FARMAKOLOGI OBAT PADA

REAKSI
HIPERSENSITIVITAS

Noor Wijayahadi

Classification
Coombs and Gell classification
1-Type I - immediate ( atopic, or anaphylactic)
2-Type II - antibody-dependent sitotoksik
anemi hemolitik
3-Type III - immune complex serum
sickness
4-Type IV - cell-mediated or delayed

Allergy

Ig E mediated
(Type I
hypersensitivity)
Non Ig E
mediated

Treatment approaches for IgE-mediated Allergy

Terapi
ANTAGONIS KIMIAWI
ANTI HISTAMIN
STEROID

ANTAGONIS FUNGSIONAL
Bronkodilator adrenalin

PENGELOLAAN SYOK ANAFILAKTIK

POSISI SYOK
ABC (Airway-Breathing- Circulation)
VASOKONSTRIKTOR ADRENALIN
CEGAH REAKSI LANJUTAN STEROID
SUPORTIF:
CAIRAN
OKSIGEN
NB: MASA KERJA ALERGEN vs OBAT

Corticosteroids
1. Imunodepresan
2. Anti-inflamasi

Bentuk Sediaan
Glucocorticoids
Short acting
Intermediate acting
Long acting

Mineralocorticoids
Inhalant steroids
Topical steroids

Pharmacokinetics
Absorption: all are rapidly & completely absorbed
Transport:
Transcortin 75%
Albumin 5%
Free form 20%

Metabolism:
by liver enzymes, conjugation & excretion by urine
partly excreted as 17-ketosteroids.
t1/2 of cortisol 1.5 hours

Short Acting Glucocorticoid (t1/2 < 12 h)

Drug

Anti-inflam. Salt retaining

Cortisol

Cortisone

Preapartions & dose

1.0

5 mg tablet
100 mg/vial (i.m., i.v)
Topical; enema

0.8

0.8

5 mg tablet
25 mg/vial (i.m)

Intermediate Acting Glucocorticoid (t1/2 = 12 -36 h)

Prednisone

0.8

Prednisolone

0.3

5, 10 mg tablet
20 mg/vial (i.m, intrarti)

Methyl
prednisolone

0.5, 1.0 gm inj. for i.m.

or slow i.v.

Triamcinolone

4 mg Tab.,
10, 40 mg/ml for i.m. &
intrarticular inj.

Drug

AntiSalt retaining
inflam.

Preapartions & dose

Long Acting Glucocorticoid (t1/2 > 36 h)

Dexamethasone

25

0.5 mg tab.
4mg/ml inj (i.m., i.v.)

Betamethasone

25

0.5, 1 mg tab.
4mg/ml inj (i.m., i.v.)

Paramethasone

10

2- 20 mg/day (oral)

Mineralocorticoids - Preparations
Drug

Antiinflammatory

Salt retaining

Preapartions &
dose

Fludrocortisone

10

150

100 mcg tab.

DOCA

100

2.5 mg
sublingual

0.3

3000

Not used
clinically

Aldosterone

Inhalant Steroids: Bronchial Asthma

Beclomethasone
dipropionate

50,100,200 mcg/md inhaler

100, 200, 400 mcg Rotacaps

Fluticasone
propionate

25, 50 mcg/md inhaler

25,50,125/md MDI
50, 100, 250 mcg Rotacaps

Budesonide

100,200 mcg/md inhaler

0.25, 0.5 mg/ml respules

Topical steroids
Drug

Topical preparation

Potency

Beclomethasone
dipropionate

0.025 % cream

Potent

Betamethasone benzoate 0.025 % cream, ointment

& B. valerate
0.12 % cream, ointment

Potent

Clobetasol propionate

0.05 % cream

Potent

Halcinonide

0.1 cream

Potent

Triamcinolone actonide

0.1 % ointment

Potent

Fluocinolone actonide

0.025% ointment

Moderate

Mometasone

0.1 % cream, ointment

Moderate

Fluticasone

0.05 % cream

Moderate

Hydrocortisone acetate

2.5 % ointment

Moderate

Hydrocortisone acetate

0.1 1.0% ointment

Mild

Topical Steroids
Benefits due to anti-inflammatory, immunosuppressive,
vasoconstrictor and anti-proliferative actions

