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Antidiabetic Agents

Name
Regular Insulin

Class/Subclass & Mechanism


of Action (MOA)
Bioengineering - from e coli.
FAST ACTING

ABDE

Give IM or IV for emergencies (only


one), up to 8 hours of duration.

Therapeutic Uses & Specificity

Used for preprandial administration


(30 minutes before meals).

Toxicity and Side Effects

Lispro Insulin
Isophane Insulin
Suspension
(NPH Insulin)
Insulin Zinc (Lente
Insulin)
Extended Insulin Zinc
Suspension
(Ultralente
Insulin)

Hypoglycemia (10-15% have 1


episode/year) for those on rigid
treatment (70-110 mg/dl).
Allergic rxns,
bovine>porcine>human
Skin rxns: urticaria, subQ
fibrosis, localized atrophy.
Insulin resistance insulin
dose.

absorption time gives greater


flexability.
Used for preprandial administration.

Same.

Used to sustain basal levels of


insulin.

Same.

Combination makes it rapidly


absorbed but sustained duration of
action (24 hours).

Used to sustain basal levels of


insulin.

Same.

Because of its very large crystals it


is released very slowly and has the
longest duration of action.

Same, plus longest lasting


hypoglycemic affect (duh!).

Insulin analog (reverse amino acids 28


and 29 on chain).
FASTER ACTING

Give IM - faster absorption from


subQ site (15 minutes) than insulin.

Crystalline zinc insulin conjugated to


protamine (polypeptide).
INTERMEDIATE ACTING

Give IM only - less soluble so slower


release from injection site. Duration
of up to 24 hours.

Combination of zinc crystalline form and


amorphous form of insulin.
INTERMEDIATE ACTING

Very large crystalline zinc insulin


suspension.
LONG ACTING

Insulin General Principles: The different insulin preparations vary primarily in their time of onset and duration of activity. This is mostly due to the size and composition of the insulin crystals. Insulin is
inactivated in the kidney and liver by insulinase. The Diabetes Control and Complications Trial (DCCT) found that by intensively controlling blood glucose levels reduced the levels of long-term
complications (retinopathy, neuropathy, etc.). It also showed though that patients who had a stricter control of their blood sugar were also more likely to have a hypoglycemic reaction. Most commercially
available insulin is made from e coli. Insulin is important for normal growth and development (it is a growth factor during development). Try to postpone use of insulin as long as possible (type II).

Tolbutamide (Orinase)

1st generation sulfonylurea. Interferes


with ATP/K+ channeldepolarization and
Ca++insulin release.

Duration of action highly variable.

Cornerstone of oral monotherapy


used in type II for patients >40yrs.
Good initial response but benefits
wane with continued use (2nd
failure). After 6-9 years only 10%
still using.

Severe side effects in only 2-4%,


weight gain, hypoglycemia, rash.
Disulfiram rxn when taken with
alcohol.
Drug interactions - bound to
plasma proteins.

1st generation sulfonylurea. Same.

Longest lasting (up to 48 hours).

Same.

Same.
Not for the elderly because of
long lasting.

Glyburide (Micronase)

2nd generation sulfonylurea. Same.

More lipophilic and more potent


(100X). Duration of effects are 12 to
24 hrs.

Same.

Same.

Glimepiride

3rd generation sulfonylurea. Same.

Same. Only hypoglycemic approved


to be taken with insulin.

Same.

Metformin
(Glucophage)

Biguanide-related. hepatic output of


glucose.

Is the only class of hypoglycemics


that does not cause severe
hypoglycemia.

Fatal lactic acidosis (rare).


Metallic after-taste.
May reduce Triglycerides.

Troglitazone (Rezulin)

Glitazone - glucose utilization and


receptor response to insulin.

May development of NIDDM.


Used with insulin.
Related to Vitamin E - antioxidant.
Can be used with sulfonylureas.

Rare but serious liver failure (like


when is liver failure not serious)
so use newer drugs
(rosiglitazone and pioglitazone).

Acarbose (Precose)

-glucosidase ihibitor (inhibits brush


border enzyme that breaks down sugars
in SI glucose uptake).

Administered prior to meals.

Only for very mild type II, not for


moderate to severe.
Can be used with sulfonylureas.

