Title: HORMONAL DRUGS
1HORMONAL DRUGS
Lector prof. Posokhova K.A.
2Hormones
- I Protein-peptide
- 1. Hypothalamus
- 2. Pituitary gland
- 3. Parathyroid glands
- 4. Pancreas
- 5. Intestinal
- II Derivatives of amine acids
- 1. Thyroid gland derivatives of
thyronin - 2. Medulla of adrenal glands
catecholamines - III Steroid
- 1. Adrenal cortex
- 2. Sex glands
3Hormones and hormonal drugs of protein and
polypeptide structure
4Influence of insulin on metabolism
Type of metabolism Stimulation Depression
Carbohydrate Synthesis of glycogen (in liver and muscles) Transport of glucose into a cell Glycolysis Phosphorilation of glucose Glycogenolysis Gluconeogenesis Glycosylying of proteins
Fat Synthesis of triglycerides Synthesis of fatty acids Income of glucose in adipocytes Activity of lipoprotein lipase Lipolysis Production of keton bodies
Protein Synthesis of proteins Absorption of amine acids Disintegration of protein
Nucleonic acids Synthesis of cyclic nucleotides (c-AMP and c-GMP) Absorption of nucleonic acids Synthesis of RNA and DNA Biosynthesis of ribonucleotides
5Metabolic Changes Occurring When Insufficient
Insulin is Released
- Hyperglycemia Increased blood sugar
- Glycosuria Sugar is spilled into the urine
- Polyphagia Increased hunger
- Polydipsia Increased thirst
- Lipolysis Fat breakdown
- Ketosis Ketones cannot be removed effectively
- Acidosis Liver cannot remove all of the waste
products
6Disorders Associated With Diabetes
- Atherosclerosis Heart attacks and strokes
related to the development of atherosclerotic
plaques in the vessel lining - Retinopathy With resultant loss of vision as
tiny vessels in the eye are narrowed and closed - Neuropathies With motor and sensory changes in
the feet and legs and progressive changes in
other nerves as the oxygen is cut off - Nephropathy With renal dysfunction related to
changes in the basement membrane of the
glomerulus
7Classifications of Diabetes Mellitus
- Type 1, insulin-dependent diabetes mellitus
(IDDM) - Usually a rapid onset seen in younger people
- Connected in many cases to viral destruction of
the beta cells of the pancreas - Type 2, noninsulin-dependent diabetes mellitus
(NIDDM) - Usually occurs in mature adults
- Has a slow and progressive onset
8Insulin drugs
Group Onset Duration of action Trade names Routs of introduction
1. Simple (short duration of action) 20-40 min 4-6-8 hours Iletin, Insul-rapid, Humalog, Humalin R, Actrapid S.c., i.m., i.v.
2. Medium (moderate) acting (on neutral protamine of Hagedorne - NPH 1-1,5 hour 12-14 hours Insuman, Humulin N S.c., i.m.
3. Long acting (contain Zinc) 6-8 hours 24 hours (till 36 hours) Insulin-Zn-suspension, Ultratard n-m S.c., i.m.
4. Standard mixtures of drugs of 1st group with NPH-insulins 20-60 min Till 18 hours Insuman Comb 30 / 70, 25 / 75, 20 / 80, 10 / 90 S.c., i.m.
9Types of Insulin Delivery
- Past
- Subcutaneous injection
- Present
- Subcutaneous injection, insulin jet injector,
insulin pen, extended insulin pump, long-acting
insulin - Future
- Implantable insulin pump, insulin patch, inhaled
insulin
10Rules of mixing drugs of insulin
- 1. Never mix crystal zinc-insulins of the 3d
group (ultralente) with simple insulin because
the Zn2 partially transforms simple insulin to
prolonged form. Therefore its absorption
decreases and onset becomes longer. Insulins of
these groups should be introduced separately,
using different places for injection. - 2. Insulin-zinc-suspensions should no be mixed
with drugs that contain phosphates because due to
this zinc phosphate is produced that leads to
decreasing of duration action of zinc-insulins. - 3. Never mix insulins with different pH level in
one syringe. For example, acid insulins of short
action arent combinable with NPH-insulins, and
surphen insulins should not be combined with
neutral drugs with short action.
