DRUGSUSEDIN ENDOCRINE DISORDERS
1

The main endocrine glands are as follows:
2
Isletsof Langerhansin
the pancreas
In females
in males

The functions of the endocrine system are:
3
 producing and secreting hormones
🞑 whichregulate body activities suchasgrowth,
development and metabolism.
 maintaining the body during times of stress
 contributing to the reproductive process.

1. Drugs Used in Diabetes
4
 Diabetes Mellitus
🞑 T
ype 1:
 Early onset
 Lossof pancreaticBcells→ absolute dependence on
insulin(diet + insulin ± oral agents)
 Ketoacidosis-prone
🞑 T
ype 2
 Usually adult onset
 ↓ response to insulin → (diet → oral hypoglycemics ±
insulin)
 Not ketoacidosis-prone

Blood glucose
5

Actions of insulin
6

Insulin preparations
7

Insulin preparations…
8

Insulin preparations….
9

Onset andduration of actionof insulinpreparations
10

11

Oral antidiabetics:
12
The oral antidiabetic drugs are:
🞑sulfonylureas,
🞑metformin,
🞑acarbose,
🞑thiazolidinediones, and
🞑repaglinide.

Sulfonylureas
13
 Mechanisms:
🞑 Normally, K+ efflux inpancreatic β cellsmaintains
hyperpolarization of membranes, and insulin is released
only whendepolarization occurs.
🞑 Glucose acts as an insulinogen by increasing intracellular
ATP→ closure of K+ channels→ membrane
depolarization →↑ Ca2+ influx → insulin release.
🞑 Theacute action of sulfonylureas is to block K+ channels
→ depolarization → insulinrelease.

14
Mode of Action of Sulfonylureas

Sulfonylureas…
15
 Drugs: Second generation:
🞑 Glyburide alsocalled Glibenclamide (5– 10 mg/ d)
🞑 Glipizide: has the shortest half-life (2–4 hours)
🞑 Glimepiride – long acting & potent
🞑 Gliclazide: has a half-life of 10 hours

Sulfonylureas…
16
 Side effects:
🞑Hypoglycemia
 Symptoms: lip/tongue tingling, lethargy, confusion,
sweats, tremors, tachycardia, coma, seizures
 Treatment: oral glucose, IV dextrose if unconscious, or
glucagon (IM or inhalation)
🞑Weight gain
 Drug interactions mainly with1st generation drugs →↑
hypoglycemia with cimetidine, insulin, salicylates,
sulfonamides

Metformin
17
 “Euglycemic,” ↓ postprandial glucose levels, but does not
cause hypoglycemia or weight gain
 Mechanisms:
🞑 Metformin ↑ tissue sensitivity to insulin and/or ↓
hepatic gluconeogenesis.
 Use:
🞑monotherapy or combinations (synergistic with
sulfonylureas)
 Side effects:
🞑possible lactic acidosis; GI distressis common

Thiazolidinediones (glitazones):
Pioglitazone And Rosiglitazone
18
 Mechanisms:
🞑 bind to nuclear peroxisomeproliferator-activating
receptors (PPAR)involved in transcription of insulin-
responsive genes → sensitization of tissuesto insulin, plus ↓
hepaticgluconeogenesisand triglycerides and ↑ insulin
receptor numbers.
 Side effects:
🞑 lesshypoglycemia thansulfonylureas,but still induceweight
gain and edema and have potential liver toxicity.

GlucosidaseInhibitors
19
 glucosidase inhibitors primarily act to decrease
postprandial hyperglycemia.
🞑 by slowing the rate at which carbohydrates are
absorbed from the gastrointestinal tract.
 They act by competitively inhibiting glucosidases
🞑 a group of enzymesintheintestinalbrushborder
epithelial cells (glycoamylase, sucrase, maltase, and
dextranase)
🞑Example: acarbose

Agents Affecting Glucagon-like Peptide-1 (GLP-1)
20
 GLP-1 is an incretin released from the small intestine.
 It augments glucose-dependent insulin secretion.
 Exenatide
🞑is a long-acting GLP-1 receptor full agonist
🞑used in combination with other agents in type 2
diabetes.
🞑S/Es: nausea, hypoglycemia when used with oral
sulfonylureas.
 Sitagliptin and Other Gliptins
🞑inhibits dipeptidyl peptidase (DPP-4) thereby
inhibiting the inactivation of GLP-1.

Action of Drugs Affecting GLP-1
21

Others
22
 Canagliflozin:
🞑 isSodium-glucoseCotransporter-2 (SGLT-2)Inhibitor in
the proximal tubule, increasing glucose excretion.
 Pramlintide:
🞑 isa syntheticversionof amylin that ↓
 the rate at which food is absorbed from the intestine,
 glucose production, and
 appetite.
🞑 It isused in type 1 and type 2 diabetes.

