Duan: Pharm Control of Pain and Inflammation Flashcards
1
Q
What is the method of action of aspirin?
A
covalently and irreversibly modifies COX1 and COX2 by acetylating serine 5-30 and preventing arachidonic acid from binding
2
Q
Which COX pathway does aspirin block? Why is this important?
A
Both COX 1 and COX2; causes both a clinical and an adverse effect
3
Q
Aspirin can inhibit (blank) production, which suppresses platelet adhesion and aggregation. This is why aspirin is the most commonly used antiplatelet agent for both the management of acut ischemic stroke and for prevention of stroke.
A
thromboxane A2
4
Q
In what types of patients is use of salicylates contraindicated in?
A
patients with bleeding disorders
5
Q
Salicylates are not recommended in pregnant women. What two things can they cause?
A
postpartum hemorrhage
premature closure of the fetal ductus arteriosus
6
Q
The effects of aspirin are (blank) dependent
A
dose-dependent
7
Q
What effects does a low dose of aspirin have?
What effects does an intermediate dose have?
What effects does a high dose have?
A
blocks platelet aggregation;
antipyretic, analgesic;
anti-inflammatory
8
Q
5 clinical uses of aspirin
A
- fever
- pain (mild-to-moderate)
- rheumatic fever
- inflammatory diseases (rheumatoid arthritis, pericarditis)
- lower doses can reduce the risk of death from a heart attack or risk of stroke
9
Q
What’s considered a low dose of aspirin? What’s a high dose?
A
low is less than 300 mg/day
high is 2400-4000 mg/day
10
Q
What type of acids are salicylates? What’s the pKa?
A
weak organic acids; pKa of 3.5
11
Q
Salicylates are rapidly absorbed from the stomach as well as the intestine where the pH is (blank) and favors (blank)
A
low; absorption
12
Q
At low and moderate doses of salicylate, what “order” elimination is occurring? At what total body salicylate concentration does elimination become zero order?!
A
1st order; >3.5g/day or 600mg
13
Q
How would you get aspirin out in the urine after an overdose?
A
give a base to raise the urine pH above 8, so that clearance is increased by 4 fold
14
Q
What is the plasma half-life of salicylate? The half-life is dose dependent, though.
If dose is 300-650, what is the half-life?
If dose is 1g, what is the half-life?
If dose is 2g, what is the half-life?
If high dose (>3.5g/day) or overdose, what is the half-life?
A
~15 minutes; 3.1 to 3.2 hours; 5 hours 9 hours 15 HOURS!!!
15
Q
why is admin of aspirin dose-dependent?
A
enzymes for glycine and glucuronide conjugation become saturated, so drug cannot be effectively eliminated
16
Q
What is the difference between first order and zero order elimination?
A
Zero order elimination: fixed elimination - the same amount is eliminated, regardless of dose.
First order: with more drug plasma, there is faster elimination.
17
Q
3 phases of inflammation
A
- acute
- subacute or delayed
- chronic proliferative
18
Q
What phase of inflammation is described:
vasodilation and capillary permeability
A
acute
19
Q
What phase of inflammation is described:
infiltration of leukocytes and phagocytes
A
subacute/delayed
20
Q
What phase of inflammation is described:
tissues regeneration and fibrosis
A
chronic proliferative
21
Q
List 5 symptoms of inflammation
A
- redness
- heat
- pain
- swelling
- loss of function
22
Q
Characterized by inflammatory changes and symptoms (pain, heat, redness, and swelling) and subsequent tissue damage with atrophy and rarefaction of the bones. In late stages, deformity and ankylosis develop.
A
arthritic disorders
23
Q
Causes of arthritic disorders are complex and usually cannot be cured. What is the goal of treatment?
A
relieve inflammation control pain improve function prevent further joint damage improve quality of life
24
Q
In the inflammatory cascade, what activates the adaptive or innate immune system? Both of these result in leukocyte and endothelial cell activation. What do these go on to activate? What does this lead to?
A
a perceived threat, infection, or tissue injury;
biochemical inflammatory mediators;
inflammation
25
Symptoms of inflammation are caused by a series of biochemical mediators. List a few.