Flatulence, diarrhea, cramps all


that yummy sugar for gut
bacteria.

Repaglinide (Prandin)

insulin release but different than


sulfonylureas. Only insulin release with
high glucose concentrations.

Give preprandially - fast acting and


will insulin with plasma glucose.

Less likely to cause hypoglycemia,


safe for elderly.

Similar to sulfonylureas.

Name

Class/Subclass & Mechanism of


Action (MOA)

Prednisone

Potent synthetic anti-inflammatory


corticosteroid with less mineralocorticoid
activity than cortisol.

Orally, IV, or IM.

Intermediate acting 18-36 hours.

Potent long acting synthetic


corticosteroid.

Orally, IV, or IM.

Long acting (1-3 days)

Chlorpropamide
(Diabinese)

Can be used in combination with


sulfonylureas.

Corticosteroid Agents

Dexamethazone
(Decadron)

ABDE

Therapeutic Uses & Specificity

Toxicity and Side Effects

Beclomethasone
(Beclovent)

Used in an inhaler for asthma


treatment.

Triamcinolone
(Azmacort)

Used in an inhaler for asthma


treatment.

General Principles: Synthetic agents much more potent anti-inflammatory (A-I) with little or no mineralocorticoid effects. A-I effects cannot be separated from metabolic effects.
Glucocorticoids suppress axis if exceed 20 mg/day hydrocortisone. Sudden cessation is very bad for patient. Major actions on immune system: PMNs in blood, all other WBC
in blood, monocytes reactivity and IL-1 and TNF secretion, inhibit T lymphocytes but little B lymphocytes, inhibits IgE mediated rxns, inhibits phospholipase A2 by lipocorton.
Bad effects of long term use include: cataracts, hypertension, peptic ulcer dz (indirectly), osteoporosis and myopathy, obesity, acne, hirsutism, hyperglycemia, muscle atrophy,
convulsions, mood changes, thin skin, striae, penis envy (just kidding - seeing if you were awake ), wound healing, suppression of cellular immunity. Treatment for

bronchiole asthma: mediator release (eos, PMNs, monos/macs), macs/T cell interactions, chemotaxis of monos and PMNs, IgE production, block late asthmatic response,
nonspecific airway responsiveness, reverse desensitization of receptors. Adverse rxns to inhaler: oral cndidiasis, dysphonia.
ANDROGEN AGENTS

Name
Testosterone

Class/Subclass & Mechanism of


Action (MOA)
Active hormones

ABDE

Acts on reproductive tissue (testes,


prostate, etc.), pituitary, hair

DHEA, androstenedione

Produced in adrenal glands, weakly


androgenic

Danazol (Danacrine)

Esterified androgens (in notes, but


not on list)
Androgen Derivatives

Methyltestosterone

Scalp hair loss, prostatic hyperplasia or


carcinoma

Duration of 2-4 weeks, IM injection

An alkylated androgen (effective


orally)

A weak androgen, progestin, and


glucocorticoid

Used in women to treat endometriosis.


Negative feedback, prevents
proliferation and menstruation of ectopic
uterine tissue

Hepatotoxicity particular to oral androgens:


cholestatic hepatitis, jaundice, adenoma,
carcinoma, peliosis hepatis

An alkylated androgen

A part of HRT during menopause (may


avoid hot flashes, etc.)

Relatively low doses used (avoids


hepatotoxicity)

Oxandrolone (Oxandrin),
Stanozolol
(Winstrol)

Anabolic androgens

Derivatives of androgens that have


metabolic effects, reproductive
effects.

Rx of anemia and to stimulate


weight gain after surgery, infection,
AIDS (oxandrolone)

Rx of heriditary angioedema
(stanozolol)

Flutamide (Eulexin)

Androgen Receptor Antagonists

Rx or prostate cancer

Cyproterone acetate
(Androcur)
Spironolactone

Toxicity and Side Effects

Diffuses into cell, binds to intracellular


receptor located primarily in nucleus

Can be converted to DHT or estradiol


within the cell

Acts on skeletal muscle, bone,


probably kidney

Dihydrotestosterone
(DHT)

Testosterone cypionate

Therapeutic Uses & Specificity

Rx of severe acne, hirsutism, virilization


Aldosterone and androgen receptor
antagonist

Rx of hirsutism

According to lecture is outdated (along w/


ketoconozole)

Finasteride (Proscar,
Propecia)

Androgen synthesis inhibitors

Blocks conversion of testosterone to DHT


by inhibiting 5-reductase II

Rx of BPH (proscar)
Rx of hair loss (propecia)

Some decrease in libido, impotence

Leuprolide (Lupron),

GnRH agonists

Chronic administration down-regulates


axis (non-physiologic tonic exposure).

