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XL tablets 1.2g
Pentasa
tablets 500mg
Foam enema 1g
Suppositories 500mg, 1g
Sulfasalazine
Tablets e/c 500mg
1.5.2 Corticosteroids
Budesonide
Capsules - Enteric coated granules 3mg
Capsules - Modified release 3mg
Hydrocortisone
Foam enema 10%
Prednisolone
Tablets (non-enteric coated) 1mg, 5mg, 25mg
Retention enema 20mg
Rectal foam 20mg
Suppositories 5mg
1.5.3 Drugs affecting the immune
response
Azathioprine U
Tablets 25mg, 50mg
Neoral
(ciclosporin) U
Capsules 10mg, 25mg, 50mg, 100mg
Oral solution 100mg/ml
Mercaptopurine U
Tablets 50mg
Methotrexate U
Tablets 2.5mg
1.6 Laxatives
1.6.1 Bulkforming laxatives
Ispaghula husk N
Sachets 3.5g
1.6.2 Stimulant laxatives
Bisacodyl N
Tablets 5mg
Suppositories 5mg (paed),
10mg
Senna N
Tablets 7.5mg sennosides
Syrup 7.5mg sennosides in
5ml
Docusate sodium N
Capsules 100mg
Paediatric oral solution
12.5mg/5ml,
Adult oral solution
50mg/5ml
Glycerol N
Suppositories 1g, 2g, 4g
Co-danthramer N
Capsules 25/200
Suspension 25/200 in 5ml
1.6.3 Faecal softeners
Arachis oil enema N
Enema 130ml
1.6.4 Osmotic laxatives
Lactulose N
Solution
Liquid Paraffin & Magnesium Hydroxide
Oral emulsion
Macrogol oral powder, compound
N
Sachets
e.g. Laxido, Movicol
Movicol
Paediatric Plain
Sachets
Phosphate N
Enema 128ml
Sodium citrate N
Micro-enema 450mg
1.6.5 Bowel cleansing solutions
Picolax
Oral powder
Klean-Prep
Oral powder
1.6.6 Peripheral opioidreceptor
antagonists
Methylnaltrexone bromide
NICE TA277: Methylnaltrexone for treating opioid-
induced bowel dysfunction in people with advanced
illness receiving palliative care (terminated
appraisal)March 2013
NICE is unable to recommend the use in the NHS of
methylnaltrexone for treating opioid-induced bowel
dysfunction in people with advanced illness receiving
palliative care because no evidence submission was
received from the manufacturer of the technology.
1.6.7 5HT4 Receptor Agonists
Prucalopride
Tablets 1mg, 2mg
1.7 Local preparations for anal and
rectal disorders
1.7.1 Soothing haemorrhoidal preparations
Anusol
Cream, 23g
Suppositories
1.7.2 Compound haemorrhoidal
preparations with corticosteroids
Scheriproct
Suppositories
Ointment
1.7.3 Rectal sclerosants
Phenol, oily
Injection 5% in 5ml
1.7.4 Management of anal fissures
Glyceryl Trinitrate
Rectogesic
Ointment 0.4% (Maximum duration of
use - 8 weeks)
Diltiazem Ointment U
Only when treatment with GTN ointment has failed
Botulinum Toxin A U
Injection 100units / vial (Xeomin)
1.9 Drugs affecting intestinal
secretions
1.9.1 Drugs affecting biliary composition and
flow
Ursodeoxycholic acid
Capsules 250mg
Suspension 250mg/5mL
1.9.2 Bile acid sequestrants
Colestyramine
Powder 4g sachet
1.9.4 Pancreatin
Creon
Capsules 10,000
Capsules 25,000 (High strength)
Capsules 40,000 (High strength)
Creon
Micro
20G Granule pack
Thank You
2.CARDIOVASCULAR SYSTEM
2.1 POSITIVE INOTROPIC DRUG
2.1 Positive Inotropic Drug (Bipiridin)
2.1.1 Cardiac Glycosides (digoxin)
2.1.2 phospodiesterase inhibitor (exoximone,
milrinore)
2.2 Diuretics
2.2.1 Thiazides and releted diuretic
(Hidroklorotiazid)
2.2.2 loop diuretics (Furosemid, bumetanide)
2.2.3 potassium sparring diuretics (Amilorid )
2.2.4 potassium sparring diuretics with other