```
vasoactive amines
platelet activating factor
complement
kinin system
cytokines
NO
adhesion molecules
arachidonic acid metabolites
```
26
What are four arachidonic acid metabolites?
thromboxane A2
HETE
leukotrienes
prostaglandins
27
What do the products of the LOX pathway, (HETE, Leukotrienes, and Lipoxins) cause?
phagocyte mobilization
changes in vascular permeability
inflammation
28
What do the products of the COX pathway (prostaglandins, prostacyclin, and thromboxane) cause?
inflammation
29
Arachidonic acids are (blank) carbon fatty acid chains that produce (blank) and (blank). They are immune system (blank)
20; prostanoids; leukotrienes; modulators
30
Membrane phospholipids form arachidonic acid via what enzyme? There are two pathways, COX-1 and COX-2. Which is constitutive and under physiological regulation? Which is inducible, and results in an inflammatory response?
phospholipase A2
COX-1
COX-2
31
The COX1 reaction forms prostaglandins associated with what three things?
platelet function
GI mucosal integrity
renal function
32
The COX2 reaction forms prostaglandins associated with what three things?
inflammation
pain
fever
33
What do prostaglandins do to pain fibers?
directly sensitize them, causing them to respond to normally innocuous stimuli
34
What is it called when a normally innocuous stimulus becomes painful?
hyperalgesia
35
What does subdural injection of PGE1 with small amounts of bradykinin or histamine cause?
headache and pain
36
A common cause of fever is the production of (blank) released by neutrophils fighting a bacterial infection.
pyrogens
37
List three pyrogens
cytokine IL-1
IL-6
TNF-alpha
38
Pyrogens are thought to cause release of (blank) in the preoptic area of the hypothalamus. The net effect is an imbalance in heat production leading to (blank). Inhibition of (blank) synthesis in the CNS can cause cutaneous vasodilation and increased heat loss, thus can reduce the (blank). A general reduction of prostaglandin synthesis in the brain and in inflamed tissues probably also reduces the symptoms of fever.
prostaglandins; fever; prostaglandin; fever
39
What do 5-LOX inhibitors and leukotriene receptor antagonists do?
block the LOX pathway --> block formation of inflammatory mediators
40
What do NSAIDS do?
block the COX pathway --> block the formation of inflammatory mediators
41
What do corticosteroids (ex: prednisone) block?
phospholipase A2 --> can't produce arachidonic acid from phospholipids
42
1950: Dr. Lawrence L. Craven of California describes his observations about aspirin's action as a (blank), and begins prescribing daily doses to his patients as a means of preventing heart attacks
1971: British pharmacologist John R. Vane discovers aspirin's mechanism of action — that it inhibits the production of hormone-like substances in the body called (blank).
1982: Sir John R. Vane is co-winner of the Nobel Prize in Medicine for his discoveries concerning prostaglandins.
blood-thinner; prostaglandins;
43
If you take antacids with aspirin, what will this cause?
reduced rate of aspirin absorption
44
If you take heparin or oral anticoagulants with aspirin, what will this cause?
hemorrhage
45
If you take probenecid or sulfinpyrazone with aspirin, what will this cause?
decreased urate excretion (not good for gout patients)
46
If you take bilirubin, phenytoin, naproxen, sulfinpyrazone, thiopental, thyroxine, or triiodothyronine with aspirin, what will this cause?
increased plasma concentration leading to prolonged half-lives, therapeutic effects, and toxicity
47
List some adverse effects of aspirin
```
GI symptoms
allergic reaction
CNS toxicity
salicylate reaction
renal damage
hematologic effects
metabolic acidosis
```
48
What three things can overdose of aspirin lead to?
Reye's syndrome (kids)
severe hepatic damage
encephalopathy
49
What dose of aspirin causes salicylism (overdose or poisoning)? What are the symptoms? In children, what are some common signs of toxicity?
>5g/d of aspirin
In adults, tinnitus, hearing loss, vertigo
Acidosis, hyperventilation, and lethargy in children
50
What can you due to "rescure" a pt that has overdosed on aspirin?
1. NaHCO3 alkalinize urine with bicarb (A-)
2. correct acid-base disturbance
3. replace electrolytes and fluids
4. cool
5. forced diuresis, hemodialysis
6. gastric lavage or emesis
51
What's "antipyretic" mean anyway? What about analgesic?
reduces fever; pain reliever
52
What effects does Ibuprofen have?
