OUTLINE

I. Adrenocorticotrophic Hormone IV. Corticosteroids Adrenal Cortex Adrenal Medulla

II. Therapeutic Uses and Diagnostic Tests of V. Therapeutic Uses of Corticosteroids 1) Zona Glomerulosa Epinephrine & Norepinephrine
ACTH VI. Corticosteroids Toxicity
= Mineralocorticoids
III. Regulation of ACTH Secretion VII. Drug Summary
= This zone has receptors for
Legend
Angiotensin II and expressed
Verbatim Book High yield
aldosterone synthase
2) Zona Fasciculata
I. ADRENOCORTICOTROPIC HORMONE = Glucocorticoids
▪ ACTH = aka corticotrophin = This zone has 17 alpha-hydroxylase
▪ A polypeptide composed of 39 amino acids and 11-beta-hydroxylase necessary for
▪ Causes increase in circulating levels of adrenocortical hormones (corticosteroids) cortisol production
▪ Corticosteroids 3) Zona Reticularis
o Cortisol (Glucocorticoid) = Androgens
o Aldosterone (Mineralocorticoid)
o Androgens D. Major Categories of Corticosteroids
Glucocorticoids Mineralocorticoids Androgens
A. ACTH Synthesis Normal metabolism Regulation of salt Androgenic activity
ACTH is synthesized from larger precursor protein: pro-opiomelanocortin (POMC) metabolism
▪ Prohormone convertase 1 enzyme → cleaves the POMC and ACTH Resistance to stress Regulation of water Estrogenic activity
Deficiency or defect in the enzyme will present as adrenal insufficiency metabolism
▪ Liberated ACTH is composed of 39 amino acids e.g. Cortisol e.g. Aldosterone, e.g. DHEA
Deoxycorticosterone
B. Processing of POMC to ACTH
Discussion Discussion
Note that the AA 6-10 is responsible for o Mother structure is the cholesterol. Cholesterol is the
steroidogenic activity of ACTH source of all steroids – which is why it is important in
o AA 15-18 is where ACTH binds to its receptor the body (and must take in the good cholesterol rather
(MC2R) than the bad cholesterol)
o Action of ACTH is mediated by GPCR (Gs) o In the orange box
o Other byproducts: ▪ This happens in zona glomerulosa
▪ y-MSH → melanin production Production of aldosterone
▪ Cholesterol → pregnenolone → progesterone →
C. Adrenal Gland deoxycorticosterone → .. → aldosterone
Discussion o In gray box
o Composed of a thin capsule, thick cortex, ▪ Happens in the zona fasciculata & reticularis
and a medulla ▪ Zona reticularis: where DHEA is being produced
o More concern on the cortex (glomerulosa, ▪ Zona fasciculata: where cortisol production
fasciculata, reticularis) occurs
Rate limiting step: production of pregnenolone

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E. Physiologic Effects of ACTH HPA-Axis Characteristics
▪ ACTH mediates its effects by binding to melanocortin receptors (MC2R) → activates 1) Diurnal Rhythm in basal steroidogenesis
Gs-adenyl cyclase-cyclic AMP-PKA pathway 2) Negative-feedback in regulation by adrenal corticosteroids
Mechanism of Action 3) Marked increases in steroidogenesis in response to stress
= Cyclic AMP – 2nd messenger for most effects of ACTH on steroidogenesis
= Temporally, the response of adrenocortical cells to ACTH has 2 phases: Arginine vasopressin
Acute phase Chronic phase = Acts a secretagogue for corticotropes → potentiating effects of CRH
▪ Occurs within seconds to ▪ Occurs hours to days = AVP binds to V1b receptors → activates Gq-PLC-IP3-Ca pathway → enhance
minutes ▪ Results largely from ACTH release (but does not increase ACTH synthesis)
▪ Largely reflects an ↑supply of ↑transcription of steroidogenic Negative Feedback on Glucocorticoids
cholesterol substrate to enzymes = At lower cortisol levels → MRs have higher affinity for glucocorticoids than GRs
steroidogenic enzymes = As glucocorticoid concentrations arise & saturate MRs → glucocorticoid
receptors (GR) become increasingly occupied
F. Adrenal Cortex = Both GRs and MRs control basal activity of HPA axis
▪ ACTH causes the secretion of cortisol, = Feedback inhibition by glucocorticoids predominantly involves GRs
aldosterone, DHEA by binding to MC2R Stress Response
▪ Corticosteroids refer to: = Stress overcomes negative-feedback regulation of HPA axis → marked rise in
o Glucocorticoids → Cortisol corticosteroid production
(Hydrocortisone) = Stress signals: injury, hemorrhage, severe infection, major surgery,
o Mineralocorticoids → Aldosterone hypoglycemia, cold, pain, fear