Precocious puberty

Endometriosis

Advanced prostate cancer


(alternative to surgical castration)

Hot flashes/sweats, impotence

Goserelin
(Zoladex)

1) Physiologic actions of androgens


a) Intracellular receptors that modulate
transcription
b) Reproductive
i) Sexual differentiation, development,
growth, and maintenance of primary
and secondary sex characteristics in
men
ii) Early stages of puberty (females)
iii) Stimulates spermatogenesis
iv) Feedback inhibition of gonadotropin
v) Libido
c) Anabolic
i) Increases protein synthesis
ii) Muscle growth
d) Effects on growth
i) Skeletal growth and closure of
epiphyses
ii) Growth of larynx w/ voice deepening
e) Metabolic/hematologic
i) Erythropoiesis (stimulates release
from kidney)
ii) Decreased synthesis of clotting
factors
iii) Sebum production in skin
iv) synthesis of HDL, synthesis of
LDL
2) Side effects of androgens
a) Common
i) Acne
ii) Gynecomastia (estradiol)
iii) Scalp hair loss (DHT)
iv) Sleep apnea
v) In women: amenorrhea and
virilization (acne, increased muscle
mass, hirstuitism, voice changes,
male pattern baldness)
b) Potentially serious adverse effects
i) Hepatotoxicity (see chart)

ii)

Premature bone maturation and


epiphyseal closure (age<13)
iii) risk of cardiovascular disease
(unfavorable lipid profile)
iv) Edema
v) Testicular atrophy and oligospermia
vi) Prostatic hyperplasia or carcinoma
(DHT)
3) Absolute contraindications
a) Carcinoma of breast or prostate
b) Pregnancy
c) Age < 13 years
4) Relative contraindications
a) Preexisting cardiac (edema), renal
(edema), or liver (hepatotoxicity) disease
b) Individuals on anti-coagulants (see
1.e.ii)

Bone Mineralization Agents

Name

parathyroid hormone
(Teriparatide)

human calcitonin
(Cibacalcin or
Calcimar)

Class/Subclass & Mechanism of


Action (MOA)

Hormones and Vitamins


Stim. Bone resorption
Increses renal absorp. of Ca++
Decreases reanal absorp. of PO4
Increases Calcitriol synthesis
(thereby increases intestinal absorp.
of Ca++ and PO4)

T1/2= minutes

Salmon prep: longer t1/2 and


duration of action; 50Xs more
potent.
Inhibits bone resorption and renal
tubular absorp. of Ca++ and PO4
Stimulated by increased levels of
serum Ca++ (but sm. Role in Ca++
homeostasis)

Blocks bone resorption (stim. OPG


production which inactivates OPGligand)
Increases Vit D. activation (kidney)

Oral (daily)

Synthetic hormone derived from


plants
Prevents bone demineralization and
vasomotor effects

Oral (daily)

Selective estrogen receptor


modulator (SERM)
Estrogenic on bone & lipid metab.
And blood clotting
Blocks estrogens effects on breast
and endometrial tissue (lowers risk
of breast CA)
Decreases LDL chol
Increases risk of thromboembolic
disease 3Xs

Oral

estrogen

esterified estrogen
tablets
(Estratab)

raloxifene (Evista)

estradiol transdermal
system
(Climara)
calcifediol (25(OH)
cholecalciferol

ABDE

As effective as Calcitriol at
increasing absorp. Of Ca++ and
PO4
Less effective at increasing bone
resorption or intestinal absorption of
Ca++ or PO4

Only used to differentiate between


true and PseudohypoPTH

Toxicity and Side Effects

Xenical (orlistat) reduces


absorption

Osteoporosis Paradoxically,
intermittent tx (once/day) causes
more bone formation than resorption

SC, IM
Inactivated by proteolysis
T1/2 = minutes
Effect begins after several hrs. and
lasts up to 10 hours.

