

OPIOID DRUGS

RECEPTOR AGONISTS AND ANTAGONISTS: Kappa receptors (KOR) agonists

Answer

A

o Nalbuphine, butorphanol, pentazocine

Question 53

Q

OPIOID DRUGS

RECEPTOR AGONISTS AND ANTAGONISTS: Mu receptor (MOR) antagonists

Answer

A

o Naloxone, naltrexone, nalmefene, methylnaltrexone

Question 54

Q

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)

Answer

A

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)

Question 55

Q

Mu agonists and their potency

Answer

A

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

Question 56

Q

OPIOID DRUGS - MORPHINE

Answer

A

 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

Question 57

Q

OPIOID DRUGS - HEROIN (Diamorphine)

Answer

A

 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

Question 58

Q

OPIOID DRUGS - THEBAIN (paramorphine)

Answer

A

 Natural form inactive; precursor for oxycodone, oxymorphone, nalbuphone, naloxone, naltrexone, buprenorphine, etorphine

Question 59

Q

OPIOID DRUGS - HYDROMORPHONE (Dihydromorphinone)

Answer

A

 Semi-synthetic; hydrophilic (poor bioavailability; no oral forms)
 Most potent in this group
 Metabolite can cause neurotoxic effects (myoclonus, hyperalgesia, restlessness)

Question 60

Q

OPIOID DRUGS - OXYMORPHONE

Answer

A

 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

Question 61

Q

OPIOID DRUGS - LEVORPHANOL:

Answer

A

 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

Question 62

Q

OPIOID DRUGS - CODEINE:

Answer

A

 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

Question 63

Q

OPIOID DRUGS - OXYCODONE:

Answer

A

 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

Question 64

Q

OPIOID DRUGS - HYDROCODONE

Answer

A

 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

Answer 65

A

 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

Answer 66

A

 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

Answer 67

A

 1/3 duration of action compared to fentanyl; fast acting; observable marked respiratory depression; fewer CV events; IV; seldom used

Answer 68

A

 Very potent analgesic and aesthetic; fast onset; IV, patch, intrathecal; marked respiratory depression

Answer 69

A

 Very potent analgesic and aesthetic; fast onset; IV, patch, intrathecal; marked respiratory depression

Answer 70

A

 Potent analgesic, mild sedative; fast onset (faster than fentanyl and sulfentanil); short duration of action (predictable termination of effect); synergistic with other hypnotics

Answer 71

A

Synthetic MOR an KOR Agonists: Potency

Tramadol, Tapendtadol: Mild or moderate pain = morphine Severe or chronic

Answer 72

A

 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

Answer 73

A

 Similar to Tramadol but more potent
 Weak serotonin reuptake inhibition (NERI)
 Blocked by adrenergic blockers

Answer 74

A

 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

Answer 75

A

 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

Answer 76

A

 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

Answer 77

A

 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

Answer 78

A

 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

Answer 79

A

NALOXONE
NALTREXONE
METHYLNALTREXONE

Answer 80

A

 Most commonly used on patients with acute opioid overdose
 Competitive inhibitor of new receptor agonists
 Short duration of action
 May produce overshoot and withdrawal

Answer 81

A

 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

Answer 82

A

 Potency similar to naltroxene
 Reverses peripheral opioid GI effects
 Poor lipid solubility
 Cannot pass BBB

Answer 83

A

 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

Answer 84

A

Morphine, Fentanyl, Remifentanil, Nalbuphine, Tramadol

Answer 85

A

Morphine, Nalbuphine, Hydrocodone, Tramadol

Answer 86

A

Loperamide, Diphenoxylate

Answer 87

A

Dextromethorphan

Answer 88

A

Methadone, Buprenorphine, Antagonists

Answer 89

A

 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)

Answer 90

A

 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)

Answer 91

A

 Complex set of aberrant behaviors typically associated with misuse of certain drugs, developing over time and with higher drug dosages

Answer 92

A

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)

Answer 93

A

 Slow tapering and removal of the drug
 Medications:
o Long acting MOR agonists (Methadone)
o Partial agonists (Buprenorphine)
o MOR antagonists (Naloxone, Naltrexone)

Answer 94

A

Aims of treatment:
o Relieve acute gouty inflammatory attacks
o Prevent recurrent gouty episodes and urate lithiasis
o Reverse hyperuricemia

Answer 95

A

Goals
o Control of inflammation:
 NSAIDs
 Colchicine
 Steroids
o Reverse hyperuricemia
 Under excreters – Uricosuric agents
 Over producers – Xanthine oxidase inhibitors

Answer 96

A

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

Answer 97

A

o Non-selective COX inhibitors
o COX 2 inhibitors
o Aspirin

Answer 98

A

Non-selective COX inhibitors
 Naproxen
 Ibuprofen
 Mefenamic Acid
 Indomethacin
 Sulindac
 Aspirin

Answer 99

A

COX 2 inhibitors
 Celecoxib
 Etoricoxib
 Diclofenac
 Meloxicam

Answer 100

A

Aspirin
 Low dose inhibit urate excretion, can cause renal calculi and inhibits uricosuric agents
 Highly discouraged to give >5 grams per day

Answer 101

A

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

Answer 102

A

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

Answer 103

A

 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

Answer 104

A

 to reverse hyperuricemia of underexcreters



Answer 105

A

 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).