G. Extra-adrenal Effects of ACTH
Large doses
▪ Ketosis ▪ Hypoglycemia (↓glucose)
▪ Lipolysis ▪ Resistance to Insulin
II. REGULATION OF ACTH SECRETION
Discussion
o Stimulus of ACTH secretion comes from the
hypothalamus in the form of CRH
Stimulus are Ach, 5-HT, NE, GABA and presence
of inflammatory mediators which in turn result
to production of cortisol
o If cortisol is already increased in the body, this
can be sensed by anterior pituitary and
hypothalamus and will send a negative feedback
to stop the production
o Cortisol can also decrease the production of
inflammatory mediators
III. THERAPEUTIC USES & DIAGNOSTIC APPLICATIONS OF ACTH
❖ Cosyntropin
= synthetic peptide similar to human ACTH
Used to test the integrity of HPA axis & used in adrenal venous sampling
Normal response after administration of 250 ug → ↑cortisol to >18 – 20
ug/dL
❖ Ovine CRH and Human CRH
Also used to test HPA axis
= ACTH-dependent hypercortisolism → will help differentiate between
pituitary from ectopic sources of ACTH
❖ ACTH assay
↑ ACTH level hypercortisolism from pituitary adenoma or non-pituitary
adenoma tumor that secrete ACTH
↓ ACTH level ↑ glucocorticoid due to primary adrenal disorders

Absorption, Fate, Toxicity

= Corticotropin is readily absorbed from parenteral sites; t ½ = 15 mins

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 IV.
▪ Glucocorticoids
▪ Mineralocorticoids
CORTICOSTEROIDS Discussion
How do you differentiate Cushing Syndrome from Cushing’s Disease?
▪ Cushing disease is very particular and specific (excess glucocorticoids due to
pituitary problem (ie. Tumor))
▪ Cushing syndrome is a wider term that encompasses Cushing’s disease. It also
includes excessive amount of glucocorticoid in the body due to increase
exogenous intake of steroids. This is a set of manifestations due to increase of
cortisol level in the body

B. Water & Electrolyte Balance

= Permissive effects on tubular function & actions that maintain GFR
= Glucocorticoid exert effects on:
o Monovalent cations & water
o Calcium metabolism (steroids interfere w/ calcium uptake in the gut and
↑ Calcium excretion in the kidneys)
GLUCOCORTICOIDS The main work is done by the mineralocorticoids
A. Metabolic Effects
❖ Carbohydrate & Protein Metabolism C. Skeletal Muscle
Liver = Gluconeogenesis from amino acids & glycerol = Permissive concentration of glucocorticoids is required for the normal function of
to be stored as glycogen skeletal muscle (seen in athletes)
Periphery = ↓glucose utilization Diminished work capacity = prominent sign of adrenocortical deficiency
= ↑protein breakdown o Addison’s disease → weakness and fatigue (main manifestations)
= Synthesis of glutamine = Glucocorticoid excess over prolonged periods → skeletal muscle wasting (Steroid
= Activate lipolysis myopathy)
= Providing amino acids and glycerol for
gluconeogenesis
D. Central Nervous System
Net Effect = ↑ blood glucose levels
Direct Effects Indirect effects
*glucocorticoids can worsen glycemic control in px w/ overt diabetes & precipitate onset of
3) Mood 6) Blood pressure
hyperglycemia
4) Behavior 7) Plasma glucose concentration
5) Brain excitability 8) Electrolyte concentration
❖ Effect on Lipid Metabolism
*Cortisol is a feel-good hormone
1) Dramatic distribution of fats (occurs in settings of * Adrenal Insufficiency = apathy, depression, irritability, psychosis
endogenous or pharmacologically-induced hypercorticism
[eg. Cushing’s Syndrome]) E. Formed Elements of Blood
o Buffalo hum (↑fat at back of neck) = Minor effects on hemoglobin and erythrocyte
o Moon facies (↑ fat in face)
Administration of glucocorticoids → ↓ number of circulating lymphocytes,
o ↑fat in supraclavicular area eosinophils, monocytes, basophils, ↑ circulating polymorphonuclear leukocytes
o Loss of fat in extremities
1 dose of hydrocortisone
2) (normal effect) Permissive facilitation of lipolytic effect of other agents → ↑ o ↓ cells w/in 4 - 6 hours → effect may persist for 24 hours
in free FA after glucocorticoid administration = Can activate apoptosis → used to treat lymphoid malignancies

