endocrine pharmacology

1. ENDOCRINE PHARMACOLOGY
For Second Year PHO Students
By: Ebabu Jember(Bpharm,Mph,Msc candidate)

2. Introduction
 The function of the body is regulated by two majo
r control systems:
 The nervous system
 The hormonal or endocrine system
 In general, the hormonal system is concerned prin
cipally
 With control of the different metabolic functions of the
body
 Controlling the rates of chemical reactions in the cells
or the transport of substances through cell membranes
or other aspects of cellular metabolism,such as growth
and secretion

3. Introduction
 Endocrine system is a system of glands, each of whi
ch secretes a type of hormone directly into the bloodst
ream.
 Influence the function of target cells at another location i
n the body
 Mainly controlled by the pituitary and hypothalamus.
 Hormones reach all parts of the body, but only target
cells are equipped to respond
 Hormones are secreted in small amounts and often in
bursts (pulsatile secretion)

4. Introduction---
 Hormones include:
 Anterior pituitary hormones: growth hormon
e, Adrenocorticotropin, thyroid–stimulating ho
rmone, follicle–stimulating hormone, luteinizi
ng hormone, prolactin and melanocyte-stimul
ating hormone
 Posterior pituitary hormones: antidiuretic ho
rmone (vasopressin) and oxytocin

5.  Adrenocortical hormones: cortisol and aldost
erone
 Thyroid hormones: thyroxine, tri-iodo-thyron
ine and calcitonin
 Pancreatic hormones: insulin and glucagons
--

6.  Ovarian hormones: estrogen and progesterone
 Testicular hormones: testosterone/androgen
 Parathyroid hormones: parathormone
 Placental hormones: chorionic gonadotropin, estrog
en, progesterone and human placental lactogen

7. Introduction…
In clinical practice, hormones and hormone-like drugs, are mai
nly used for:
1. Replacement therapy
E.g. insulin in diabetes mellitus
2. Diagnosis
Testing the functional integration of an endocrine system
E.g. corticotrophin in diagnosis of adrenocortical dysfunction
3. Treatment of non-endocrine diseases
e.g. corticosteroids –inflammatory condition (Rheumatic arthritis
)

8. Thyroid and Antithyroid Drugs
 The thyroid gland has diverse and important effects on many
aspects of metabolic homeostasis.
 Thyroid gland secrets 3 hormones:
 Traiodothyronine, or T4
 Triiodothyronine or T3
 calcitonin

9. Thyroid and cont…
 T4 and T3:
 iodine-containing amino acid derivatives and
 are unique in that they have no discrete target tissue.
 Every tissue in the body is affected in some way, and
 almost all cells appear to require constant optimal amounts
for normal operation.
 Calcitonin:
.Regulate bone mineralization
 Two types of thyroid hormone related disorders:
-Hypothyroidism(under secretion)
-Hyperthyroidism(over secretion)

10. Treatment of Hypothyroidism
 The only effective treatment of hypothyroidis
m, unless it is due to iodine deficiency (treate
d with iodide) is to administer the thyroid hor
mones themselves:
 Thyroxin (levothyroxine, T4)
 standard replacement therapy
 Triiodothyronine (liothyronine, T3)
 three to four times more potent than T4
 reserved for the rare condition of myxedema coma when i
ts more rapid action is required for emergency treatment

11. Levothyroxine Sodium(T4)
 Is the sodium salt of the naturally occurring T4.
 Drug of choice for maintenance of plasma T4 and T3 in repla
cement therapy.
 Absorbed intact from the GIT, and its long half-life allows fo
r convenient once-daily administration.
 The TSH-suppressive effects of exogenous T4 also prove usef
ul in removing the stimulatory effects of TSH on the thyroid
gland in the management of simple goiter and chronic thyroi
ditis.

12. Liothyronine Sodium(T3)
 Is the sodium salt of the naturally occurring levorotatory iso
mer of T3.
 Short plasma half-life and duration of action
 not used for maintenance replacement therapy.
 The use of T3 alone is recommended only in special situation
s, such as,
 initial therapy of myxedema and myxedema coma and
 short-term suppression of TSH in patients undergoing surg
ery for thyroid cancer.

13. Adverse Effects of Treatment With Thyroid Hormone
 The most common adverse effects are the result of a drug ove
rdose; Symptoms of hyperthyroidism,
 Include:
 cardiac palpitation and arrhythmias, tachycardia,
 weight loss, tremor, headache, insomnia, and heat intoler
ance.

