IV MPPT Lecture for Nurses

1. Allan D. Corpuz MD, FPCP
!
Fellow, Section of Rheumatology
UP-Philippine General Hospital
IV Methylprednisolone Therapy
for Systemic Lupus Erythematosus

2. Pre-test
1. Methylprednisolone is a:!
a. mineralocorticoid b. glucocorticoid
!
2. It is used for the following diseases:!
a. post-traumatic osteoarthritis b. COPD exacerbations
c. SLE nephritis d. all of the above
e. none of the above
!
3. The effect of methylprednisolone on the immune system is to promote
inflammation:!
a. true b. false

3. Pre-test
4. Pulse therapy is done to:!
a. decrease side effects and enhance therapeutic effects
b. enhance therapeutic effects despite enhanced side effects
!
5. The usual adult MPPT dose is:!
! ! ! a. 1 gm/day for 7 days b. 1gm/day for 3 days
c. 1 gm/day for 5 days d. any of the above

4. Methylprednisolone
• Mechanism of Action
• Indications
• Administration
• Adverse Effects

5. Mechanism of Action
• Is a synthetic glucocorticoid
• Glucocorticoids
• steroid hormones, naturally occurring (i.e. cortisol) and synthetic
drugs (prednisone, hydrocortisone, dexamethasone,
methylprednisolone)

7. Mechanism of Action
• Is a synthetic glucocorticoid
• Glucocorticoids
• steroid hormones, naturally occurring (i.e. cortisol) and
synthetic drugs (prednisone, hydrocortisone, dexamethasone,
methylprednisolone)
• functions to regulate BP and electrolyte balance and
physiologic stress response
• effect on immune system: reduces inflammation and inhibits
immune response

8. Genomic & Non-Genomic Effects
At any therapeutic
relevant dosage
High doses/Pulse
Therapy
- Exhibit pharma effect via Classic
Genomic mechanisms
- At least 30mins before clinical
effect begins to show*
- Early rapid non-genomic effect
and a delayed and more sustained
classic genomic effect (biphasic)**
- Non-genomic mechanisms rapid/
within minutes via (1) specific
receptor mediated activity or
(2)non-specific membrane-
associated physicochemical
activity***
Genomic/Non-genomic effects cannot be separated clinically!
*Barnes(PJ:(An-.inflammatory(ac-ons(of(glucocor-coids:(molecular(mechanisms,(Clin(Sci((Lond)(94:557–572,(1998.(
**Lipworth(BJ:(Therapeu-c(implica-ons(of(non.genomic(glucocor-.(coid(ac-vity,(Lancet'356:87–89,(2000.((
***BuRgereit(F,(Wehling(M,(Burmester(GR:(A(new(hypothesis(of(modular(glucocor-coid(ac-ons:(steroid(treatment(of(rheuma-c(diseases(revisited,(Arthri,s'
Rheum'41:761–767,(1998.((
(

9. Genomic Mechanisms
Transactivation
Transrepression
- Responsible for side
effects of GC (DM,
Osteoporosis, Skin
atrophy, Growth
retardation and
Cushingoid appearance
- Anti-inflammatory effect
within a few days
- Responsible for anti-
inflammatory effects (within
a few hours)
SELECTIVE GC AGONISTS: MORE FAVORABLE BALANCE*

10. Genomic Mechanisms
Transactivation
Transrepression
- Responsible for side
effects of GC (DM,
Osteoporosis, Skin
atrophy, Growth
retardation and
Cushingoid appearance
- Anti-inflammatory effect
within a few days
- Responsible for anti-
inflammatory effects (within
a few hours)
SELECTIVE GC AGONISTS: MORE FAVORABLE BALANCE*

13. Steroid Dosing (Prednisone Equivalent)
• Low dose: <7.5 mg
• Medium dose: 7.5-30mg/day
• High dose: >30 but <100 mg/day
• Very high: >100 mg/day
• Pulse therapy

14. Indications
in
Rheumatologic
Diseases
Acute exacerbations of
rheumatic disorders:
!
✴ Post-traumatic OA and
synovitis
✴ Rheumatoid Arthritis
✴ Psoriatic arthritis
✴ Ankylosing spondylitis
✴ SLE
✴ Polymyositis
✴ Polyarteritis nodosa
✴ Acute rheumatic carditis

