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B6 Pharm Exam 1 (Lectures 1-7)

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Adenohypophyseal Physio - - 3 func anat components = hypoth, adenohypophysis (ant pit), periph endoc gl/tiss - hypoth secr 2 horm types to hypoth-hypoph port sys in med emin = rel horms (RH, liberins) & rel-inhib horms (IH, statins) w/ hypoth-hypoph port sys carrying horms to ant pit Synthesis...

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adenohypophyseal physio
gh deficiency
srls
b6 pharm exam 1 lectures 1 7
synthesis regulation of growth hormone
physiologic pharmacologic stimulation of gh
physiologic pharmacologic inhibition of gh

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B6 Pharm Exam 1 (Lectures 1-7)
Adenohypophyseal Physio - - 3 func anat components = hypoth, adenohypophysis (ant
pit), periph endoc gl/tiss
- hypoth secr 2 horm types to hypoth-hypoph port sys in med emin = rel horms (RH,
liberins) & rel-inhib horms (IH, statins)
w/ hypoth-hypoph port sys carrying horms to ant pit

Synthesis & Regulation of Growth Hormone (GH, somatotropin) - - synth by ant pit
somatotropes (30-40% ant pit c)
- +by hypoth GHRH & Dopa
- -by GH, IGF-1, hypoth GHIH/somatostatin

Receptor, Target Organs, Peripheral Hormone Released by GH - -GH-r = tyr kin-assoc
R, memb JAK/STAT superfam
- Targets = liv, bone, musc, adip, kidney
- Periph horm = IGF-1

Physiologic & Pharmacologic Stimulation of GH - - Physio = GHRH, ghrelin, ADH,
GABA, NE, Dopa, serot, estrog, sleep, stress, exerc
- Pharm = alpha-ag, BB, Dopa ags (ie. Bromocriptine), GABA ag

Physiologic & Pharmacologic Inhibition of GH - - Physio = somatostatin, elev IGF-1, GH,
progest, GCs, postprand hypergly, elev FFAs
- Pharm = Dopa antag, alpha antag, beta ag, serot antag

General Effects of GH - (+) visc+sk growth, lipolysis, prot synth, IGF-1 prod --> suppr liv
gluc prod, incr periph gluc util, inhib insul secr
(-) insul sensit --> hypergly

Features of GH Deficiency (hypopituitarism) in Children & Adults - - Children & adols =
congen/acq def --> growth stunt, dwarf, +fat-musc mass ratio, hypogly by unopp insul
- Adult = -lean bod mass, +body fat to obes, -musc mass, asthenia (phys weak), -BMD,
dyslip, -CO

Examples, MOA, Administration, PK of Recombinant human GH (rhGH) - incl
Somatrem (protropin) & Somatropin (10 diff brand names)
- MOA = mimic GH physio actions
- Admin = 6-7x/wk
- PK = peak pl levs 2-4hrs w/ 36hr persis
- Route = IM & SQ, must be injec b/c is prot & not abs orally

Indications for rhGH - - Children & Adols = idiop short stat (ISS); **many growth fail
indics NOT assoc w/ GH def**
- Adults = AIDS-assoc wasting synd (cachex); UNSUBST for "anti-aging" or athletic perf
enh

,B6 Pharm Exam 1 (Lectures 1-7)
AEs & CIs for rhGH - - AEs = rare pseudotum cerebri (idiop intracran HTN), slipped cap
fem epiph, hypergly, DM, **asphyx in sev obese/resp impaired Prader-Willi synd** in
children+adols; more comm periph ed, myalg, arthralg, CTS in adults
- CIs = Prader-Willi w/ airw obstr/sleep ap/sev obes; active malig/neop, ac crit illness, ac
resp fail --> incr mort; active/sev diab retinop, closed epiph in peds

Clinical Notes for rhGH - - GCs may inhib growth-prom effs
- concom androg, estrog, thyr horm, anab sters may accel epiph clos comprom final
height
- GH treat crit ill pts incr mort

Examples, MOA, Indications of Recombinant human IGF-1 (rhIGF-1) - incl Mecasermin
(increlex, plain IGF1) & Mecasermin rinfabate (Iplex, rhIGF1+rhIGFBP-3)
- MOA = mimic IGF1 physio actions
- Indics = SQ 2x/d for IGF1 def, pts nonresp to GH (ie. GHR muts, GH ABs)

Description & Treatment Options for Excess GH (hyperpituitarism) - acromeg/gigantism
by incr GH and/or GH-secr pit adeno
- Nonpharm = transphen srug resec GH-secr adeno (rare complics CSF leak, mening,
arachnoiditis, DI, pit fail), rad ther for poor surg candids, fail surg/med ther resp
- Pharm = Somatostatin Analogs (ocreotide, lanreotide, pasireotide), GHR Antag
(pegvisomant), Dopa Ags (bromocriptine, cabergoline) for surg/rad CI, poor surg
success likelihood, rap sx control, ther fail

Categories & Examples of GH Antagonists for GH Excess - - Somatostatin analogs
(somato R ligs) = Ocreotide, Ocreotide LAR (long-ac rel), Lanreotide, Pasireotide
- GH-R antag = Pegvisomant
- Dopa ags = Bromocriptine, Cabergoline

Examples, MOA, Indications of Somatostatin Rec Ligands (SRL) - incl Ocreotide,
Ocreotide LAR (long-ac rel), Lanreotide, Pasireotide
- MOA = -GH rel (same as endog somatost)
- Admin = SQ Ocreo q8h, IM Ocreo LAR q28d (1mt IM dose), deep SQ Lanreo Depot
q28d
- Indics = Ocreo 1st line for acromeg, also carcinoid synd, VIPoma, esoph varices;
Lanreo 1st line for acromeg