14. Treatment of Hyperthyroidism
 Treatment options
 Surgical removal of the gland
 Radiation therapy I 131(radioisotope of I)
 Antithyroids
 β Adrenergic BLOCKERS

15. Radiation therapy
 Radioiodine( 131 I) :- works by destruction of t
he gland by beta particles emitted
 first line treatment
 half-life of eight days
 used in one single dose
 Hypothyroidism will eventually develop, but is easil
y managed by replacement therapy with thyroxin
 should be avoided in children and also in pregnant
patients because of potential damage to the fetus

16. Antithyroids
 Thioamides
 Propylthiouracil(PTU)
 MOA
 In the thyroid gland, they inhibit the activity of
the enzyme TPO, which is required for
 The intra-thyroidal oxidation of I
 The incorporation of I into TG, and
 The coupling of iodotyrosyl residues to form thyroid
hormones
 Also inhibit peripheral conversion of T4 to T3

17. Antithyroids cont…
 Iodine
 It is converted in-vivo to iodide which temporarily
inhibits the release of thyroid hormones
 When high doses of iodine are given to Thyrotoxic
patients, the symptom subsides within 1to 2 days
 There is inhibition of secretion of thyroid hormone
s and over a period of 10– 14 days, a marked red
uction in vascularity of the gland, which becomes
smaller and firmer
 Iodine solution in KI (Lugol’s iodine) is given orall
y

18. β Adrenergic BLOCKERS
 Propranolol (and other nonselective β blockers)
 alleviate manifestations of thyrotoxicosis that are due to sy
mpathetic overactivity:
 palpitation, tremor, nervousness, severe myopathy, sweating.
 They are used in hyperthyroidism in the following situations
.
 While awaiting response to carbimazole or 131I.
 Along with iodide for preoperative preparation before subtotal thyr
oidectomy
 thyroid storm (thyrotoxic crisis)- is an emergency
 afford dramatic symptomatic relief

19. Pancreatic Hormones and
Antidiabetic Drugs
 The pancreas is both an
 Endocrine gland that produces the peptide hormones i
nsulin, glucagon, somatostatin and pancreatic polypept
ide, and
 Exocrine gland that produces digestive enzymes

20. Pancreatic Hormones----
 Insulin
 It controls the metabolism of carbohydrate, fat and prot
ein and normally determines blood glucose concentrati
on
 Glucagon
 It increases blood glucose level
 Somatostatin
 It has an indirect paracrine role in that it inhibits secreti
on of insulin and glucagon.

21. Regulation of blood glucose level

22. Actions of insulin

23. Diabetes Mellitus
 Diabetes Mellitus is a disease that occurs
 as a result of absolute or relative deficiency of insulin Or
 as result of cellular resistance to insulin's actions
 The etiologies include
 Obesity
 hereditary,
 damage of pancreatic tissue,
 diabetogenic hormones excess (GH,TH, epinephrine, cortiso
l),

24. Types of DM
 Two main forms (TypeI &Type II)
 Both have similar signs & symptoms
 Major differences in etiology, prevalence, treatments & o
utcomes (illness severity and deaths)
 Gestational DM
 Diabetes that appears during pregnancy
 Then subsides rapidly after delivery
 cause
 Placental hormones
 High production of cortisol
 both antagonize the action of insulin
 Managed by diet & insulin therapy

27. The common signs an
d symptoms include
 Polyphagia (excess ap
petite)
 Polyuria (excessive uri
nation)
 Dehydration due to glu
cosuria
 Polydipsia (excessive t
hirst)
complications:
Short term
Ketoacidosis (in type I)
hyperglycemic osmolal non
ketotic coma (in type II),
Long term (>90% of
diabetic deaths)
cardiovascular
nephropathy,
Retinopathy (blindness)
neuropathy.
Amputation
impotence

28. Diagnosis
Test type Diabetes if
Fasting plasma glucose ≥126 mg/dL
Casual plasma glucose ≥200 mg/dL plus Classic symptoms
Oral glucose tolerance
test (OGTT)
2-hr plasma glucose ≥200. mg/dL,7
5 gm of anhydrous glucose dissolv
ed in water

29. Diagnosis---
 Fasting
 is defined as no caloric intake for at least 8 hours.
 Casual
 is defined as any time of day without regard to meals.
 Classic symptoms of diabetes include polyuria, polydi
psia, and unexplained weight loss(for type I).
 OGTT,
 plasma glucose content is measured 2 hours after ing
esting the equivalent of 75 gm of anhydrous glucose di
ssolved in water.
 not recommended or needed for routine clinical use.