15. Acute exacerbations of
rheumatic disorders:
!
✴ Post-traumatic OA and
synovitis
✴ Rheumatoid Arthritis
✴ Psoriatic arthritis
✴ Ankylosing spondylitis
✴ SLE
✴ Polymyositis
✴ Polyarteritis nodosa
✴ Acute rheumatic carditis

16. Pulse GC
• first used in patients with SLE
to treat DPGN
• Pulse-GC doses (0.5-1g of MP
IV daily) also effective for
pneumonitis, serositis,
vasculitis and
thrombocytopenia
• also for neuropsychiatric SLE*

17. Pulse GC
• for very severe DPGN or RPGN:
• Pulse-GC doses work faster than
oral high dose GC therapy
• probably permit use of both a
moderate dose of GCs (0.5mkd)
at therapy initiation and a faster
tapering dose of GC
• synergistic with IV
Cyclophosphamide
• Pulse GC: nongenomic effects that
allow faster and more effective
action than conventional high dose
GCs

18. Pulse GC
• RCT on RA: Pulse-GC cause no
bones loss compared to oral GC
• Lipodystrophy and diabetogenic
effects of pulse GC may also be
less severe
• Complications such as GC-
induced osteonecrosis, major
infections and mood disorders or
psychosis may still occur
• Seizures, myalgia, arthralgias,
dangerous cardiac arrhythmias
secondary to potassium deficits
and anaphylaxis: rare but reported

19. High vs Low dose Pulse GC
• Badsha et al: 55 patients!
• 500mg MP IV x 3 days: fewer serious infections (7/26) but same therapeutic
response
• Most infections were gram-negative bacteria and occurred within 1 month of
administration
• Hypoalbuminemia was a risk factor
• Magbitang, et al.: 42 patients!
• MEX-SLEDAI: 14
• 83% had lupus nephritis
• Anemia, hypoalbuminemia and significant proteinuria
• 67%: 1gram/day x 3 days
• 64% In-hospital complication rate, 21% mortality rate
• High dose MPPT: high In-hospital complication rate, but no mortality
• Nephritis and low platelet counts at baseline associated with mortality

20. Methylprednisolone Na succinate
Available preparations
• Pfizer (Zuellig)!
• Solu-Medrol!
• US FDA Pregnancy Category: C!
• Regulatory Classification: Rx!
• pH: 7-8 when reconstituted!
• Packaging:!
• Solu-Medrol powd for inj 1g/16mL (P5,030.97)
• Solu-Medrol powd for inj 125mg/2mL (Act-O-Vial) (P1212.04)
• Solu-Medrol powd for inj 40mg/mL (Act-O-Vial) (P644.55)
• Solu-Medrol powd for inj 500mg/8mL (P3467.74)

21. Dosing
• Pulse therapy (“MPPT”):
• suprapharmacologic doses; intermittent manner to
enhance the therapeutic effect and reduce the side effects
• arbitrarily defined as treatment with more than 250 mg
prednisone or its equivalent per day, for one or more
days1
• No guidelines on the frequency or timing of
administration of the i.v. pulses; includes single boluses,
daily boluses given for 3 days in a row, or on alternate days
for up to 12 days1
1 Sinha A, Bagga A. Pulse Steroid Therapy. Indian J Pediatr 2008; 75 (10): 1057-1066

22. Administration
• IM Injection: - Use solution as reconstituted1 and inject a maximum of 250 mg deep into a
large muscle (i.e.gluteal muscle)
• Rotate injection sites
• SUBCUT Injection: - Not recommended (no information).
• IV Injection: - Doses up to 250 mg should be given over a period of at least 5 minutes and
doses greater than 250 mg should be given over at least 30 minutes.
• IV Infusion: - For intermittent infusion, dilute with a compatible fluid to a maximum
concentration of 3 g/100 mL and infuse over at least 30 minutes. For patients at risk of
cardiovascular adverse effects the infusion should be given over 2 to 3 hours.
• For continuous infusion, dilute to the desired volume with an appropriate infusion solution to
a concentration of 1 mg/mL.
• For infants and children: Dilute dose to 125 mg/mL or weaker and give intravenously over at
least 5 minutes. For doses of 2 mg/kg or more the dose should be diluted and infused over at
least 30 minutes.