2. Sex Hormones
23

Actionsof oestrogens and progestins
24

Actions of oestrogens and progestins…
25
Progestins
Oestrogens

Estrogens
26
 Estradiol is the major natural estrogen.
🞑 R
ationale for syntheticsisto
 ↑ oral bioavailability,
 ↑ half-life, and
 ↑ feedback inhibition of FSHand LH.
 Drugs:
🞑 Ethinyl estradiol and mestranol—steroidal

27
 Clinical uses:
🞑 Female hypogonadism
🞑 Hormone replacement therapy (HRT)in menopause →↓
bone resorption (↓ PTH)
🞑 Contraception—feedback ↓ of gonadotropins
🞑 Dysmenorrhea
🞑 Uterine bleeding
🞑 Acne

28
 Side effects:
🞑 General: Nausea, Breast tenderness, Endometrial
hyperplasia, ↑ gallbladder disease, cholestasis, Migraine,
Bloating
🞑 ↑ blood coagulation-via ↓ antithrombin III and ↑ factors II,
VII, IX, and X (only at high dose)
🞑 Cancer risk
↑ endometrial cancer (unless progestins are added)
↑ breast cancer—questionable, but caution if other
risk factors are present

Clomiphene (fertility pill)
29
🞑 Mode of action:
 estrogen antagonist; ↓ feedback inhibition →↑ FSHand LH
→↑ ovulation→ pregnancy
🞑 Use: fertility drug
🞑 Dose:50 mgPO× 5 d; if noovulation ↑ to 100 mg × 5 d
@ 30 d later;
 ovulation usually 5–10 d postcourse, time coitus with
expected ovulation time
🞑 Adverse effect:
↑ multiple births

Selective estrogen-receptor modulators (SERMs):
30
 Tamoxifen
🞑Variable actions depending on “target” tissue
E-receptor agonist (bone), antagonist (breast), and
partial agonist (endometrium)
🞑P
ossible ↑ risk of endometrial cancer
🞑 Usedinestrogen-dependent breast cancerand for
prophylaxis in high risk patients.

Raloxifene
31
🞑 E-receptor agonist (bone), antagonist breast & uterus
🞑 When used in menopause, there is no ↑ cancer risk
🞑 Use:prophylaxis of postmenopausalosteoporosis,breast
cancer
 Comparison of Tamoxifen & Raloxifene in Various Tissues
Drug Bone Breast Endometrium
Tamoxifen Agonist Antagonist Agonist
Raloxifene Agonist Antagonist Antagonist

Progestins
32
 Pharmacology:
🞑 Progesterone isthe major natural progestin.
🞑 Rationale for synthetics is ↑ oral bioavailability & half-
life relative to progesterone and ↑ feedback inhibition of
gonadotropins, especially LH.
 Drugs:
🞑 Medroxyprogesterone (Depo-Provera)
🞑 Norethindrone
🞑 Desogestrel isa syntheticprogestindevoid of
androgenic & antiestrogenic activities, commonto other
derivatives.

Classification of synthetic Progestins
33

34
 Clinical uses:
🞑Contraception
oral with estrogens
depot (medroxyprogesterone 150 mg IM q3
months)
🞑 Hormonereplacement therapy (HRT)—with estrogens
to ↓ endometrial cancer

35
 Side effects:
🞑 ↓ HDLand ↑ LDL
🞑 Glucose intolerance
🞑 Breakthrough bleeding
🞑 Androgenic (hirsutism and acne)
🞑 Antiestrogenic (block lipid changes)
🞑 Weight gain
🞑 Depression
 Antagonist:
🞑 Mifepristone: abortifacient (use with PGs [misoprostol])

36

Mechanism of action of contraceptives
37

Combined oral contraceptives
38
 Pharmacology:
🞑 Combinationsof estrogens (ethinyl estradiol, mestranol)
with progestins (norgestrel, norethindrone) in varied dose,
with mono-, bi-, and triphasic variants
🞑 Suppress gonadotropins, especially midcycle LHsurge
 Side effects: seen those of estrogens & progestins.
🞑 Interactions:↓ contraceptive effectivenesswhenusedwith
antimicrobials& enzyme inducers.

39
 Benefits:
🞑↓ risk of endometrial and ovarian cancer
🞑↓ dysmenorrhea
🞑↓ endometriosis
🞑↓ pelvic inflammatory disease (PID)
🞑↓ osteoporosis

Combination oral contraceptives…
40
Preparations ESTROGEN (μg) PROGESTIN
(mg)
Monophasic combination
Ethinyl estradiol/desogestrel 30 0.15
Ethinyl estradiol/drospirenone 30 3
Ethinyl estradiol/levonorgestrel 20 0.1
Mestranol/norethindrone 50 1
Biphasic combination
Ethinyl estradiol/norethindrone
35 0.5 (10 tabs)
35 1(11 tabs)
Triphasic combination
Ethinyl estradiol/levonorgestrel
30 0.05 (6 tabs)
40 0.075 (5 tabs)
30 0.125 (10 tabs)