diuretic (amiloride, triamteren)
2.3. ANTI ARRHYTHMIC DRUG
2.3.1 Drugs for arrhytmia (qinidin sulphate)
2.4 Beta-adrenoceptor blocking drugs
(propanolol, atenolol)
2.5 Drug Effecting the renin-angiotensin system
and some other antihypertensive drug
2.5.1 Vasodilator anti hypertensive drug (Hidralazin, minoxidil
)
2.5.2 centrally acting anti hypertensive drug (klonidin,
metildopa)
2.5.3 adrenergic neurone bloking group (reserpin, guanetidin)
2.5.4 Alpha adrenoceptor blocking drugs (prazosin, doxazosin)
2.5.5 drugs affecting the renin angiotensin system
2.5.5.1 angiotensin converting enzyme inhibitor(captopril,
lisinopril, ramipril)
2.5.5.2 angiotensin II receptor antagonist (valsartan)
Cont
2.5.6 Ganglion blocking drugs (trimetafan)
2.5.7 Tyrosine hydroxylase inhibitor (trimetaphan)
2.6 Nitrate, Ca Channal Blocker and Potassium activator
2.6.1 Nitrate(ISDN)
2.6.2 Ca Channel blocker (amlodipin, nifedipin)
2.6.3 potassium channel blocker (amiodaron, dofetilide)
2.6.4 peripheral and cerebral vasodilator
2.6.4.1 peripheral vasodilator and related drugs
(Minoxidil)
2.6.4.2 cerebral vasodilation (nitrixe oxide)
2.7 SYMPATHOMIMETIC
2.7.1 Inotropic Sympathomimetic (dopamin,
dobutamin, isoprenasin)
2.7.2 vasoconstriction Sympathomimetic
(noradrenalin, norepinephrine)
2.7.3 cardiopulmonary recucitation (adrenalin,
amiodaron, atropin)
2.8 anticoagulant and protamine
2.8.1 Parenteral anticoagulants (heparin)
2.8.2 oral anticoagulants (aspirin, sulfinpirazon,
dipiridamol)
2.8.3 Protamin sulphate (u/ menetralkan
antikoagulan heparin, ex: Protamin sulphate )
2.9 antiplatelet drug (Aspirin, clopidogrel)
2.10 Myocardial Infarction and
fibrinolisis
2.10.1 Fibronolytic drugs (streptokinase,
urokinase)
2.11 antifibrinolytic drug and hemostatics (asam
traneksamat)
2.12 Lipid regulation drugs (simvastatin)
2.13 local sclerosants (sodium tetradecyl
sulphate )
TERIMAKASIH
3. Respiratory system
1. Bronkodilator
1.1 Adenoreseptor agonis (Bronkodilatasi)
ex : Noradrenaline, phenylephrine, xylometazoline. (Alfa 1
agonist)
1.2 Selective beta blocker
ex : Salbutamol, Folmeterol, terbutaline
1.3 Other adenoreseptor agonist
ex : Alfa 2 agonist (Agmatine, clonidine, xylazine
dexmedetomidine.
1.4 antimuscarinic bronkodilator (menghambat asetilkolin)
ex : Atropin, lipratopium bromide
1.5 Theophyline (golongan metilxantin, menghambat enzim
fosfodiesterase)
Other preparations
Aminophylline injection
Caffeine citrate oral solution
Caffeine citrate intravenous injection
1.6 Coumpound broncodilator preparations
ex : salbutamol
1.7 Peak flow meter, inhaler devices and nebuliser.
ex : Nebuchamber
,
Volumatic
,
AeroChamber Plus
,
Pari
Vortex
2. Cortocisteroid (relaksasi otot polos jalan nafas)
ex : Methylprednisolone, prednison
3. Cromoglicate, related therapy and leukotriens
reseptor antagonist
3.1 Cromoglicate, related therapy
ex : Cromolyn Dan Nedocromil
3.2 leukotriens reseptor antagonist (menurunkan
reaktivitas bronkus, edema, hipersekresi)
ex : Zafirlukost, montelukost, zileuton
4. Antihistamin, hiposensitisation, and allergic emergency
4.1 Antihistamine
Non-sedating antihistamines should be offered first line
to all patients, especially children and adolescents.