30. Drugs for the Treatment of
Diabetes Mellitus
 Insulin
 Oral hypoglycemic agents

31. Insulin
 Used to treat both type I and Type II
 It is the main hormone controlling intermediary
metabolism, having action on liver, muscle and
fat
 Its overall effect is to conserve fuel by facilitati
ng:
 uptake, utilization and storage of glucose, amino aci
ds and fats after meal
 It reduces blood sugar Acutly

32.  Administration
 Because insulin is a protein, it is degraded in the GIT it
taken orally. It is therefore generally administered
parenterally usually subcutaneously, but IV or
occasionally IM in hyperglycemic emergency
 Goal of insulin administration ……. To mimc
 Basal insulin secretion
 Overnight
 Fasting
 Between meals
 Prandial
Basal insuli
n secretion
Meal time insulin secr
etion

33. Insulin preparation
 Fourtypes of insulin preparations are available bas
ed on the onset and duration of action
 Ultra-short-acting
 short acting
 Intermediate acting
 Long acting insulin preparations

34. Insulin preparation----
 Ultra-short-acting
 insulin lispro, insulin aspart
 short acting
-Regular insulin
 Intermediate acting:
-Isophane Insulin suspension(NPH)
-Lente insulin
 Long acting:
 -Ultra lente
 Protamine zinc

35. Insulin preparation----
 Insulin preparations differs in
 Recombinant technique employed
 a.a sequence
 Stability
 Solubility
 Onset of action
 Duration of action

36. insulin preparations----
Type Appearance Onset (hr) Duration (hr)
i. Rapid
Regular soluble (Crystalline)
Insulin Lispro (ultra short)
Clear
Clear
0.5 -0.7
0.25
5-8
2-5
ii). Intermediate
Neutral protamin Hagedorn (NPH) or isophane
Lente (semilente insulin)
Cloudy
Cloudy
1-2
1-2
18-24
18-24
iii). Slow
Ultralente
Protamine zinc
Glargine
Cloudy
Cloudy
Clear
4 -6
4 -6
2-5
20 -36
24 -36
18 -24

37. Insulin---
1. Regular insulin (Natural insulin):
 short acting, soluble, crystalline zinc insulin
 is usually given subcutaneously; 30-45’ before meals
 Slower acting (30-45’) & short duration(6-10 hrs)
2. Lispro, Aspart, & Glulisine preparations (analogues)
 ultrashort acting forms with onset more rapid than regula
r insulin and a shorter duration.
 These are less often associated with hypoglycemia.
 Lispro insulin is given 15 minutes prior to a meal.

38. NPH insulin(Neutral protamine Hagedorn insulin)
 is a suspension of crystalline zinc insulin combined with pro
tamine (a polypeptide).
 The conjugation with protamine delays its onset of action an
d prolongs its duration of action.
 Turbid liquid(shaken before use)
 Injected S.C. (Only)
 Onset of action 1 - 2 hr
 Peak serum level 5 - 7 hr
 Duration of action 13 - 18 hr

39. NPH-----
• It is usually given in combination with reg
ular insulin.
• Insulin mixtures
 75/25 70/30 50/50 ( mix isophane with ultra-
short or short acting insulin).
Isophane (NP
H)
Ultra-short or short acting

40. Lente insulin
 Mixture of
 30% semilente insulin (small crystals rapidly acting)
 70% ultralente insulin (large crystals slow acting with prolonged durat
ion)
 Injected S.C. (only)
 onset of action 1 - 3 hr
 Peak serum level 4 - 8 hr
 Duration of action 13 - 20 hr
Note.
 Lente and NPH insulins have the same effect.
 given once or twice a day.
 Never given iv – turbid liquid prepns.
 Thus not used in emergencies (e.g. diabetic ketoacidosis).

41. Indications of Insulin
 Type I diabetes mellitus,
 type II diabetes mellitus,
 DKA/diabetic coma
 hyperkalemia,
 Pregnant women with type II or gestational DM
 should take insulin by injection and avoid taking oral hypoglycemi
cs

42. Insulin Dosing
 Commonly used regimen for type I DM
 Twice daily injection of an intermediate insulin (NPH/Lente) mixed
with short acting insulin (Lispro/Aspart)
 Drawbacks :
 Doesn’t produce a near-normal glycemic control

43. AEs of Insulin Therapy
1. Severe Hypoglycemia (< 50 mg/dl ) - life-threatening
- can result in shock and possible death.
The Challenge!
To balance glucose and insulin levels in the body.
insufficient caloric intake: missed meal, improper meal co
ntent, delayed meal, etc.)