23. Stability
• Reconstituted Solution: - Store at room
temperature and use within 24 hours of
reconstitution.
• Diluted Solution: - Stable up to concentration
of 3 g/100 mL for 24 hours at room temperature

24. Compatibility
• Compatible Fluids: - Glucose 5%, sodium chloride 0.9%,
glucose 5% in sodium chloride 0.9%
• Compatible Drugs: - Chloramphenicol, clindamycin, dopamine,
granisetron, heparin, noradrenaline, ranitidine, verapamil
• Compatible via Y-Site: - Aciclovir, amifostine, amiodarone,
aztreonam,, bivalirudin, cefepime, ceftazidime,
dexmedetomidine, dopamine, granisetron, linezolid,
metronidazole, midazolam,, morphine sulfate, pethidine,
piperacillin-tazobactam, remifentanil, tacrolimus,
• Compatible in Syringe: - Metoclopramide

25. Incompatibilty
• Incompatible Fluids: - No information.
• Incompatible Drugs: - Aminophylline,
benzylpenicillin, calcium gluconate,
ciprofloxacin, cisatracurium, dolasetron,
filgrastim, glycopyrrolate, insulin soluble,
metaraminol, ondansetron, pantoprazole,
potassium chloride, propofol, rocuronium,
tigecycline

26. Special Considerations
• Each gram of methylprednisolone sodium
succinate contains 2 mmol of sodium.
• Solutions with a slight haze should be
discarded.
• There are reports of cardiac arrhythmias and/or
circulatory collapse and/or cardiac arrest
following rapid administration of large IV doses
(over less than 10 minutes).

27. Dosing
• Pulse therapy (“MPPT”):
• Adults, usually 1-2 g of methylprednisolone
• Initially the duration of infusion was based on a study in
normal adults, and was 10 to 20 minutes.1
• Rapid infusions associated with higher risk of hemodynamic
abnormalities, and hence administration over 1-3 hours is
preferred. 2
• Dexamethasone may also be used
1 Novak E, Stubbs SS, Seekman CC, Hearron MS. Effects of a single large intravenous dose of methylprednisolone sodium succinate.
Clin Pharmacol Ther 1970; 11 : 711-717.!
!
2 Miura M, Ohki H, Yoshiba S, Ueda H, Sugaya A, Satoh M et al. Adverse effects of methylprednisolone pulse therapy in refractory
Kawasaki disease. Arch Dis Child 2005; 90 : 1096–1097.

28. Administration: Methylprednisolone sodium succinate
(Solu Medrol)
• SOLU-MEDROL should not be diluted or mixed with other
solutions
• Use only the accompanying diluent or Bacteriostatic Water For
Injection with Benzyl Alcohol when reconstituting SOLU-
MEDROL. Use within 24-48 hours after mixing.
• to avoid compatibility and stability problems, whenever possible,
it is recommended that SOLU MEDROL be administered separate
from other drugs and as either IV medication chamber, or as an IV
"piggy-back" solution

29. • Cardiac arrhythmias and/or cardiac arrest have been reported after
rapid administration (greater than 0.5 gram administered over a
period of less than 10 minutes).
• Bradycardia has been reported, may be unrelated to the speed or
duration of infusion.
• When high dose therapy is desired, the recommended dose of
SOLU-MEDROL Sterile Powder is 30 mg/kg administered
intravenously over at least 30 minutes. This dose may be
repeated every 4 to 6 hours for 48 hours.
Administration: Methylprednisolone sodium succinate
(Solu Medrol)

30. Suggested dosing: Solu Medrol
Rheumatic disorders
1 g/day for one, two, three or four days IV or 1 g/month for six months IV
!
Systemic lupus erythematosus
1 g/day for three days IV
!
Multiple sclerosis
1 g/day for three days IV or 1 g/day for five days IV
!
Edematous states e.g. glomerulonephritis, lupus nephritis
30 mg/kg every other day for four days IV or 1 g/day for three, five or
seven days IV

31. Pharmacology
• Pharmacodynamics
• has a greater anti-inflammatory potency than prednisolone and even
less tendency than prednisolone to induce sodium and water retention
• Pharmacokinetics
• Absorption
• 30 mg/kg over a 20 minute period or 1 g over 30 to 60 minutes,
peak methyl-prednisolone plasma concentrations of
approximately 20 mcg/mL were achieved
• Distribution
• widely distributed throughout the body ; readily crosses the
blood-brain barrier; crosses the placental barrier