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F. Anti-Inflammatory & Immunosuppressive Actions = Glucocorticoids are absorbed from synovial spaces,
Most important action of glucocorticoids conjunctival sac, respiratory tract
= Prevent and suppress inflammation in response to multiple stimuli (radiant, Distribution, = 90% or more of cortisol are reversibly bound to protein
mechanical, chemical, infectious, immunological) Metabolism, = 2 plasma proteins account for all of the steroid-binding
= Mechanisms of suppression by glucocorticoids: Excretion capacity: CBG (transcortin) and albumin
o ↓release of vasoactive & chemo attractive factors = CBG – high affinity for steroids, low binding
o ↓secretion of lipolytic & proteolytic enzyme = Albumin – low affinity, large binding capacity
o ↓extravasation of leucocytes to areas of injury = Aldosterone levels rise 3 – 10 fold in pregnancy
= In settings which enzymatic activity is impaired, use
o ↓fibrosis
steroids that do not require enzymatic action (eg.
o ↓expression of pro-inflammatory enzymes (COX-2 & NOS)
hydrocortisone, prednisolone)
Table 46-2: INHIBITORY EFFECTS OF GLUCOCORTICOIDS ON INFLAMMATORY/IMMUNE
RESPONSES
CELL TYPE FACTOR INHIBITED COMMENTS i. Classification of Glucocorticoids
Macrophages & Arachidonic acid, PG, LT mediated by glucocorticoid inhibition of COX- Short-acting Intermediate-acting Long-acting
Monocytes 2 and PLA2 Cortisone Prednisolone Dexamethasone
Cytokines: IL-1, IL-6, TNF-a Production and release are blocked; cytokines Hydrocortisone Prednisone Betamethasone
exert multiple effects on inflammation (↑T Methylprednisolone
cells, ↑Fibroblast proliferation)
Triamcinolone
Acute phase reactants Including the 3rd component of complement
Endothelial ELAM-1 & ICAM-1 ELAM-1 and ICAM-1 are critical for leukocyte
cells localization Glucocorticoids Routes Half-life
Acute Phase reactants Same as above for macrophages and Cortisol IM, IV, Oral Short
Cytokines (IL-1) monocytes Cortisone IM, IV, Oral Short
Arachidonic Acid derivatives Prednisone Oral Intermediate
Basophils Histamine, LTC4 IgE-dependent release ↓ by glucocorticoids Methyl prednisone IM, IV, Oral Intermediate
Fibroblasts Arachidonic acid metabolites Same as above for macrophages and Dexamethasone IM, IV, Oral, Topical Long
monocytes. Glucocorticoids ↓ growth factor- Betamethasone Oral, Topical, Inhalational Long
induced DNA synthesis and fibroblast Triamcinolone Intraarticular, Topical, Intermediate
production Inhalational
Lymphocytes Cytokines (IL-1, IL-2, IL-3, IL-6, Same as above for macrophages and
TNF-a, GM-CSF, Interferon-y) monocytes

Discussion
o Glucocorticoids can suppress the arachidonic acid metabolism at higher levels with the
help of PLA2 (phospholipase A2) → everything else down the pathway will be suppressed

ADME
Absorption = Hydrocortisone is orally effective
= Water-soluble esters of hydrocortisone are
administered IV
= Prolonged effects are achieved through IM

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 Discussion Tertiary Adrenal Insufficiency = Tumor of hypothalamus
Fludrocortisone acts like aldosterone. This gives the highest Na-retaining potency = Sudden exogenous steroid withdrawal
Long acting ones has the highest anti-inflammatory activity