44. Hypoglycemic signs and symptoms
 Tachycardia
 Shakiness
 Dizziness
 Sweating
 Hunger
 Headache
 Pale skin
 Sudden moodiness or behavior changes
 Confusion or difficulty paying attention
 Diabetics are usually really good at recognizi
ng hypoglycemic symptoms

45. AE----
2. Hypokalemia: Insulin draws K+into the cell with
glucose.
3. Insulin resistance (when the patient needs more than 200 units/da
y) (IgG anti-insulin antibodies, infection, expired
insulin(rare)).
4. Lipodystrophy at injection site - Make 1 inch apar
t among injection sites(Site rotation)
5. Weight gain

46. Oral Hypoglycemic Agents
 Are useful in the treatment of patients who have
NIDDM but cannot be managed by diet alone.
 The patient most likely to respond well to oral hy
poglycemic agents is one who develops diabetes
after age 40 and has had diabetes less than 5 years
.
 Patient with long-standing disease may require a c
ombination of a hypoglycemic drug and insulin

47. Oral hypoglycemic agents----

48. Sulfonylureas -----
 Pharmacokinetics
 Metabolized by the liver and are excreted by the liver or ki
dney
 Contraindicated in patients with hepatic or renal insuffici
ency (Because their accumulation in such patients results
in hypoglycemia)
 The sulfonylureas traverse the placenta and secreted in brea
st milk , can deplete insulin from the fetal pancreas and the i
nfant .
 Therefore the NIDDM pregnant women should be trea
ted with insulin alone.
 Also contraindicated in breast feeding

49.  .
Sulfonylureas
 Side Effects
 Hypoglycemia
 Stimulate appetite => weight gain
 Cardiovascular deaths (Because they non-selectively bl
ock K+ channels found in the heart or blood vessels)
 Contraindications
 Sulphonyl Ureas are contraindicated in
1. Obesic diabetic patients
2. Patients with hepatic or renal insufficiency
3. Obesic pregnant women
4. Alcoholic patients (because Sulphonyl Ureas inhibit alc

50. B. Biguanides
 Examples include :-Metformin, Phenformin, Butformin
 Mechanisms of action
 They decrease glucose production by liver
 They increase glucose uptake by skeletal muscles
 They lower plasma lipids (LDL)

51. Biguanides ---
 Advantage of Biguanides over Sulphonyl Ureas:
 suppress appetite (therefore they can be safely be given for Obes
ic diabetic patients)
 Does not cause hypoglycemia
 -because it does not stimulate insulin release
 They can be safely used in pregnant women
 Side effects
 GI disturbance
 Rarely, potentially fatal lactic acidosis
 Long-term use may interfere with B12 absorption
 Contraindications
 Renal and hepatic insufficiency

52. C. Glucosidase inhibitor
 Drugs :- Acarbose, Miglitol
 MOA: Inhibition of α(Acarbose ) and Beta(Migiltol)- gluco
sidases enzymes (Intestinal enzymes that digest bigger suga
rs) → decrease digestion and absorption of sugars → ↓postp
randial glucos
 Uses
 Mono Tx for type II
 Adjunctive Tx with other OHGA (SU, Metformin, etc)
 Side Effects
 Flatulence
 Diarrhea
 Abdominal cramping

53. D. Meglitinides
Example: Repaglinide
 The meglitinides are a new class of insulin secretagogu
es
 MOA: Modulate β cell insulin release by regulating pot
assium efflux through the potassium channels. Are helpf
ul in patients with a known allergy to sulfa drugs
 SE: Hypoglycemia is the common SE with meglitinides

54. Treatment algorism for type II
 a stepwise approach is often used
 Step 1. Implement lifestyle changes:
 caloric and carbohydrate restriction, exercise, and wei
ght loss.
 Step 2. Initiate therapy with just one oral hypo
glycemic drug
 Drug selection is based on the patient's body compo
sition and degree of hyperglycemia
 For lean patients, try a sulfonylurea. Why?
 For obese patients, try metformin. Why?

55. Answers for Why
 Because lean patients are usually insulin defi
cient, and sulfonylureas stimulate insulin rele
ase.
 Because in obese patients, insulin's target cel
ls tend to be insulin resistant.
 Metformin can reduce insulin resistance, and has t
he added benefit of suppressing appetite, which c
an help the patient lose weight.