32. Pharmacology
• Pharmacokinetics
• Metabolism
• metabolised in the liver to inactive metabolites
• Excretion
• mean elimination half-life ranges for total
methylprednisolone is in the range of 1.8 to 5.2 hours
• 75% in urine, 9% in feces, rest in bile
• N o d o s e a d j u s t m e n t n e c e s s a r y f o r re n a l f a i l u re ;
methylprednisolone is dialyzable

33. Contraindications
Methylprednisolone sodium succinate is contraindicated:
• in patients who have systemic fungal infections
• in patients with known hypersensitivity to methylprednisolone or any
component of the formulation
• for use by intrathecal, epidural, local injection or any other
unspecified route of administration
!
Administration of live or live, attenuated vaccines is
contraindicated in patients receiving immunosuppressive doses
of corticosteroids

34. Drug interactions
Drugs that inhibit CYP3A4 activity generally decrease hepatic
clearance, resulting in increased plasma concentration of
methylprednisolone:
!
• Antifungals such as ketoconazole and itraconazole
• Antiemetics such as aprepitant and fosaprepitant
• Immunosuppressants such as ciclosporin
• Macrolide antibacterials such as clarithromycin, erythromycin and
troleanomycin
• HIV-Protease inhibitors such as indinavir and ritonavir
• Calcium channel blockers such as diltiazem.
• Isoniazid
• Oral contraceptives such as ethinylestradiol and norethisterone
• Grapefruit juice

35. Drug interactions
Drugs that induce CYP3A4 activity generally decrease hepatic
clearance, resulting in decreased plasma concentration of
methylprednisolone:
!
•Anticonvulsants such as phenobarbital, phenytoin,
carbamazepine and primidone
•Bactericidal antibiotics such as rifampicin and rifabutin

36. Adverse Effects:
What to watch out for…
Most symptoms were transient in duration, mild in severity, and required no
medical treatment1.!
!
42 possible complications occurring within two weeks of HIVMP therapy. !
!
In 18 instances medical intervention was required for problems that
included hypertension, seizures, gastric erosions, sepsis, and
other infections. It is impossible to attribute all of the complications to
HIVMP alone because of underlying disease, use of other medications at
the time of therapy, or both.
1 Baethge BA, Lidsky MD, Goldberg JW A study of adverse effects of high-dose intravenous (pulse)
methylprednisolone therapy in patients with rheumatic disease. The Annals of Pharmacotherapy [1992, 26(3):316-320]!

37. Adverse Effects
Pertains to its physiologic effects as a glucocorticoid - recall:
HYPERTENSION!
ARRHYTHMIAS!
HYPERGLYCAEMIA!
SEIZURES!
GASTRIC EROSIONS/
ULCERS!
S E P S I S a n d O T H E R
INFECTIONS!

38. Adverse Effects:
What to watch out for…refer the following immediately
HYPERTENSION!
ARRHYTHMIAS!
HYPERGLYCEMIA!
SEIZURES!
GASTRIC EROSIONS/ULCERS!
SEPSIS and OTHER INFECTIONS!
1 Baethge BA, Lidsky MD, Goldberg JW A study of adverse effects of high-dose intravenous (pulse)
methylprednisolone therapy in patients with rheumatic disease. The Annals of Pharmacotherapy [1992, 26(3):316-320]!

39. Questions ?

40. Post-test
1. Methylprednisolone is a:!
a. mineralocorticoid b. glucocorticoid
!
2. It is used for the following diseases:!
a. post-traumatic osteoarthritis b. COPD exacerbations
c. SLE nephritis d. all of the above
e. none of the above
!
3. The effect of methylprednisolone on the immune system is to promote
inflammation:!
a. true b. false

41. Post-test
4. Pulse therapy is done to:!
a. decrease side effects and enhance therapeutic effects
b. enhance therapeutic effects despite enhanced side effects
!
5. The usual adult MPPT dose is:!
! ! ! a. 1 gm/day for 7 days b. 1gm/day for 3 days
c. 1 gm/day for 5 days d. any of the above

42. THANK YOU FOR YOUR KIND ATTENTION!
More patient
information on
Rheumatologic
Diseases:
www.allancorpuzmd.com