```
antipyretic
analgesic
anti-inflammatory
mild & short-lasting antiplatelet effect
vasoconstriction
```
53
What are some bad things that ibuprofen can cause?
long-term use can cause hypertension in women
vision damage
weaker GI reactions
54
NSAID commonly used for the reduction of pain, fever, inflammation, stiffness. Clinical applications: migraine, osteoarthritis, gout, rheumatoid arthritis, psoriatic arthritis, kidney stones, ankylosing spondylitis, menstrual ramps, tendinitis and bursitis. primary dysmenorrhea
Naproxen (aleve)
55
NSAID with stronger efficacy, controlling special types of fever. Treatment of ankylosing spondylitis, reiter syndrome, and acute gouty arthritis
Indomethacin (indocin)
56
Indomethacin is not recommended as a simple analgesic or antipyretic. Why? When is it appropriate to use in children?
potential for severe adverse effects (bleeding, ulceration, headache);
use in children only for speed of the closure of a patent ductus arteriosus in premature infants
57
Which NSAIDs are proprionic acid derivatives?
naproxen (aleve)
| indomethacin (indocin)
58
NSAID which an oxicam derivative of enolic acid. Has a half-life of 45 hrs. It is a long lasting anti-inflammatory and analgesic agent.
Bleeding and ulceration are more than other NSAIDs. Long term use can lead to hemorrhage and ulcers in GI tract.
piroxicam
59
Selectively Inhibits, especially at its low therapeutic dose, COX-2 over COX-1. In synovial fluid, concentrations range from 40% to 50% of those in plasma.
The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma.
The significance of this penetration is unknown, but it may account for the fact that it performs exceptionally well in treatment of arthritis in animal models.
meloxicam (mobic)
60
```
Equal to ASA in analgesic and antipyretic effects
Lack of anti-inflammatory effects (not generally classified as NSAIDS)
no gastric irritation (pKa 9.5)
no platelet function interference
half life 2 –3 hr
weak inhibitor of COX-1, COX-2; COX-3?
not contraindicated for asthma
not associated with Reye’s Syndrome
```
Acetaminophen (Tylenol)
61
What is the major difference between Tylenol (acetaminophen) and aspirin (NSAIDs)
Tylenon has a WEAK anti-inflammatory effect, while NSAIDs have a STRONG one
62
What is the major concern with acetaminophen? What dose should not be exceeded?
toxic metabolite inactivated by glutathione and at high doses can lead to liver toxicity; DO NOT EXCEED 4Gg/day.
63
To treat acetaminophen toxicity, what should be administered by gastric lavage? What should be administered to replenish glutathione stores in the liver?
activated charcoal
| N-acetyl cysteine
64
What is the method of action of NSAIDs?
NSAIDs inhibit the enzymes that produce prostaglandin H synthase (COX) which converts arachidonic acid to prostaglandins, TXA2, and prostacyclin.
65
What does aspirin do to COX-1 and COX-2 that distinguishes it from other NSAIDs?
IRREVERSIBLY inactivates COX-1 and COX-2 by acetylation of a specific serine residue; other NSAIDs use reversibly inhibit COX-1 and COX-2
66
How do NSAIDs reduce pain?
peripheral inhibition of prostaglandin production;
inhibition of pain stimuli at a subcortical site. They prevent the potentiating action of prostaglandins on mediators of peripherl nerve stimulation
67
How do NSAIDs reduce fever?
inhibition of prostaglandins induced by IL-1 and IL-6 in the hypothalamus - this resets the thermoregulatory system, which leads to vasodilation and increased heat loss
68
Which NSAID is only a mild anti-inflammatory drug?
acetaminophen
69
Which NSAID is an antiplatelet -- inhibits platelet aggregation, prolong bleeding time; have anticoagulant effects?
aspirin
70
First-line drugs used to arrest inflammation and the accompanying pain of rheumatic and nonrheumatic diseases, including rheumatoid arthritis, juvenile arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, Reiter syndrome, and dysmenorrhea, hyperuricemia (acute gout,
NSAIDs
71
Do inflammation of bursitis and tendonitis also respond to NSAIDs
True
72
Do NSAIDs significantly reverse the progress of rheumatic disease? What DO they do?