AEs, Advantages, Disadvantages, Clinical Notes for SRLs - - AEs = GI n/d, abd cramp,
flatul, steat; injec site p; gallst w/ long-term; bradyarrhyth
- Adv = good @ decr GH, normalizing IGF1 most pts
- Disad = cost, weekly IM/deep SQ injec
- Notes = suppr GH, normaliz IGF1 (might be secondarily elev b/c GH incr), sx control

MOA, Indications, AEs, Advantages, Disadvantages of Pegvisomant for GH Excess - -
MOA = daily SQ GH-R antag normaliz IGF1 levels; modif GH blocking actual GH
binding to rec

,B6 Pharm Exam 1 (Lectures 1-7)
- Indics = 2nd line for acromeg in fail IGF1 reduction w/ SRL
- AEs = injec site p, GI n/d, elev hep aminotransf levels (LFTs to breakdown GH not
binding rec anymore)
- Adv = very effec IGF1 red
- Disad = expensive, LT effic+safety not det
- Notes = MONITOR b/c doesn't red GH, normaliz IGF1, sx control, hep func tests

Examples, MOA, Indications of Dopamine Agonists for GH Excess - incl Bromocrip &
Cabergoline
- MOA = D2 R antag w/ non-sel bromo, long-acting selec caberg; **paradox decr GH
prod in acromeg**
- Indics = 2nd line for acromeg (Caberg over Bromo); hyperprolactinemia (esp Bromo)

AE, CI, DI, Advantages of Dopamine Agonists for GH Excess - - AE = GI upset so take
w/ food, ortho hypoTN
- CI = uncontr HTN; breastfeed, sync migr w/ bromo; card valv dis,
pulm/pericard/retroperit fibr disords w/ caberg
- DI = **bromo w/ antimigr Triptans --> +prol vasospastic rxns by further narrowing cer
BVs**
- Adv = cost cheaper than SRLs, PO admin

ACTH Synthesis & Release - - synth by ant pit corticotropes w/ 10mins circ t1/2 (short
acting)
- pulsat rel peaking in morning

Difference b/w Peptide & Steroid Hormone Binding and Action - - Pep horms bind rec
already synth+expr on cell surf for quick rapid action
- Steroid horms bind intracell/nucl rec to incr DNA transcr+prot synth as TFs for slower
action but sust eff

Results of Adrenal Hyperactivation (Cushing synd) - - z glom --> +aldost --> decr
K+&H+ causing hypokal+metab alk, high Na+, high BP
- z fasc --> +cort --> incr gluc for hypergly
- z retic --> +androg/testost --> high testost causing viriliz+hirsut in females

Results of Adrenal Hypoactivation (Addison's dis) - - z glom --> -aldost --> incr K+&H+
for hyperkal+metab acid, hyponat, low BP
- z fasc --> -cort for decr gluc+hypogly
- z retic --> -androg --> decr sex drive

Physiological Effects of Mineralocorticoids - - Na+ abs reg in kid, col, sw+saliv gl
- aldost --> +Na ret, K+ excr by incr ENaC apic memb & Na/K ATPase basolat memb in
kid coll d

Aldosterone Regulation - - +by incr K+ & Angiotensin
- min + by ACTH

, B6 Pharm Exam 1 (Lectures 1-7)
- aldost has little -FB on ACTH

Types of Adrenal Insufficiency - - Prim AI (Addison's) = autoimm adr cort destr decr all
adrenocort horms
- Sec AI = hypoth/pit disords --> -CRH/ACTH --> -cortisol+androg but prob NO DECR
aldost; prol exog GCs --> -FB on CRH+ACTH; -cort+adr andorg synth but NOT
ALDOST

Description n& nEffects nof nAdrenal nHypofunction n(Congenital nAdrenal nHyperplasia) n-
ngroup ninher ndis nenz ndefs nimpair ncort+aldost nsynth, nincr nadr nandrog n-->
nvirilization+hirsut nin nfems
- most nby n21-hydrox ndef

Hydrocortisone nfor nAdrenal nInsufficiency n& nHypofunction n- nPO nsuppr nACTH nsecr
- 1:1 nGC nto nMC nactiv nNOT nsuffic nfor nMC nrepl

Fludrocortisone nfor nAdrenal nInsufficiency n& nHypofunction n- nprov nMC nactiv
- min n1st-pass nhep nmetab n(unlike naldost nitself) nw/ nhigh nMC nto nGC npotency n250:10
n -->
**PREF nfor nLONG nTERM ntreatment**

Treatment nof nAddison's nDisease n- nPO nHydrocort+Fludrocort
- AVOID nlong nacting nsynth nGCs nw/o nsalt-ret nactiv

Treatment nof nAcute nAdrenal nInsufficiency n(med nemerg) n- nimmed nIV nHydrocort nuntil
nstable n& ntreat nelectrol nabnorms
- switch nto nPO nmaint nHydrocort nonce nstable
- Fludrocort nonce nhydrocort<50mg/d

Treatment nof nCongenital nAdrenal nHyperplasia n- nac ncare nw/ nIV nelectrols+Hydrocort
- maint nPO nhydrocort+fludrocort; nalternate nday nPO nPrednisone nfor ngreater nACTH
nsuppr

AEs nof nGlucocorticoids n- n- nmoon nface
- buffalo nhump
- hirsut
- wt ngain
- musc nwaste+weak
- acne
- bruising
- thin nskin
- mood nch
- growth nretard
- hypergly
- HTN
- hypokal
- osteop
- cataracts
- glauc

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