Good response
Atopic eczema,
Allergic contact dermatitis,
Lichen simplex,
Primary irritant dermatitis,
Seborrheic dermatitis,
Psoriasis of face,
Varicose eczema

Slow response
Cystic acne
Alopecia areata
Discoid LE
Hypertrophied scars
Keloids
Lichen planus
Psoriasis of palm, sole,
elbow & knee

Topical Steroids
Penetration differs at different sites:
High: axilla, groin, face, scalp, scrotum
Medium: limbs, trunk
Low: palm, sole, elbow, knee

Occlusive dressing enhance absorption (10 fold)

Absorption is greater in infants & Children
Absorption depends on nature of lesion:
High: atopic & exfoliative dermatitis
Low: hyperkeratinized & plaque forming lesions

More than 3 applications a day is not needed

Choice of vehicle is important
Lotions & creams: for exudative lesions
Sprays & gels: for hairy regions
Ointments: for chronic scaly lesions

Therapeutic principles

Dose selection by trial & error; Needs

frequent evaluation
Single dose: No harm
Few days therapy unlikely to be harmful
Incidence of side effects related to duration
of therapy
Use is only palliative (except replacement
therapy)
Abrupt cessation of prolonged high dose
leads to adrenal insufficiency
(contraindicated)

Siklus Sirkadian

Dosis
Goal of therapy:
To relieve pain or distressing symptom (e.g.,
rheumatoid arthritis): start with low dose
To treat life threatening condition (e.g., pemphigus):
initial dose must be high

Prevention of HPA axis suppression:

Single dose (morning)
Alternate dose therapy (short lived glucocorticoids)
Pulse therapy (higher glucocorticoid therapy)

Steroid withdrawal
Longer the duration of therapy, slower the withdrawal
Less than 1 week: withdrawal in few steps
Rapid withdrawal: 50% reduction of dose every day
Slow withdrawal: 2.5 5 mg prednisolone reduced at an interval
of 2-3 days

Longer period & high dose:

Halve the dose weekly until 25 mg prednisolone or equivalent is
reached
Later reduce by about 1mg every 3-7 days.

HPA axis recovery may take months or up to 2 years

Adverse reactions (1/2)

Metabolic toxicity:
Iatrogenic Cushings syndrome
Hyperglycaemia, glycosuria, diabetes
Myopathy (negative nitrogen balance)
Osteoporosis (vertebral compression fracture)
Retardation of growth (children)
Hypertension, oedema,CCF
Avascular necrosis of femur

Adverse reactions (2/2)

HPA axis suppression
Behavioral toxicity: Euphoria, psychomotor
reactions, suicidal tendency
Ocular toxicity: steroid induced glaucoma,
posterior subcapsular cataract.

Others:

Superinfections
Delayed wound healing
Steroid arthropathy
Peptic ulcer
Live vaccines are dangerous

Contraindications

Infections
Hypertension with CCF
Psychosis
Peptic ulcer
Diabetes mellitus
Osteoporosis
Glaucoma
Pregnancy : (prednisolone preferred)

Precautions during therapy

Following examinations of the patient to be
done before, during and after steroid therapy

Body weight
X-ray of spine
Blood glucose
Examination of the eye
B.P.