No; they slow destruction of cartilage and bone and allow patients increased mobility and use of their joints
73
Effect of NSAIDs?
Clinical usage?
Side effects?
inhibit PGs and TxA2 synth by inhibiting COX;
rheumatic, rheumatoid, trauma;
GI reactions
74
Effects of glucocorticoids?
Clinical use?
Side effects?
inhibition of phospholipase A2;
various inflammation;
various side effects, such as metabolism disturbance, damage of defense
75
NSAIDs can me used to alleviate mild-to-moderate pain (headache, myalgia, neuralgia, post-op pain, dysmenorrhea). NSAIDs are more effective against pain associated with (blank) structures than with pain associated with the viscera.
integumental
76
Compare effects, clinical usage, and side effects of NSAIDs vs opioids
NSAIDs inhibit PGs and TxA2 synthesis by inhibiting COX, while opioids stimulate opioid receptors. NSAIDs are used clinically for headache, toothache, neuralgia, courbature, and menalgia, while opioids are used for various pain including severe pain. Side effects of NSAIDs include GI reactions, but no addiction. Sife effects of opioids include addiction :(
77
NSAIDs reduce elevated body temp, with little effect on normal body temp (anti-pyresis). They relieve but do not eliminate the cause of the fever, which is often infection. What NSAID is recommended as a substitute for children with fever of unknown etiology?
acetaminophen
78
The use of aspirin and other salicylates to control fever during viral infections in children and adolescents is associated with an increased incidence in (blank)
Reye's syndrome (an illness characterized by vomiting, hepatic disturbances, and encephalopathy)
79
Effects: inhibits thermotaxic center in the the hypothalamus. The body temp changes according to the environment.
Clinical usage: artificial hibernation & hypothermic anesthesia
Side effects: extrapyramidal effects
Chloropromazine
80
NSAIDs inhibit production of prostaglandins (PGs) and alleviate most of the pathologic effects associated with inflammation, but they also interfere with the physiologic role of PGs.
Consequently, long-term therapy with nonspecific NSAIDs is frequently limited by their adverse effects, particularly those caused by erosion of (blank).
gastric mucosal protection
81
Adverse GI effects of high-dose aspririn use
```
nausea
vomiting
diarrhea/constipation
dyspepsia
ulceration or aggravation of existing ulcers
gastric bleeding
```
82
What is the mechanism of GI effects of NSAIDs?
could be the direct chemical effect of an organic acid on gastric cells
also, a decrease in production of prostaglandins and loss of protection from gastric mucosa
83
What can help decrease the damaging GI effects of NSAIDs?
admin of PGE2 (misoprostol)
84
- substitution of enteric-coated or timed-release preparations
- the use of nonacetylated salicylates
- taken with food or after meal
ways to decrease gastric irritation caused by NSAIDs
85
Specifically inhibition of COX-2 would reduce the inflammatory response and pain but not inhibit the cytoprotective action of prostaglandins in the stomach, which is largely mediated by COX-1. What are a few COX-2 selective drugs?
Celecoxib (Celebrex)
Rofecoxib (Vioxx)
Meloxicam (Mobic)
Valdecoxib (Bextra)
86
What happened to the incidence of endoscopic gastroduodenal ulcers with a COX-2 specific inhibitor Celecoxib?
Rates of gastroduodenal ulceration with naproxen were statistically higher (*P < 0.01) than rates with celecoxib or a placebo.
87
Is Celecoxib (Cox-2 specific inhibitor) associated w an increase in cardio events for duration of use from 12-52 weeks? Is it associated with increased cardio events compared to non-selective NSAIDs?
No and no
88
Several COX-2 selective drugs have been taken off the market due to doubling the incidence of heart attack and stroke. Which one is still on the market, but has a boxed warning highlighting the potential for increased risk of cardio events?
Celecoxib
89
What is the following adverse effect of NSAIDs:
relatively uncommon with the use of aspirin (0.3% of patients)
Results in rash, bronchospasm, rhinitis, edema, or an anaphylactic reaction with shock, which may be life threatening.
The incidence of intolerance is highest in patients with asthma, nasal polyps, recurrent rhinitis, or urticaria. Aspirin should be avoided in such patients.
Cross-hypersensitivity may exist:
to other NSAIDs
to the yellow dye tartrazine, which is used in many pharmaceutical preparations.
hypersensitivity
90
What's this?