Answer 106

A

 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.

Answer 107

A

ABATACEPT

2. RITUXIMAB

Answer 108

A

 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

Answer 109

A

 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.

Answer 110

A

 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.

Answer 111

A

 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)

Answer 112

A

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

Answer 113

A

 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.

Answer 114

A

 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

Answer 115

A

 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

Answer 116

A

METHOTREXATE
SULFASALAZINE
AZATHIOPRINE
CYCLOPHOSPHAMIDE

Answer 117

A

AICAR which accumulates intracellularly, inhibits AMP deaminase
AMP accumulation
AMP is released and converted to adenosine (potent inhibitor of inflammation)
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

Answer 118

A

 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

Answer 119

A

 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

Answer 120

A

 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

Answer 121

A

 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

Answer 122

A

 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.

Answer 123

A

 Effective in rheumatoid arthritis and reduces radiologic disease progression in juvenile chronic arthritis, and in ankylosing spondylitis with its associated uveitis

Answer 124

A

 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.

Answer 125

A

 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

Answer 126

A

 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.

Answer 127

A

 Prodrug of mercaptopurine and functions as an antimetabolite
 Rheumatoid arthritis
 Showed efficacy in psoriatic arthritis, reactive arthritis, polymyositis, systemic lupus, erythematosus, Bechet’s disease

Answer 128

A

 Bone marrow suppression
 Gastrointestinal disturbances
 Infection risk
 Rarely: lymphoma risk, fever and rash, hepatotoxicity signal acute allergic reaction

Answer 129

A

 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

Answer 130

A

 Active against rheumatoid arthritis: 2 mg/kg/day given orally
 Different dosage when given intravenously

Answer 131

A

 Wegner’s granulomatosis
 Systemic lupus erythematosus
 Vasculitis
 Other severe rheumatic diseases

Answer 132

A

 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

Answer 133

A

 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

Answer 134

A

 Treatment of rheumatoid arthritis: 2 g/d

 There is no well-controlled data regarding efficacy

Answer 135

A

 Treatment of renal disease due to systemic lupus erythematosus
 Vasculitis
 Wegner’s granulomatosis

Answer 136

A

 Gastrointestinal disturbance (nausea, vomiting, diarrhea, dyspepsia and abdominal pain)
 Can cause hepatotoxicity, leucopenia, thrombocytopenia and anemia
 Headache
 Hypertension
 Reversible myelosuppression (primarily neutropenia)

Answer 137

A

CYCLOSPORINE
CHLOROQUINE &HYDROXYCHLOROQUINE
LEFLUNOMIDE

Answer 138

A

 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.

Answer 139

A

 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

Answer 140

A

 Rheumatoid arthritis and retards the appearance of new bony erosions
 Used for systemic lupus erythematosus, polymyositisand dermatomyositis, Wegener’s granulomatosis, and juvenile chronic arthritis

Answer 141

A

 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

Answer 142

A

 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

Answer 143

A

 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

Answer 144

A

 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

Answer 145

A

 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

Answer 146

A

 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

Answer 147

A

 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.

Answer 148

A

 Approved for the treatment of rheumatoid

arthritis including inhibition of bony damage

Answer 149

A

 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

Answer 150

A

ADALIMUMAB

2. INFLIXIMAB

Answer 151

A

 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

Answer 152

A

 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

Answer 153

A

 Rheumatoid arthritis
 Ankylosing spondylitis
 Psoriatic arthritis
 Juvenile idiopathic arthritis
 Plaque psoriasis
 Crohn’s disease
 Decreases the rate of formation of new erosions

Answer 154

A

 Bacterial infections
 Increased macrophage-dependent infection (including tuberculosis and other opportunistic infections)
 Rarely: clinical lupus, leucopenia, vasculitis

Answer 155

A

 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

Answer 156

A

 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

Answer 157

A

 Rheumatoid arthritis
 Ankylosing spondylitis
 Psoriatic arthritis
 Juvenile idiopathic arthritis
 Plaque psoriasis
 Crohn’s disease

Answer 158

A

 Bacterial infections

 Increased macrophage-dependent infection (including tuberculosis and other opportunistic infections)

Answer 159

A

 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

Answer 160

A

 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

Answer 161

A

 Rheumatoid arthritis
 Ankylosing spondylitis
 Psoriatic arthritis
 Juvenile idiopathic arthritis
 Plaque psoriasis
 Crohn’s disease

Answer 162

A

 Bacterial infections

 Increased macrophage-dependent infection (including tuberculosis and other opportunistic infections)

Answer 163

A

 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

Answer 164

A

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

Answer 165

A

conjugation with glucoronic acid = ester and ether glucoronides
conjugation with glycine = salycyluric acid
oxidation = gentisic acid