❖ Deficiency of Aldosterone
MINERALOCORTICOIDS = Aldosterone synthase deficiency
Electrolyte & Water Balance = Secondary to a pituitary or hypothalamic problem
❖ Aldosterone (Mineralocorticoids) ❖ Excessive number of corticosteroids in the body
= Acts on distal tubules & collecting ducts of kidney to enhance reabsorption of Excess cortisol (Cushing Syndrome) Excess aldosterone
sodium (Hyperaldosteronism)
= ↑excretion of K and H ▪ Endogenous: usual adrenal pathology (eg.
= Most potent endogenous corticosteroids w/ respect to fluid and electrolyte tumor; Cushing’s disease)
balance ▪ Exogenous: ↑oral steroids for certain diseases

❖ Aldosterone Excess V. THERAPEUTIC USES OF CORTICOSTEROIDS

= Hyperaldosteronism A single dose of glucocorticoid, even a large one, is virtually without harmful effects, and a short
o Sodium balance with consequent expansion of ECF course of therapy (up to 1 week), in the absence of specific contraindications, is unlikely to be
o NI or slight increase in plasma sodium concentration harmful. As the duration of glucocorticoid therapy is increased beyond 1 week, there are time- and
o Hypokalemia (↓K) dose-related increases in the incidence of disabling and potentially lethal effects. Finally, abrupt
o Alkalosis cessation of glucocorticoids after prolonged therapy is associated with the risk of adrenal
insufficiency, which may be fatal.
= Chronic Hyperaldosteronism → hypertension
= Management: depends on underlying cause
❖ Replacement Therapy (Endocrine)
❖ Mineralocorticoid Deficiency Acute Adrenal Insufficiency Chronic Adrenal Insufficiency
= Sodium wasting & contraction of ECF, hyponatremia (↓Na), hyperkalemia Immediate management: isotonic Hydrocortisone 20 – 30 mg/d (lower:
(↑K), acidosis NaCl solution + 5% glucose + 15 – 20 mg/d)
corticosteroids Cortisone acetate 25 – 37.5 mg/d
Appropriate therapy for precipitating Glucocorticoids given in divided doses
❖ Aldosterone deficiency
causes (eg. infection, trauma, (2/3 in AM, 1/3 in PM)
= Leads to hypotension (↓BP) and vascular collapse
hemorrhage) Mineralocorticoid replacement:
Monitored for volume overload (eg. fludrocortisone acetate 0.05 – 0.2
❖ Skeletal Muscle ↑central venous pressure / pulmo mg/d
= Muscle weakness in primary aldosteronism (mainly due to hypokalemia and edema)
not from direct effect on skeletal muscle) IV bolus of 100 mg hydrocortisone
= Treatment: Fludrocortisone given by continuous rate of 50 – 100
mg q 8 h
A. Summary of Pathology As px stabilizes, hydrocortisone may
❖ Deficiency = lack of corticosteroids (both cortisol & aldosterone) be decreased to 25 mg q 6-8 h
Same fashion as chronic adrenal
Primary Adrenal Insufficiency = 80% due to Addison’s disease
insufficiency
= Others: Idiopathic, CAH, Adenoma
Congenital Adrenal Hyperplasia
Secondary Adrenal Insufficiency = Pituitary adenoma
= Sheehan’s Syndrome All px w/ classical CAH require replacement therapy with hydrocortisone + those with
salt wasting must require mineralocorticoid replacement