Prostaglandins are involved in regulating renal blood flow. Chronic users of NSAID analgesics disrupt this regulatory function, which may lead to papillary necrosis and secondary interstitial nephritis. The damage may progress to irreversible renal insufficiency.
This is not thought to be a problem for low-dose chronic use in prophylaxis of MI.
Phenacetin has been linked to this problem, but other agents (such as acetaminophen) probably also cause nephropathy. At one time, the prevalence of APCs (aspirin, phenacetin and caffeine combos no longer used in the US) was strongly associated with renal disease.
analgesic abuse nephropathy
91
MOA of aspirin (3 PI's)
pyrogen inhibitor
pain inhibitor
platelet inhibition
92
Clinical use of aspirin
low dose?
middle dose?
high dose?
low: platelet aggregation (PA)
middle: pain and fever (PF)
high: rheumatoid arthritis (RA)
93
Major side effects of aspirin (HUMBLe ASPIRIN)
hepatotoxicity
uric acid in serum increase in low doses
metabolic acidosis
bleeding GI
```
salicylism
peptic ulcers
irritation of GI tract
Reye's syndrome and respiratory changes
intolerance to glucose
nephrotoxicity
```
94
Major side effects of Ibuprofen mneumonic
AA worsens GI IBUPROFEN
```
aspetic meningitis
ashtma worsens GI
irritation of GI tract
bleeding
ulceration
pruritus
rush
ototoxicity, leading to tinnitus and dizziness
fluid retension
eye disturbances
nephrotoxicity
```
95
Major side effects of celecoxib (CELECoxib)
cardio thrombotic events following long term use
edema
less GI irritation, bleeded and ulcers than other NSAIDs
elevated blood pressure
caution: as a sulfonamide derivative may cause allergic reaction
96
Acetaminophen is an APAP. What does that mean?
anti-pain
| anti-pyretic
97
Acetaminophen is "a set of minor fence for all COXs." What does this mean?
weak inhibitor of all COXs
98
These drugs inhibit eicosanoid production, by inhibiting induction of COX-2 expression and Lipcortin
corticosteroids (glucocorticoids) --> prednisone and dexamethasone
99
How do corticosteroids cause their anti-inflammatory effects?
they regulate gene transcription of IFN-gamma, GM-CSF, IL-2, 3, 6, 8, and 12 and TNF-alpha
100
Slow onset of effect
Most effective anti-inflammatory drug
Worst drug for adverse effects
corticosteroids
101
What are some results of toxicity of chronic systemic glucocorticoids?
```
euphoria
buffalo hump and moon face
cataracts
thinning skin
easy bruising
poor wound healing
glucose intolerance
osteoporosis** (prevent w bisphosphonates)
gastric ulcers** (prevent w omeprazole or misoprostol)
increased susceptibility to infection
growth inhibition in children
```
102
Anti-inflammatory and immunosuppressive effects
Can be used to bridge gap between initiation of DMARD therapy and onset of action
Intra-articluar injections can be used for individual joint flares and this is the major benefit in rheumatic arthritis
pros of corticosteroids
103
Does not conclusively affect disease progression
Tapering and discontinuation of use often unsuccessful
Low doses result in skin thinning, ecchymoses, and Cushingoid appearance
Significant cause of steroid-induced osteopenia
cons of corticosteroids
104
List 4 corticosteroids with a more potent anti-inflammatory activity than cortisol
cortisone
prednisone
triamincinolone
dexamethasone
105
MOA of corticosteroids
Gene regulation: binding to nuclear glucocorticoid receptors (GR) → the glucocorticoid response element (GRE) in the nucleus→ gene transcription and expression → ↓inflammation and↓ immunity
106
Clinically used In ATTAACK
Clinical use: (In ATTAACK the expanded defense)
Inflammation: RA and Asthma
Adrenal insufficiency hormone supplement for cortisone
Tumor: Acute lymphoblastic leukemia (ALL), lymphomas, multiple myeloma
Transplantation: for prophylaxis and treatment of organ rejection
Autoimmune disorders: such as SLE
Allergy: such as angioedema
Cerebral edema and Cancer-related hypercalcemia
Kidney diseases (nephrotic syndrome)
107
2 major corticosteroids
prednisone
| dexamethasone
108
Major side effects of corticosteroids (IM 4 HOPEs)
Infections Iatrogenic Cushing’s syndrome, Myopathy
Hyperglycemia, Hypertension, Hypokalemia, Hypomania
Osteoporosis Osteonecrosis (aseptic necrosis of the hip)
Peptic ulcers Pancreatitis, Edema, Eye disorder (cataracts)
109
```
a familial disease characterized by:
recurrent hyperuricemia
arthritis
severe pain
caused by deposition of uric acid xtals in the joint space with hyperuricemia, resulting in an inflammatory reaction. Granulocytes phagacytose the xtals. Since lactate production is fairly high in synovium, the acidic environment promotes further xtalization. Symptoms are typically seen in the distal phalangial joints.