Glucocorticoids antagonists
Mitotane: structure similar to DDT, used in
inoperable adrenal cancer

Metyrapone: inhibit 11 -hydroxylase

Aminoglutethamide: inhibit conversion of
cholesterol to pregnolone, medical adrenelectomy

Trilostane: inhibit conversion of pregnolone to

progesterone; used in Cushings syndrome

Ketoconazole: anti-fungal, inhibit CYP450

enzymes, inhibit steroid synthesis in ad.cortex and
testis; used in Cushings syndrome & Ca.prostate

Mifepristone: glucocorticoid receptor antagonist;

anti-progesterone, used in Cushings syndrome

Disease-Modifying Antirheumatic Drugs

Nonbiologic DMARDs
Name

Target of Activity

Biologic DMARDs

Azathioprine

Purine synthesis; inhibits Tlymphocyte proliferation

Name

Target of Activity

D-Penicillamine

Unknown

Adalimumab

TNF-

Hydroxychloroquine

T-lymphocytes?

Etanercept

TNF-

Infliximab

TNF-

Abatacept

CD28

Anakinra

IL-1

Rituximab

CD20

Tocilizumab

IL-6 receptor

IVIG*

Fc receptors

Leflunomide

Pyridine synthesis

Methotrexate

Dihydrofolate reductase; folate

metabolism

Sulfasalazine

Uncertain; multifactorial,
including impairment of lymphocyte
function and cytokine synthesis

Synthetic DMARDs

Methotrexate
Sulphasalazine
Chloroquine
Hydroxychloroquine
Leflunomide

HISTAMIN
&
AUTAKOIDS

Mediator
Perubahan Vaskular pada Inflamasi
Mediator perubahan aliran darah dan
permeabilitas vaskuler:
-

vasoactive amina (histamin, serotonin)

vasoactive peptida (bradykinin)
vasoactive lipid (prostaglandin, leukotrien)

Mediator kemotaksis leukosit

-

leukotrien B4
Eosinophil chemotactic factor of anaphylaxis

Penyebab Cedera Jaringan pada

Inflamasi dan Penyakit Autoimmune
Pembentukan reactive oxygen species (O2-,
H2O2, HOCl) and enzime proteolitik
(kolagenase, elastase) oleh sel fagosit
Cytotoxic complement proteins
Respons imun seluler dan humeral
Pelepasan sitokin pro-inflamasi

HISTAMIN
Komponen bisa/racun serangga/tumbuhan
Tersimpan di Mast Cell & Basofil
(di lokasi trauma: hidung, mulut, kaki)

Terlepas pada:
1. Respons Imun
Immediate (Type I) Allergic Reaction
Inflamasi akut

2. Respon Kimia (gol. Amine: morfin)

EFEK: - Triple Response: merah, edema, nyeri

- Shock anafilaktik
- Rangsang ujung saraf tepi
nyeri, gatal
H1
- Vasodilatasi + edema jaringan
nadi
tensi
- Bronkokonstriksi provocatif test
- Kontraksi otot polos:
H2
GI
: peristalsis
diare
Uterus : aborsi
Lambung: sekresi HCl
- Pengelolaan:
1. Antagonis Fisiologis: epinefrin
2. Antagonis Reseptor : CTM, Burimamide anti-H2
3. Release Inhibitor: Cromolin, Nedocromil

H1 ANTAGONIS
Gen 1: sedatif, blok reseptor otonom
Gen 2: <<sedatif ( distribusi di CNS<<)
- p.o. absorbsi cepat (peak 1-2 jam, durasi 4-6 jam)
- Metabolisme di hepar
- Efek:
- sedasi
- anti-nausea/ anti-emetik
- anti-Parkinson (Bromokriptin: anti-kolinergik)
- anti-kolinergik (Etanolamine, Etilendiamine)
- -adrenoceptor blocker: hipotensi postural
(Fenotiazin, Prometazin)
- Serotonin blocker (Siproheptadin)
- Anestesi lokal (Difenhidramin, Prometazin)

H1 Antagonists Generasi I vs. II

Generasi-1 antagonis reseptor H1 tidak spesifik
- diphenhydramine muscarinic receptors
- Promethazine dopamine, muscarinic, 1
- Cyproheptadine serotonergic receptors