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 Oral dose of hydrocortisone 0.6 mg/kg daily in 2 – 3 divided doses
Fludrocortisone acetate 0.05 – 0.2 mg/d
Unconfirmed Acute Adrenal Insufficiency
Initial mgt: 4 mg dexamethasone (can be substituted for hydrocortisone)
Failure to respond to cosyntropin → diagnostic of adrenal insufficiency
Adrenal Sufficiency (during surgery)
Glucocorticoid adjusted: hydrocortisone 100 mg parenterally every 8 h
Dose is halved each day until it is reduced to routine maintenance levels
❖ Non-endocrine Uses
Rheumatic disorders: PAN, GC is the mainstay tx
Wegener’s granulomatosis; For serious disorders: Prednisone 1mg/kg/d in
Churgstrauss syndrome; divided doses
Giant cell arthritis Often in conjunction with immunosuppressive agts
GC used as stabilizing agents in RA (dose of pred 5
– 10 mg/d)
Intraarticular injections given with intervals of 3
mos
Renal diseases GC as first-line tx in both adulst and children
Pred 1-2 mg/kg for 6 weeks → tapering for 6-8 wks
Membranous glomerulonephritis: alternate-day GC
for 8-10 weeks (pred 120 mg every other day) → 1
– 2 months tapering
Allergic diseases Severe disease: IV GC
Methylpred 125 mg IV every 6 h
Allergic rhinitis: intranasal steroids
Bronchial asthma
Preterm infants Antenatal glucocorticoids are used
Betamethasone 12mg IM every 24 h for 2 doses
Dexamethasone 6mg IM every 12h for 4 doses
These are given to women w/ signs of premature
labor bet 26 and 34 weeks
Ocular diseases, GI diseases, Administered topically for outer eye and anterior
Malignancies, organ segment
transplant, spinal cord injury, Intraocular injection for posterior segment of eye
cerebral edema 1% hydrocortisone ointment – eczematous
eruption
Severe episodes of acute dermatologic disorders
and chronic exacerbations – Prednisone 40mg/d
Pemphigus – Prednisone 120 mg
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Autoimmune hepatitis – Initial, Prednisone 40 – 60
mg tapered to 7.5 – 10mg daily
Malignancy – GC as component of combination
therapy
Cerebral Edema Dexamethasone 4 – 16 mg every 6 h
Miscellaneous uses For sarcoidosis (w/ pulmo involvement:
Prednisone 20 – 40 mg/d)
For thrombocytopenia, prednisone 0.5 mg/kg
Idiopathic thrombocytopenia – Prednisone 1 – 1.5
mg/kg
For autoimmune destruction of erythrocytes –
Prednisone 1mg/kg/d
Organ transplantation – Prednisone 50 – 100 mg +
immunosuppressive agents
Spinal Cord Injury – Methylprednisolone Na
succinate 30mg/kg → 5.4 mg/kg/h for 23 h
❖ Diagnostic Application
▪ Overnight Dexamethasone Suppression Test
= Determines if patient w/ clinical manifestations of hypercortisolism
with evidence of ↑cortisol biosynthesis
= Patients are given 1mg of dexamethasone orally at 11pm then
cortisol is measured at 8 am the next morning
Dexamethasone
= Used as first line agent to diagnose hypercortisolism and to
differentiate among the different causes of cushing
syndrome
Formal Dexamethasone Suppression Test
= Used in differential diagnosis
= Determination of baseline cortisol levels for 48 h → dexa 0.5
mg every 6 h orally for 48 h (dose suppresses cortisol levels
in normal subjects)
= High-dose phase of test: dexa 2mg orally every 6 h for 48 h
(patients with Cushing → respond with ↓cortisol levels
however px w/ ectopic prod of ACTH or tumors → do not
exhibit ↓cortisol levels)
▪ Metapyrone
= Inhibitor of CYP11B1
= To check for integrity of entire HPA axis
= Dose: 30 mg/kg (Max: 3 g) administered orally w/ a snack at
midnight
= Plasma cortisol & 11-deoxycortisol: measured at 8am the next
morning
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 AE: hyperglycemia, gallstones, transient GI discomfort
Plasma cortisol <8 ug/dL = validates adequate inhibition of CYP11B1
11-deoxycortisol <7 ug/dL = highly suggestive of impaired HPA function Cabergoline
▪ Long acting D2 receptor agonists
VI. CORTICOSTEROID TOXICITY ▪ For hyperprolactinemia
▪ Sudden withdrawal of corticosteroids after prolonged therapy → acute adrenal Inhibits ACTH secretion from corticotroph tumors (which are often D2 receptor
insufficiency (most severe) positive)
o Fever o Malaise
o Myalgia o Pseudotumor cerebri (↑intracranial ❖ INHIBITORS OF STEROIDOGENESIS
o Arthralgia pressure w/ papilledema) Ketoconazole
Most frequent problem in steroid withdrawal → flare up of underlying disease ▪ At higher doses → Inhibits activity of CYP17 → inhibition of adrenal & gonadal
Patients who have received supraphysiological doses (2-4 weeks) → HPA steroidogenesis
impairment Even higher doses: inhibits CYP11A1
▪ Continued use of supraphysiological corticosteroid doses can result to ▪ Indication: Cushing disease
complications ▪ Dose: 600 – 800 mg/day in 2 doses
Fluid & Electrolyte Hypokalemic alkalosis, edema, hypertension, SE: hepatic dysfunction
Problems hyperglycemia, glycosuria
Immune response ↑susceptibility to infection Metyrapone
Risk for reactivation of latent TB ▪ Selective inhibitor of CYP11B1 (11-hydroxylase) → impaired cortisol production
Peptic ulceration → ↑precursor levels (11-deoxycortisol)
Myopathy Weakness of proximal limb muscles Used to diagnose patients w/ Cushing’s syndrome & treat hypercorticism
Behavioral changes Adjunctive treatment in patients who have received pituitary irradiation
Cataracts Related to both dosage & duration of therapy SE: hirsutism
Children – particularly at risk Others: Etomidate (off-label use, inhibits CYP11B1; bolus of 0.03 mg/kg IV), Mitotane
Osteoporosis 30-50% of patients (for tx of inoperable adrenocortical carcinoma; inhibits CYP11A1)
↓bone density
Inhibition of gonadal steroid hormone ❖ GLUCORTICOIDS ANTAGONIST
Diminished intestinal uptake of calcium Mifepristone
Prevention: Bisphosphonate (alendronate, ▪ Progesterone receptor antagonist
etidronate) Can terminate early pregnancy
Osteonecrosis Avascular / aseptic necrosis ▪ Higher doses: inhibits GR, blocking feedback regulation of HPA axis
Femoral head frequently affected Indicated for patients with hypercorticism due to its ability to inhibit
Earliest signs: joint pain & stiffness glucocorticoid action
Growth retardation Even in small doses especially children Recommended only for patients with inoperable causes of cortisol excess
Orphan drug status for tx of hyperglycemia secondary to endogenous Cushing
❖ INHIBITORS OF ACTH SECRETION syndrome in px who have T2DM
Pasireotide
▪ Somatostatin analog ❖ ANTI-MINERALOCORTICOID
Inhibits ACTH secretion & ↓circulating levels of cortisol in patients with ACTH- Spirinolactone
producing pituitary tumors ▪ Mineralocorticoid antagonist
FDA-approved for use in px with Cushing disease who are not candidates for ▪ MOA: competes with binding of receptors for aldosterone in the distal
surgery convoluted tubule
Subcutaneous doses of 0.6 – 0.9 mg twice daily ▪ Sodium and water are excreted but K is retained