```
gout
110
an alkaloid used for relief of inflammation and pain in acute gouty arthritis. Drug of choice for acute attacks.
Reduction of inflammation and relief from pain occur 12—24 hours after oral administration.
The mechanism of action in acute gout is unclear but it may
prevent polymerization of tubulin into microtubules and inhibits leukocyte migration and phagocytosis.
inhibit cell mitosis.
colchicine
111
Colchicine:
Adverse effects after oral admin?
IV admin can be used, but what's the risk?
What can high doses cause?
nausea, voomiting, abdominal pain, DIARRHEA
IV admin can lead to sloughing skin and subcutaneous tissue
high doses can result in liver damage and blood dyscrasias
112
are organic acids used to treat gout
reduce urate levels by acting at the anionic transport site in the renal tubule to prevent reabsorption of uric acid.
used for chronic gout, often in combination with colchicine.
probenecid
| sulfinpyrazone
113
Increased urinary concentration of uric acid may result in the formation of (blank) (urolithiasis). This risk is decreased with:
the ingestion of large volumes of fluid or
alkalinization of urine with potassium citrate.
urate stones
114
Common adverse effects of probenecid and sulfinpyrazone?
GI disturbance
| dermatitis
115
Drug used for gout. Inhibits the synthesis of uric acid by inhibiting xanthine oxidase, an enzyme that converts hypoxanthine to xanthine and xanthine to uric acid.
Is metabolized by xanthine oxidase to alloxanthine, which also inhibits xanthine oxidase. Also inhibits de novo purine synthesis.
Commonly produces gastrointestinal disturbances and dermatitis. This agent more rarely causes hypersensitivity, including fever, hepatic dysfunction, and blood dyscrasias.
Should be used with caution in patients with liver disease or bone marrow depression.
allopurinol
116
This drug blocks the action of xanthine oxidase by substrate competition and is also metabolized by it to form alloxanthine which also inhibits xanthine oxidase
Allopurinol
117
What is acute gout treated with? Why are these preffered to colchicine?
treated with nonsalicylate NSAIDs; preferred because colchicine causes diarrhea
118
What is chronic gout treated with? One thing increases elimination of uric acid, and the other inhibits uric acid production...
1. uricosuric agents (probenecid and sulfin)
| 2. allopurinal
119
Maintenance drugs are allopurinol (Zyloprim), probenecid (Benemid) and sulfinpyrazone (Anturane).
Colchicine needed for several weeks to prevent acute attacks while serum levels are being lowered
Need high fluid intake, alkaline urine to prevent renal calculi
guidelines for treating gout
120
A category of otherwise unrelated drugs defined by their use in rheumatoid arthritis to slow down disease progression
disease-modifying antiarthritic drugs (DMARDs)
121
How do DMARDs differ from NSAIDs and corticosteroids?
they RETARD OR HALT the underlying progression**
they limit the amount of joint damage that occurs in rheumatoid arthritis while lacking the anti-inflammatory and analgesic effects observed with NSAIDs.
they have an effect on rheumatoid arthritis that is different and more delayed in onset than either NSAIDs or corticosteroids.
122
This DMARD is a purine synthesis inhibitor
azathioprine
123
This DMARD is a calcineurin inhibitor
ciclosporin
124
This DMARD is a purine metabolism inhibitor
methotrexate
125
This DMARD is a pyrimidine synthesis inhibitor
leflunomide
126
Infliximab
Adalimumab
Entanercept
Anakinra
anti-TNF alpha DMARDs