Generasi-2 antagonis reseptor H1:

-

Spesifik pada H1 receptors

Tidak menembus blood-brain barrier sedasi kurang
Half-lives lebih panjang
Indikasi utama: allergic rhinitis
Astemizole, Terfenadine aritmia

Penggunaan H1 antagonists
Allergic rhinitis e.g.chlorpheniramine, loratidine
Motion sickness eg. meclizine, chlorcyclizine
Hypnotic agents e.g.doxylamine, diphenhydramine
Pruritis e.g. hydroxyzine
Serum sickness- e.g. promethazine
Anti-emetics- e.g. promethazine
Antitussive e.g. diphenhydramine
Carcinoid tumors (serotonin-mediated)
cyproheptadine
Allergic conjuctivitis e.g. levocobastine

Drugs

Usual Adult
Dose

Anticholin
ergic
Activity

Comments

48 mg

+++

Slight to moderate sedation

Dimenhydrinate (salt of
diphenhydramine)
(Dramamine)

50 mg

+++

Marked sedation; anti-motion

sickness activity

Diphenhydramine
(Benadryl, etc)

2550 mg

+++

Marked sedation; anti-motion

sickness activity

1.2525 mg

nd

Marked sedation; now available

only in OTC "sleep aids"

Pyrilamine (Neo-Antergan)

2550 mg

Moderate sedation; component

of OTC "sleep aids"

Tripelennamine (PBZ, etc)

2550 mg

Moderate sedation

Hydroxyzine (Atarax, etc)

15100 mg

nd

Marked sedation

Cyclizine (Marezine)

2550 mg

Slight sedation; anti-motion

sickness activity

Meclizine (Bonine, etc)

2550 mg

Slight sedation; anti-motion

sickness activity

FIRST-GENERATION ANTIHISTAMINES
Ethanolamines
Carbinoxamine (Clistin)

Doxylamine
Ethylaminediamines

Piperazine derivatives

Alkylamines
Brompheniramine
(Dimetane, etc)

48 mg

Slight sedation

Chlorpheniramine (ChlorTrimeton, etc)

48 mg

Slight sedation; common

component of OTC "cold"
medication

1025 mg

+++

Marked sedation; antiemetic

Moderate sedation; also has

antiserotonin activity

60 mg

Lower risk of arrhythmia

Loratadine (Claritin)

10 mg

Longer action

Cetirizine (Zyrtec)

510 mg

Phenothiazine derivatives
Promethazine (Phenergan,
etc)
Miscellaneous
Cyproheptadine (Periactin, 4 mg
etc)
SECOND-GENERATION ANTIHISTAMINES
Piperidines
Fexofenadine (Allegra)
Miscellaneous

Penggunaan Klinis Antihistamin

- Reaksi Alergi: rinitis, urtikaria
asma ? (tidak efektif)
- Motion sickness
- Gen 1: difenhidramin/ dimenhidrinat, prometazin
sikloserin, meclizine: less sedatif
- Obat lain : skopolamin
- + efedrin/amfetamin: >>efek
- Nausea/Vomiting pd kehamilan
piperasin : teratogenik

Toksisitas
mirip keracunan Atropin
eksitasi, konvulsi, koma
- Astemizole, Terfenadine aritmia
pada penderita hepar
interaksi dg ketokonazole, makrolid
juice anggur
dilarang di USA

H2 ANTAGONIS
- Cimetidine
- Ranitidine
- Famotidine
- Nizatidine
- Mengurangi sekresi HCl lambung
- Menghambat enzim hepar

Penggunaan Klinis H2 Antagonists

Ulkus Gastric dan duodenal
Reflux Gastroesofagus
Esofagitis Erosif
Heartburn

Lipid Autacoids

EICOSANOIDS:

PROSTAGLANDINS
THROMBOXANES
LEUKOTRIENES