56. DRUGS ACTING ON THE UTERUS
 Phsiologicaly labor, delivery, and birth require a complex inter
play of hormonal action, neuronal activity, and uterine smooth
muscle contraction.
 During the first two trimesters of pregnancy, the uterus remain
s in a relatively quiescent state, demonstrating little or no contr
action of the myometrium.
 This inactivity is largely the result of the inhibitory action of high circul
ating levels of progesterone on the uterine musculature.
 At the end of pregnancy to facilitate birth,the cervix begins to
soften (cervical ripening) ; this process may involve the action
s of the peptide hormone relaxin, which is produced both in th
e corpus luteum and in the placenta.

57. DRUGS ACTING ON THE UTERUS---
 Release of oxytocin at this stage of parturition promotes prost
aglandin production, particularly of the E and F series, within
the decidua; these prostaglandins are powerful myometrial sti
mulants and thus further enhance uterine contractions
 Generally two classes of drugs that act on the utrus:
 Utrine Stimulants (OXYTOCICS)
 Utrine Relaxants(Tocolytics)

58. OXYTOCICS
Drugs that cause contraction of the uterus
Include:
 Oxytocin
 Prostaglandins
 Ergometrine
Oxytocic agents have three applications:
 induction or augmentation of labor,
 control of postpartum bleeding, and
 induction of abortion.

59. Oxytocin -----
 Actions:
 Stimulates the uterus and cause physiologic type of contraction
 Causes ejection of milk
 Use:
 Induction of labor near term - check for cervical ripening 1st
 Relief of breast engorgement during lactation-
 Reduction in postpartum hemorrhage
 Note: Oxytocin is generally considered to be the drug of choice for in
ducing labor at term.
 S/Es:
 Rupture of the uterus in woman with uterine scar

60. Oxytocin----
 Precautions and contraindications
 Improper use of oxytocin may result in uterine rupt
ure and leads to death to the mother as well as the i
nfant.
 Thus, in presence of fetal malpresentation, placenta
l abnormalities, umbilical prolapse, previous uterin
e surgery, and fetal distress the likely hood of trau
ma is high.

61. Prostaglandins
 Misoprostol (PGE1 analogue)
 Carboprost (PGF2α analogue)
 Dinoprostone (PGE2 analogue)

62. PGs use
 Induce labor at anytime during pregnancy
 Misoprostol
 to initiate ripening of the cervix prior to induction of l
abor
 (Dinoprostone, Misoprostol) = vaginally
 To induce abortion
 (Mifepristone + Misoprostol) = early in pregnancy (within 7 weeks
), in the second trimester
 (Carboprost, Dinoprostone) = 2nd trimister only
 for controlling postpartum hemorrhage (Carboprost)
 to protect against peptic ulcers (Misoprostol)

63. Prostaglandins…
 A/Es:
 abdominal pain, nausea, vomiting, diarrhea, head
ache, fever (PGE2), Bronchospasm (PGF2α), Flu
shing (PGE2), vaginal bleeding, etc.
 C/Is:
 ectopic pregnancy, hemorrhagic disorders, use of
anticoagulant drugs, glucocorticoid therapy (Mifep
ristone blocks GC receptor), Fetal distress.

64. Ergometrine (Ergonovine)
It initiates strong and prolonged uterine contraction
Completely absorbed after sc and iv administration.
Metabolized in the liver and eliminated in the bile & urine
 Use:
To prevent postpartum bleeding
Note:. If used to induce or augment labour it causes uterine rupture a
nd fetal hypoxia.

65. Ergometrine-----
 Side effects
 By constricting blood vessels it may result; increase in bloo
d pressure, nausea, vomiting, blurred vision, and headache..
 Contraindications
• Hypertension
• induction or augmentation of labour.
• presence of labor
• Pelvic inflammation
• For abortion purpose

66. Tocolytics
 Drugs that cause uterine relaxation
• 2-adrenergic agonist (e.g. Retodrine)
• Ca2+-channel blocker (e.g. nifedipine)
• PG-synthase inhibitors (NSAIDs)
• Magnesium sulfate
 Clinical use
 Delay premature labor

67. Magnesium sulfate (MgSO4)
 It is a drug of choice for suppressing preterm labor
 It is the most commonly used anticonvulsants in the tr
eatment of pregnancy induced hypertention(preeclam
psia)
 Mechanism of action:
 It inhibits Ach release at uterine neuromuscular
junctions.
 Side effects
 Muscle weakness.