Initial Tx of severe hyperCa++


Pagets disease (osteitis
deformans) (increased bone
remodeling).
Postmenopausal osteoporosis

Posmenopausal hormone
replacement therapy (HRT)

Prevention of Osteoporosis in

Prevention of Osteoporosis

combo w/ progesterone, Ca++, and


Vit. D.

NO increase in endometrial
hyperplasia

Patch (once/wk) - 0.025mg/wk lowest


estrogen replacement dose to prevent
osteopor.

Therapeutic Uses & Specificity

Prevention and Treatment of Post


menopausal Osteoporosis
Cuts spinal fx by 50%
Increases spine and hip bone
mineral density

Prevention of Osteoporosis

Osteomalacia secondary to liver


disease (doesnt require liver
activartion)
Renal osteodystrophy (secondary
to Chronic renal disease)
Advantage: less effective at stim.
Ca++ uptake, therefore, less
effective at causing hyperCa++

Salmon prep: long-term pts


develop antibodies, local inflamm.
reactions, hypersensitivity rxns
(bronchospasm, anaphylaxis)
Flushing of face/hands and n/v
(minimized by giving at bedtime)
Urinary freq. (w/ human calcitonin)
Pathophysiological comp:
Increased risk in women prone to
breast or endometrial CA
SE: n/v, migraine, breast
tenderness, spotting, pelvic
discomfort, mood changes,
endometriosis

Bone Mineralization Agents

Name

calcitriol (Rocaltrol;
1,25(OH)2D

Class/Subclass & Mechanism of


Action (MOA)

ABDE

Active form of Vit D.:


Increases intestinal absorption of
Ca++ and PO4
Stimulates bone resorption by
facilitating effects of PTH
Stimulates renal absorption of Ca++
and PO$

Therapeutic Uses & Specificity

Vitamin D2
(ergocalciferol)

Requires activation in liver and


kidney

Vitamin D3
(cholecalciferol
)

requires activation in liver and


kidney

Does Not require activation by the


kidney
Requires activation in the liver
(requires 1-2 weeks to increase
serum Ca++, but less $ (vs)
Calcitriol

dihydrotachysterol

Toxicity and Side Effects

DOC when rapid action is required


(it can raise Ca++ in 1-2 days)
Osteodystrophy (secondary to
malabsorb. Of Vit. D and Ca++)
given with Ca++
X-linked hypoPO4 rickets (from
decreased PO4 reabsorption by the
PT.
Type I Vit.D- dependent rickets
(deficient a-1hydroxylation) or can
give pt. Vit. D
Type II Vit. D-dep. Rickets
(decreased target organ sensitivity)
must give large doses
Postmenopausal Osteoporosis
(due to estrogen defic.) also give
with estrogen, Ca++ and Vit. D
Hypoparathyroidism (because
decreased PTH decreases calcitriol)
Nutritional Rickets too little sun
or poor diet

X-linked hypoPO4 rickets (from


decreased PO4 reabsorption by the
PT.
Renal osteodystrophy (secondary
to Chronic renal disease)
Disadvantage: hyperCa++ can occur
Hypoparathyroidism (because
decreased PTH decreases calcitriol)

Hypocalcemia

Calcium

Symptoms: Tetany, paresthesias,


neuromuscular excitability,
laryngospasm, muscle cramps, and
convulsions.

Causes: deprivation of Ca++ , Vit D. or


hypoparathyroidism, use of antiepileptics
(phenytoin, phenobarb) glutethimide, or
rifampin.

Element: Ca++ salts

Low Ca++ tetany

Ca++ has little effect on rapid bone loss


right after menopause, but reduces later
bone loss at total intake of 1200-1500
mg/day
Ca-Gluconate

Slow IV infusion (rapid can cause cardiac


arrhythmias)

Ca-gluceptate

IV or IM

Hypercalcemia (this is the major SE of


all Calcium preparations)
IV Calcium can ppt. Arrhtthmias in
patients taking Digitalis (it enhances its
action)
Interactions: Ca++ can reduce the
bioavailability/absorption of some drugs

Severe hypocalcemia
More irritating, can cause local reaction,
Metalic taste

phosphate

Ca-chloride

IV (NOT IM)