(Cetirizine, Fexofenadine, loratadine)
Sedating antihistamin
(Chlorphenamine (chlorpheniramine), Alimemazine (trim
eprazine), Hydroxyzine
4.2 Allergic immunotherapy (ex : Omalizumab)
4.3 Allergic emergency
ex : Adrenaline injection
5. Respiratory stimulant and pulmonary surfactant
5.1 Respiratory stimulant (ex : doxapram)
5.2 Pulmonary surfactant (ex : poractant)
6. Oxygen
7. Mucolytics
ex: Bromhexine, N-acetylcystein, Ambroxol
8. Aromatic inhalation
ex : Aromatic ammonia
9. Cough preparations
9.1 Cough suppresant
ex : Codein, DMP
9.2 Expectorant and demulcent preparation
ex : Doveri, glyceril guaiacolate, potio nigra conta
tussim
10. Systemic nasal decongestant
ex : Pseudoefedrin, efedrin
4.CENTRAL NERVOUS SYSTEM
1. Hipnotik & Anxiolitik
Hipnotik Golongan obat yang dapat menyebabkan
kantuk dan memudahkan seseorang tertidur. Ex:
Valium/Diazepam, Lorazepam, Midazolam, Alprazolam
Anxiolitik: Benzodiazepin, non-Benzodiazepin (Buspiron)
Barbiturat: Dietilbarbiturat, Fenobarbital, Tiopental,
Pentobarbital
2. Psikosis
Antipsikotik: Chlorpromazine, Halloperidol, Risperidon
Antimanik: Litium Carbonat, Karbamazepin
3. Antidepresan
Trisiklik: Amitriptilin, Imipramin
Monoamine-Oxidase Inhibitor (MAOI): Moclobemide
Selective Serotonin Reuptake Inhibition (SSRI): Sentralin,
Fluvoxamin, Fluoxetin, Paroxetin
Antidepresan lain: Trazodon, Mianserin, Maprolitin
4. Central Nervous System Stimulants
Amfetamin
Dekstroamfetamin
Metamfetamin
MDMA (ecstasy)
Metilfenidat
Pemolin
5. Drugs used in the tratment of obesity
5HT (5 hidroksi triptofan)
reuptake norepinephrine inhibitor (sibutramine)
Stimulan (methylphenidate)
lipase inhibitor (orlistat)
agonist serotonin (phentermine)
6. Drugs used in nausea and vertigo
Betahistin Dihidroklorida
Meklizin
Dimenhidrinat
Perfenazin
Skopolamin (emplastrum)
7. Analgesik
Non-opioid: Parasetamol, Asetosal
Opioid: Morfin, Heroin, Kodein, Petidin, Metadon
Neuropatic pain: Natrium Diklofenak, Meloxicam
Antimigrain: Ergotamin, Caffein, Flunarizine, Cinnarizine
8. Antiepileptik
Control of epilepsy: Fenitoin, Fenobarbital, Karbamazepin,
Diazepam, Klorazepam, Klobazam, Asam Valproat
Status epileptikus: Diazepam, Fenitoin, Fenobarbital
Febril Konvulsi: Diazepam, Fenobarbital
9. Drugs used in Parkinsonism
Dopaminergik sentral: Levodopa, Bromokriptin, Carbidopa
Antimuskarinik: oxybutynin klorida, tolterodine, trospium
klorida, darifenacin, fesoterodine fumarat
Mengurangi gejalan Parkinson: Pramipexole (untuk
mengurangi gejala dari Parkinson seperti tremor, kekakuan
dan gerak yang lambat)
10. Drugs used for Dementia
Galatamin
Rivastigmin
Donepezil
Pentoxifilin
Piracetam
Ginkogiloba
5.ANTIBIOTIK
ANTIBACTERIAL DRUGS
Penicillins
Benzypenicillin and phenoxymethyplenicillin
Benzylpenicillin, Phenoxymethylpenicillin (Penicillin
V), Benzathine benzylpenicillin, Procaine
benzylpenicillin
Penicillinase-resistant penicillins Flucloxacillin
Broad-spectrum penicillins Amoxicillin, Co-
amoxiclav
Antipseudomonal penicillins Piperacillin with
Tazobactam
Mecillinams Pivmecillinam
Cephalosporins Cefalexin, Cefotaxime,
Cefixime, Ceftazidime, Ceftriaxone,
Cefuroxime
Tetracyclines Oxytetracycline, Doxycycline
Aminoglycosides Gentamicin, Tobramycin,
Neomycin sulphate