11Indication for usage of insulin drugs
- Patients with diabetes
mellitus - Absolutely indicated in case of diabetic coma
and precoma. - Diabetes mellitus of I type if diet therapy and
other sugar decreasing means arent enough
effective. - 3. Diabetes of any type if it is accompanied
by complications (ketoacidosis, infection,
gangrene etc.) - 4. Surgeries, pregnancy.
- Other cases
- In case of long-lasting exhausting illnesses.
- In case of heart, liver, kidney diseases the
drugs are administered with glucose or as a
component of polarizing mixture. - 7. Shock therapy of schizophrenia.
12Variants of insulin therapy 1. traditional
2. intensive
13Traditional insulin therapy
- adjusting of lifestyle and nutrition of patient
at strictly established dose of insulin. - The simplest variant is administration of
standard mixtures of short and NPH-insulin in two
injections 2/3 of dose before breakfast, 1/3
before dinner. - Advantages simplicity of performing, glycemia
needs not to be controlled often, control is
possible according to level of glucosuria - Disadvantages hyperinsulinemia, which demands
additional meals, larger risk of hypoglycemia,
increased frequency of late complications of
diabetes mellitus, bad compensation of sugar
level
14Intensive (basis-bolus) insulin therapy
- the patient himself makes daily a selection of
insulin dose based on measuring of glycemia level
with glucometr. Insulin of medium durability is
used twice a day (to create a basal level of
hormone) and before the breakfast, lunch and
dinner additionally insulin of short action
duration is introduced (imitation of bolus
physiological secretion of insulin as a respond
to food consumption). - Advantages effective compensation of
glycemia, more liberal diet (only easy
assimilable carbohydrates and alcohol are
prohibited), flexible day schedule, decreasing
risk of development of late complications - Disadvantages it is necessary to constantly
control glycemia, teaching the patient
(additional expenses), often light hypoglycemia
15 TREATMENT OF HYPERGLYCEMIC KETOACIDIC COMA
- Introduction of insulin (only insulin of short
action is used) - intravenously dropply counting 0,1 ?D/kg of body
weight per hour. First two hours with the speed
of 8 ?D/hour. If the initial glycemia is higher
than 33,3 mmol/l? insulin dose in first hour is
increased till 16 OD. In case of decreasing of
sugar level on 25-50 from the initial level the
speed of introduction of insulin is
correspondingly decreased on 25-50 . If glycemia
is lower than 16,6 mmol/l insulin should be
introduced with the speed of 4 OD/hour. In case
of decreasing of sugar level lower than 11
mmol/l, it is recommended to transfer to
subcutaneous introduction of the drug every 6-8
hours. - Glycemia should not be decreased faster than 5
mmol/l/hour, otherwise it is possible to promote
brain edema. The level of glycemia should be
examined every 30-60 minutes. - 2. Elimination of dehydration and hypovolemia
intravenous dropping introduction of liquids
during 1st hour 1 l of 0,9 NaCl (better
Ringers solution) is introduced, during the next
2 hours 500 ml of 0,9 NaCl each hour, and
after not more than 300ml/hour. In case of
decreasing of glycemia level lower than 14
mmol/l, 0,9 NaCl should be substituted by 5-10
glucose solution - 3. Acidosis correction solution of sodium
hydrocarbonate (if pH lower than 7,1) - 4. Correction of electrolyte disorders after 2
hours from beginning of treatment intravenous
dropping introduction of ??? dosed 2 g/hour
should be started under the constant control of
potassiumemia. - 5. Symptomatic treatment of correction of blood
pressure only introduction of mesatone is
possible, since other adrenomimetics stimulate
glycogenolysis and increase sugar level in blood.
16COMLICATIONS OF INSULIN THERAPY OF DIABETES
- Hypoglycemic coma
- allergy
- lipodystrophy
- resistance to the drug (daily dose of insulin
grows to 200 U and more) -
- it is caused
- ?) production of antibodies towards insulin,
- b) increasing of binding with plasma proteins,
- c) decreasing of receptors sensitivity to
insulin, - d) obesity,
- e) increasing of contrainsular hormones level,
- f) pseudoresistance injecting the drug into
places of lipodystrophy (considerable worsening
of drug absorption).