Ca-carbonate

Oral (better w/ meals depends on


stomach acid for solubilization)

Ca-citrate

Oral doesnt depend on acid, better for


elderly pts

Tri-Ca++ PO4
Di-Ca++ PO4 (used for simultaneous Tx.
of hypoCa++ and hypoPO4)

IV or Oral (IV is more dangerous than


oral)

Very irritating enterally or parentally


Mild hypo Ca++

Oral phosphate: used primarily for Xlinked familial hypoPO4

Oral and IV phosphate can cause


ectopic calcification, kidney failure, and
death. Monitor serum Ca++ and PO4 to
avoid these hypoCa++ and hypoPO4.

Bone Mineralization Agents


Name

etidronate (Didronel)

Class/Subclass & Mechanism of


Action (MOA)
Bisphosphonates/related drugs

reduces osteoclast # and or activity


which slows bone resorption

ABDE

Oral absorption is dose dependent


(food or divalent cations reduce
absorp)
IV achieves much higher blood
levels
of absorbed drug accumulates in
bone & turns over, the rest is rapidly
excreted by the kidney

Therapeutic Uses & Specificity

Toxicity and Side Effects

As good as of better than Calcitonin


for Pagets disease
Advantage:1)oral efficacy 2) lower cost
3)lacks antigenicity 4) better outcome
Disadvantage: 1)high dose tx impairs
mineralization of osteoid, causing
osteomalacia, leading to incresed risk of
fractures

After hip replacement or spinal


injury

Hypercalcemia of Malignancy (IV)

Tx of choice for mod-severe


hyperCa++ associated with
malignant neoplasms
Tx of Pagets disease

weekly after pt is rehydrated and


has adequate urine flow

edatate (EDTA,
Chealamide)
pamidronate (Aredia)

100Xs more potent than Etidronate


more efficacious
doesnt affect bone mineralization

ONLY given IV

alendronate (Fosamax)

Oral (absorption is decreased in


presence of food, antacids, or Ca++
supplements)

risedronate (Actonel)

Hypercalcemia

Mostly Asymptomatic
Sx: polyuria, n/v, constipation,
neuropsychiatric d/os

furosemide
(Lasix)

Inhibits the Na/K/2Cl cotransport in


the thick ascending limb

plicamycin (Mithracin)
(formerly mithramycin)

corticosteroids
(Prednisone)

Only Bisphosphate for tx of


Postmenopausal and
glucocorticoid-induced
osteoporosis

Strong irritant effect mild to severe


(ulcerative) esophagitis (risk is
decreased if taken 30 minutes
before 1st food/drink of day

Pagets disease

Tx depends on the underlying cause

Given with Ca++ freessaline to increase


renal excretion of Ca++

Mild hyperCa++

Hypokalemia
Ototoxic (mild)
dehydration

cytotoxic antibiotic that blocks


nucleic acid and protein synthesis in
OSTEOCLASTS

severe hyper Ca++ from carcinomas


w/ or w/o mets

Thrombocytopenia (w/ hemorrhage


Hepatotoxic
Nephrotoxic
Must follow Platelets, LFTs, and
kidney function tests

Vit D. toxicity: reduces Vit. D


enhanced intestinal absorp. of Ca
Sarcoidosis: shrinks sarcoid tissue
and reduces Calcitriol production
Toxic to glucocorticoid sensitive
tumors

Used if hyperCa++ is due to: 1)


Vit.D toxicity 2)sarcoidosis
3)multiple myeloma

*Partlow Take Home Message


Name

Thyroid-Antithyroid Agents
Class/Subclass & Mechanism of
Action (MOA)

ABDE

Therapeutic Uses & Specificity

Toxicity and Side Effects

levothyroxine
(Synthroid,
Levothroid,
Levoxyl)

Thyroid hormone
Na+ salt of T4

propylthiouracil (PTU)

Na+ salt of T3

Antithyroid drugs:Thioamides
Block thyroid synthesis

#Competition for albumin binding


sites w/ salicylates or dicumarol
the free level of active thyroid
hormone. Death has occurred
due to arrhythmias with thyroid
hormone replacement.*