Macrolides Clarithromycin, Erythromycin,
Azithromycin
Clindamycin Clindamycin
Some other antibacterials Vancomycin,
Sodium fusidate, Chloramphenicol
Sulphonamides and trimethoprim
Trimethoprim, Co-trimoxazole, Sulfadiazine
Antituberculous drugs Rifampicin,
Isoniazid, Ethambutol, Pyrazinamide,
Streptomycin
Antileprotic drugs Dapsone
Metronidazole Metronidazole
Quinolones Ciprofloxacin
Urinary-tract infections Nitrofurantoin,
Fosfomycin
ANTIFUNGAL DRUGS
Triazole antifungals Fluconazole,
Itraconazole, Voriconazole
Imidazole antifungals Ketoconazole
Polyene antifungals Amphotericin
Echinocandin antifungals Caspofungin
ANTIVIRAL DRUGS
HIV infection Stribild
Herpes virus infections
Herpes simplex and varicella-zoster infection
Aciclovir, Valaciclovir
Cytomegalovirus (CMV) infection Valganciclovir
Viral hepatitis Adefovir dipivoxil, Entecavir,
Tenofovir disoproxil, Boceprevir, Telaprevir
Influenza Oseltamivir, Zanamivir
Respiratory syncytial virus (RSV) Palivizumab
ANTIPROTOZOAL DRUGS
Antimalarials Doxcycycline, Quinine
sulphate, Quinine dihydrochloride,
Artesunate, Clindamycin, Pyrimethamine/
Sulfadoxine, Artemether with lumefantrine,
Chloroquine sulphate, Primaquine
Amoebicides Metronidazole
Trichomonacides Metronidazole
Antigiardial drugs Metronidazole
Leishmaniacides Sodium stibogluconate
Trypanocides
Drugs for toxoplasmosis Pyrimethamine,
Sulfadiazine
Drugs for pneumocystis pneumonia Co-
trimoxazole, Pentamidine isetionate
ANTIHELMINTICS DRUGS
Drugs for treadworms Mebendazole, Piperazine
Ascaricides Mebendazole, Levamisole
Drugs for tapeworm infections Niclosamide,
Praziquantel
Drugs for hookworms Mebendazole
Schistosomicides Praziquantel
Filaricides Diethylcarbamazine, Ivermectin
Drugs for cutaneous larva migrans Tiabendazole,
Albendazole
Drugs for strongyloidiasis Albendazole, Ivermectin
6. Endocrine system Drugs
Drugs used in diabetes
Insulin
Type of Insulin &
Brand Names
Onset Peak Duration
Role in Blood
Sugar
Management
Rapid-Acting
Humalog or lispro 15-30 min. 30-90 min 3-5 hours
Rapid-acting insulin
covers insulin
needs for meals
eaten at the same
time as the
injection. This type
of insulin is often
used with longer-
acting insulin.
Novolog or aspart 10-20 min. 40-50 min. 3-5 hours
Apidra or glulisine 20-30 min. 30-90 min. 1-2 hours
Short-Acting
Regular (R)
humulin or novolin
30 min. -1 hour 2-5 hours 5-8 hours
Short-acting insulin
covers insulin
needs for meals
eaten within 30-60
minutes
Velosulin (for use in
the insulin pump)
30 min.-1 hour 2-3 hours 2-3 hours
Intermediate-Acting
NPH (N) 1-2 hours 4-12 hours 18-24 hours
Intermediate-acting
insulin covers
insulin needs for
about half the day
or overnight. This
type of insulin is
often combined
with rapid- or short-
acting insulin.
Long-Acting
Long-acting insulin
covers insulin
needs for about
one full day. This
type of insulin is
often combined,
when needed, with
rapid- or short-
acting insulin.
Lantus (insulin
glargine)
1-1 hour
No peak time;
insulin is delivered
at a steady level
20-24 hours
Levemir (insulin
detemir)
1-2 hours 6-8 hours Up to 24 hours
Pre-Mixed*
Humulin 70/30 30 min. 2-4 hours 14-24 hours
These products are
generally taken two
or three times a day
before mealtime.