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 Treatment for primary & secondary hyperaldosteronism
Treatment for edema and hypertension

VII. DRUG SUMMARY: CORTICOSTEROIDS & ANTAGONISTS

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Chapter 35: IMMUNOSUPPRESANTS & TOLEROGENS
Note: In this chapter, please read more on your book. Only included tables for this part.
A. Summary of Topics
Immunosuppressive Drugs ▪ Glucocorticoids
▪ Calcineurin inhibitors
▪ Antiproliferative/antimetabolic agents
▪ Biologicals
Tolerogens ▪ Sirolimus (mTOR inhibitor)
▪ Abatacept/Belatacept (T-cell costimulatory blocker)
Immunotherapy for Multiple Sclerosis

Table 35-1: SITES OF ACTION OF SELECTED IMMUNOSUPPRESSIVE AGENTS ON T-CELL

ACTIVATION
DRUG SITE (AND MECHANISM OF ACTION)
Glucocorticoids Glucocorticoid response elements in DNA (regulate gene transcription)
Cyclosporine Calcineurin (inhibits phosphatase activity)
Tacrolimus Calcineurin (inhibits phophatase activity)
Azathioprine DNA (false nucleotide incorporation)
Mycophenolate mofetil Inosine monophosphate dehydrogenase (inhibits activity)
Sirolimus mTOR, protein kinase involved in cell-cycle progression (inhibits activity)
Everolimus mTOR, protein kinase involved in cell-cycle progression (inhibits activity)
Belatacept Costimulatory ligands (CD80 & CD86)
Present on antigen presenting cells (inhibits activity)
Alemtuzumab CD52 protein, widely expressed on B cells, T cells, macrophages, NK cells
(induce lysis)
Murmonab-CD3 T-cell receptor complex (blocks antigen)
Daclizumab, IL-2R (block Il-2 mediated T cell activation)
Basiliximab

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