Preferable Tx for myxedema coma


(rare) due to quick response*

See # above

ATDs alone for hyperthyroidism


Advantagesavoid surgery and
radioactive Iodine, no danger to
parathyroids and nerves, incidence
of progressive opthalmopathy may
be lower, remission more likely in
younger pts, no danger of fatality,
cheap, no hospital stay.
Disadvantageshigh incidence of
relapse when withdrawn, requires
periodic checkups and dosing over
years.
ATDs + radioactive IodineATDs
used while awaiting gland destruct.
ATDs + SurgeryATDs used to
make pt euthyroid prior to surgery to
reduce operative mortality.
Thyroxine or Iodide is added
immediately preoperatively

Contraindicated in nursing
mothers, but used with great
caution in hyperthyroidism
complicated by pregnancy.
Preferred over methimazole but
can cause neonatal goiter
Agranulocytosisthe most
serious adverse reaction(.44%
PTU, .12% methimazole) Appears
suddenly, first months of therapy,
preceded by sore throat and
fever.* Pts must be warned of
this, more common in older pts
and those on higher doses.
Bleedingmonitor with PT time
Rashmost common side
effect(cross-sensitization is rare
so change ATD)

See above section

quick response, short time course


Effects after parenteral admin begin
4-6 hr, max at 2 days, disappear
with time of 8 days
Oral absorp95%
T1/2=1day

protein binding80%
cross placentalow
enter milklow (10% [plasma])
T1/21-2 hrs
Bioavailability80-95%

Thyroid hormone

triiodothyronine,
liothyronine
(Cytomel)

Hypothyroidism (distinguish 1 from


2 because 2 must be treated first.
Test with TSH and TRH)
In healthy younger pts full dose can
be given. Those over 60 must
receive lower initial doses due to
potential heart problems.
Titration of hormone dosage*-Plateau levels should not be
measured until 4-6 weeks after
beginning or changing thyroid dose.
Check T4 and TSH. Check
hormone levels if changing brands.

Dose is 4x T3 due to its potency


Effects after parenteral admin are
max after 9 days, disappear with
time of 11-15 days.
Oral absorp50-80%
30-40% recovered in stool
Applies to T4 and T3absorption
better on empty stomach, certain
drugs block absorp (cholestyramine
resin, sucralfate, Fe suppl, AL(OH)).
Terminated by conjugation w/
glucuronic or sulfuric acids and
excreted in bile. Use ok in
pregnancy due to poor placental
transfer*, dose may have to be
increased
T1/2=7 days, hormonal effects
outlast hormone in the blood.

methimazole
(Tapazole)

Antithyroid drugs:Thioamides
Block thyroid synthesis

Iodide

Antithyroid drugs: other

protein binding0%
cross placentahigh
enter milkhigh (100% [plasma])
T1/23-5 hrs
Bioavailability80-95%

hyperthyoidismnot used much


anymore.

contraindicated in nursing
mothers
Agranulocytosis, bleeding, rash
see above
effects wane with time

blocks synthesis and secretiona little is


required but too much shuts down the
gland

Thyroids continued
Name

radioactive iodine

Class/Subclass & Mechanism of


Action (MOA)

ABDE

Antithyroid drugs: other

Damages gland via selective uptake


followed by local radiation damage

Thyroid traps iodide, 90% of a dose


can be accounted for in thyroid or
urine

Therapeutic Uses & Specificity

propranolol(Inderal)

Beta-adrenergic antagonist
Blocks the adrenergic activity in
hyperthyroidism, reducing tachycardia
and arrhythmias
conversion of T4 to T3. Inhibits hepatic
monodeiodinase. Might explain unique
value of propanolol over other Beta
blockers. Serum T3 levels fall by 20%
once daily Beta blockers are more
convenient and in some cases Beta1
selective agents might be better because
of other pathological conditions

Toxicity and Side Effects

Treat hyperthyroidism
Advantagesavoids surgery, no
lethality, risk to parathyroids or
nerves, or risk of disfigurement
Cheap, no hospitalizations

Suppresses signs and symptoms of


thyrotoxicosis (its major therapeutic
use)* Usually used in combo with a
thioamide and/or iodide

High incidence of hypothyroidism


Can require multiple exposures to
control and therefore can take up
to a year during which ATDs are
usually used to cover the
hyperthyroidism