Novolin 70/30 30 min. 2-12 hours Up to 24 hours
Novolog 70/30 10-20 min. 1-4 hours Up to 24 hours
Humulin 50/50 30 min. 2-5 hours 18-24 hours
Humalog mix 75/25 15 min. 30 min.-2 hours 16-20 hours
*Premixed insulins are a combination of specific proportions of intermediate-acting and short-acting
insulin in one bottle or insulin pen (the numbers following the brand name indicate the percentage of
each type of insulin).
Oral Antidiabetics drugs
Golongan Senyawa Mekanisme Kerja
Sulfonilurea Gliburida/Glibenkla
mida
Glipizida
Glikazida
Glimepirida
Glikuidon
Merangsang sekresi insulin di
kelenjar pankreas, sehingga hanya
efektif pada penderita diabetes yang
sel-sel pankreasnya masih
berfungsi dengan baik
Meglitinida Repaglinide Merangsang sekresi insulin di
kelenjar pankreas
Turunan
fenilalanin
Nateglinide Meningkatkan kecepatan sintesis
insulin oleh pankreas
Biguanida Metformin Bekerja langsung pada hati (hepar),
menurunkan produksi glukosa hati.
Tidak merangsang sekresi insulin
oleh kelenjar pankreas
Tiazolidindion Rosiglitazone
Troglitazone
Pioglitazone
Meningkatkan kepekaan tubuh
terhadap insulin. Berikatan dengan
PPAR (peroxisome proliferator
activated receptor-gamma) di otot,
jaringan lemak, dan hati untuk
menurunkan resistensi insulin
Inhibitor -
glukosidase
Acarbose
Miglitol
Menghambat kerja enzim-enzim
pencenaan yang mencerna
karbohidrat, sehingga
memperlambat absorpsi glukosa ke
dalam darah
Terapi hipoglikemia
1. Segera mengkonsumsi pisang atau roti atau karbohidrat kompleks
lainnya
2. Bisa juga menggunakan teh gula, air gula kental atau madu yang
dimasukkan di bawah lidah.
3. Jika penderita tidak sadar, injeksi glukosa 40% Intra vena 25 ml
(encerkan 2x dengan aqua injeksi) juga infus glukosa 10% atau
Dekstrose 10%. Bila belum sadar dapat diulang 25 cc glukosa 40%
setiap 30 menit. Dapat diulang sampai 6x sampai penderita sadar. 1
flakon D40% 24 meq dapat menaikkan kadar gula darah 25-50
mg/dl. Periksa Gula Darah Sewaktu 30 menit setelah Intra vena
terakhir.
4. injeksi efedrin 25-50 mg (bila tdk ada kontra indikasi jantung pada
jantung) atau glukagon 1 mg Intra muskuler.
5. Sementara obat anti diabetes dihentikan dulu.
Treatment of hypoglicemic
Nephropathy
1. Istirahat
2. Diet
Diet disesuaikan dengan kebutuhan penderita, 35
Kcal/kgBB/hari
Protein dibatasi 0,8 g/kgBB/hari bila ada albuminur
ACEI/ACEI+antagonis kalsium bila ada hipertensi
3.Medikamentosa
Obat pertama :
Insulun, bila gula darah tidak terkontrol dengan diet
4.Hemodialis
5.Transplantasi ginjal
Treatment of diabetic nephropathy and
neuropathy
Diagnostic and monitoring agents
Laboratory Tests in the Diagnosis and Management of Hyperglycemic
Emergencies
Plasma glucose Sodium
SUN Potassium
Creatinine Bicarbonate
Ketone bodies Chloride
Osmolality Blood pH
Criteria for the Diagnosis of Diabetes
Symptoms of diabetes and a casual plasma glucose > 200 mg/dl. Casual is defined as any
time of day without regard to time since last meal. The classic symptoms of diabetes
include polyuria, polydipsia, and unexplained weight loss
OR
FPG 126 mg/dl. Fasting is defined as no caloric intake for at least 8 h. Should be
repeated on a separate occasion.
OR
2-h plasma glucose 200 mg/dl during an OGTT. The test should be performed as
described by the World Health Organization, using a glucose load containing the equivalent
of 75 g anhydrous glucose dissolved in water.
OR
A1C 6.5%. The test should be performed in a laboratory using a method that is NGSP
certified and standardized tot he DCCT assay.