Combined oral contraceptive preparations
41

Schedule for use of combined pill
42

Progestin-only pills(minipills)
43
 Norethindrone (0.35mg), Norgestrel (0.75mg)
⯈ Thesecontain low dose of progestin without any estrogen.
⯈ Theseare lesseffective than combined OCPs.
⯈ Breakthrough bleeding is as high as 25%.
⯈ Thickening of cervical mucusis major mechanismof minipills.
⯈ Minipills are preferred in women where estrogen is contra-
indicated e.g.
🗸Smokers, >35 years of age
🗸R
isk factors of thromboembolism
🗸Lactating women

Implanon
44
⯈ Subdermal placement in the upper arm (contraception for
3 years)
⯈ Contain etonogestrel (metabolite of desogestrel)
⯈ The implant is asreliable assterilization, and the
contraceptive effect is reversible when removed.
⯈ Progestin implants and intrauterine devices are known as
long-acting reversible contraceptives (LARC).
⯈ Adverse effects: irregular menstrual bleeding and
headaches.

Parenteral contraceptives
45

Progestin intrauterine device
46
⯈ Various levonorgestrel-releasing intrauterine devices offer a
highly effective method of contraception for 3 to 5 years.
⯈ It should be avoided in patients with pelvic inflammatory disease
or a history of ectopic pregnancy.
⯈ The levonorgestrel intrauterine device is a highly effective
treatment for heavy menstrual bleeding.
⯈ The non-hormonal copper intrauterine device provides
contraception for up to 10 years.

Vaginal ring
47
⯈ Thecontraceptive vaginal ring contains ethinyl estradiol and
etonogestrel.
⯈ Thering is inserted into the vagina and left in place for 3
weeks.
⯈ After 3 weeks, the ring is removed, and withdrawal bleeding
occursduring the 4th week.

Emergency contraception
48

Uterine stimulants and relaxants
49
Uterine stimulants (oxytocics, abortifacients)
🗸 These drugs increase uterine motility,especially at term.
1. Posterior pituitary hormone:O xytocin
2. Ergot alkaloids:Ergometrine & Methylergometrine
3. Prostaglandins:Misoprostol
Uterine relaxants (tocolytics)
🗸 Theseare drugs whichdecrease uterine motility
⯈ delay or postpone labour & arrest threatened abortion
⯈ Nifedipine, Magnesium sulphate

Thyroid and Antithyroid Drugs
50
Control of thyroid hormone synthesisand release

Features of hyperthyroidism and hypothyroidism
51

Features of hyperthyroidism and hypothyroidism..
52
Hyperthyroidism (thyrotoxicosis) Hypothyroidism (myxoedema)

Thyroid hormone synthesis
53

T3 and T4
55

Levothyroxine (T4)
 isa syntheticpreparation of thyroxine
 identical structure to that of the natural hormone.
 is the drug of choice for most patients who require thyroid
hormone replacement.
 Absorption of oral levothyroxine is reduced by food.
 should be taken on an empty stomachin the morning, at
least 30 to 60 minutesbefore breakfast.
 can produce nearly normal levels of both T3and T4.

Antithyroid Agents

Thioamides
 Thyroid peroxidase enzyme catalyzes three reactions
(oxidation, organification and coupling).
 Carbimazole, methimazole and propylthiouracil act by
inhibiting this enzyme.
 Carbimazole is a prodrug and acts after conversion to
methimazole.

Thioamides…
🗸 Methimazole
 is a first-line drug for hyperthyroidism.
 safer and moreconvenientthanPTU,and henceis
preferred for most patients— except women who
are pregnant or breast-feeding.
 ADRs: Agranulocytosis, hypothyroidism, avoid during
the first trimester.

Thioamides…
🗸 PTUismuchlike methimazole, but withfour significant
differences:
 PTUcan cause severe liver injury, but methimazole doesn’t.
 PTUhas a shorter half-life than methimazole
 PTUcrossesthe placenta less readily than does methimazole.
 PTUblocks conversion of T4to T3in the periphery, whereas
methimazole doesnot.

PKof methimazole & PTU

Thioamides…
🗸 There are three groups for whom PTUispreferred:
 Pregnant women, but only during the first trimester.
(Methimazole is preferred during the second and third
trimesters).
 Patients experiencing thyroid storm (Because PTUcan block
conversionof T4 to T3, it may be more effective than
methimazole).
 Patients who are intolerant of methimazole.

Thioamides…
🗸 Adverse Effectsof PTU
 Themost commonundesired effect isrash.
 Liver Injury (Liver toxicity is unrelated to dosage or
duration of treatment)
 Agranulocytosis
 PTUmay alsocause nausea, arthralgia, headache,
dizziness, and paresthesias.

64
 Iodide
🞑Potassiumiodide plusiodine (Lugol’ssolution)
possibleuseinthyrotoxicosis:used
preoperatively →↓ gland size,fragility, and
vascularity.
🞑No long-term use because thyroid gland
“escapes” from effects after 10 to 14 days
 I131: most commonly used drug for hyperthyroidism

R
eading assignment: steroidal drugs

END
66