Thyroid and Antithyroid Drugs
Thyroid hormones
Antithyroid drugs
ANTITIROID
Proses dihambat Contoh
Transport I- Perchlorat, fluoborat, SCN
Iodinasi tiroglobulin Thionamid, PTU, Mtimazol
Reaksi Coupling Thionamid, Sulfonamid
Pelepasan Hormon Garam Li, Iodida
Deiodinasi iodotirosin Nitrotirosin
Deiodinasi periver Der. TU, Amiodaron
Corticosteroid
corticoteroids Compared
Type Drug Equivalent
Doses
Relative
Glucocorticoid
Potency
Relative
Mineralocorticoi
d Potency
Short-acting.
Biological half
life*:
8-12 hours
Cortisol
Hydrocortisone
20 mg
25 mg
1
0.8
2
2
Intermediate-
acting.
Biological half
life:
18-36 hours
Prednisolone
Triamcinolone
Methylprednisolo
ne
5 mg
4 mg
4 mg
4
5
5
1
0
0
Long-acting.
Biological half
life:
36-54 hours
Dexamethasone
Betamethasone
0.75 mg
0.75 mg
25-50
25-50
0
0
Mineralocorticoi
ds
Aldosterone
Fludrocortisone
0.3 mg
2 mg
0
15
300
150
*Duration of adrenocorticotrophic hormone (ACTH) suppression after a single dose of the drug.
Sex Hormones
Hormone Function
Progesterone Prepares uterus to receive conceptus
Maintains uterus during pregnancy
Stimulates growth of mammary glands
Regulates secretion of LH and FSH
Androgens Required for spermatogenesis
Induce and maintain secondary sex characteristics of males
Regulate secretion of LH and FSH
Promote increase in muscle mass and tone
Estrogens Necessary for oogenesis
Stimulates growth and activity of mammary glands
Stimulate growth of uterus
Induce and maintain femal body shape and fat distribution
Regulate secretion of LH and FSH
Required for skeletal maturation and bone mineralization in
male and females
Reproductive hormones
Hormone Primary Source
Steroid Hormones
Progestins Ovary, Placenta
Androgens Testis
Estrogens Ovary, Placenta
Protein Hormones
FSH Anterior Pituitary
LH Anterior Pituitary
Prolactin Anterior Pituitary
hCG Placenta
Peptide Hormones
GnRH Hypothalamus, Placenta
Oxytocin Posterior Pituitary
Natural
Hormone
Agonist Antagonist Use
Progesterone Levonorgestrel Contraceptive
RU-486 Abortifacient
Estrogen Mestranol Contraceptive
Raloxifene Breast Cancer
-endorphin Naloxone
Male erectile
dysfunction
Examples of Reproductive Hormone Agonists and Antagonists
Hormone replacement therapy (HRT) replaces two female
hormones that a womans body is no longer producing due
to menopause. These hormones are:
oestrogen: the oestrogen used in HRT is taken from plants or from
the urine of pregnant horses
progesterone: HRT uses a synthetic version of progesterone
called progestogen because it is easier for the body to absorb
While there are more than 60 different preparations of HRT, the three
main types are discussed below.
Oestrogen-only HRT
Oestrogen-only HRT is usually recommended for women who have
had their womb and ovaries removed during a hysterectomy. There
is no need to take progestogen because there is no risk
ofendometrial cancer (cancer of the lining of the womb).
Oestrogen and HRT
Jenis Kontinyu Dosis
Estrogen konjugasi Oral 0.3-0.4 mg
17 estradiol
Oral 1-2 mg
Transdermal 50-100 mg
Subkutan 25 mg
Estradiol valerate Oral 1-2 mg
Estradiol Oral 0,625-1,25
Dosis Anjuran Sulih Estrogen
Dosis Anjuran Sulih Progesteron
Jenis Sekuensial Kontinyu
Progesteron 300 mg 100 mg
Medroksiprogesteron asetat (MPA) 10 mg 2,5-5 mg
Siproteon asetat 1 mg 1 mg
Didrogesteron 10-20 mg 10 mg
Normogestrol asetat 5-10 mg 2,5-5 mg
Hypothalamic and anterior pituitary
hormones and anti-oestrogens
Anterior pituitary hormones
Tetracosactide
Synacthen