17TREATMENT OF HYPOGLYCEMIC COMA
- Intravenous bolus introduction of 20-50 ml of 40
glucose (dextrose) solution. - If the condition doesnt improve, after 10-20
minutes the injection should be repeated. - In case of absence of effect intravenous dropping
infusion of 5 glucose solution should be
started. - Correction of blood pressure and stimulation of
glycogenolysis adrenalin hydrochloride. - Prophylaxis and treatment of brain edema
mannit, glucocorticosteroids.
18- SYNTHETIC ANTIDIABETIC PREPARATIONS
- (taken orally)
19Derivatives of sulfonilurea 4 generations
- ? (appeared in the 50-s) chlorpropamid,
butamid, bucarban - ?? (introduced after 1967) glybenclamid
(maninil) - ??? glymeperid (amaryl)
- ?? repaglynid.
20Possible mechanism of hypoglycemic action of
derivatives of sulfonilurea
butamid, chlorpropamid
Block of ATP-dependent ? -canals of ?-cells
Depolarization of membranes of ?-cells
Opening of potential-depending ?? 2 -canals of
?-cells
Entering of ?? 2 into ?-cells
Secretion of insulin
21Mechanism of action of sulfonilurea derivaties
- Blockade of ATP-depended ? - canals of ?-cells
of Langergans isles depolarization of ?-cells
membranes opening of potential-depending
??2-canals increasing of ??2 income into
?-cells activation of insulin excretion. - Similar mechanism if responsible for secretion of
insulin under the influence of glucose. But in
this case the signal for closing of of ? -canals
is increasing of correlation ATP/ADP, which is
caused by intracellular metabolism of glucose.
Therefore derivatives of sulfonilurea imitate
signal of increased concentration of sugar in
blood.
22Indications for administration of drugs
derivatives of sulfonilurea
- diabetes mellitus of ?? type, if
- ?) all the possibilities of diet therapy are used
up - b) diabetes is diagnosed after the age of 40
- c) patient suffers from diabetes no more than 10
years - d) there are no complications and pregnancy.
23Classification of biguanids
-
- Phenilethylbiguanids (phenphormin)
- Buthylethylbiguanids (buphormin-glibutid)
- Dimethylbiguanids (methphormin glucophage).
24Mechanism of action of biguanids
- Mechanism of sugar-decreasing action of biguanids
influence of peripheral tissues - 1. increasing of action of endogen insulin due to
increasing of quantity and sensitivity of insulin
receptors - 2. decreasing of absorption of glucose in
intestines, blockade of gluconeogenesis - 3. increasing of synthesis of glycogen in liver
- 4. increasing of glucose metabolism till stage of
lactate in muscles. - Biguanids depress lipogenesis and stimulate
lipolysis, which leads to body weight loss in
obese patients
25Inhaled Insulin Sanofi-Aventis-Pfizer
- powder
- before every meal, small onset
- for diabetes type 2, which is not controlled by
peroral hypoglycemic drugs - as additional therapy for type 1 diabetes
treatment
26Sites of Action of Drugs Used to Treat Diabetes
27Types of Glucose-Elevating Agents
- Diazoxide (Proglycem)
- Can be taken orally
- Glucagon (GlucaGen)
- The hormone produced by the alpha cells of the
pancreas to elevate glucose levels - Can be given only parenterally preferred for
emergency situations
28 Hormonal preparations of thyroid gland
29Actions of the Thyroid Gland
- Produces two thyroid hormones using iodine found
in the diet - Tetraiodothyronine or levothyroxine (T4)
- Triiodothyronine or liothyronine (T3)
- Removes iodine from the blood, concentrates it,
and prepares it for attachment to tyrosine, an
amino acid
30Thyroid Control of Hormone Levels
31Regulation of thyroid hormones synthesis
32Functions of Thyroid Hormones
- Regulate the rate of metabolism
- Affect heat production and body temperature
- Affect oxygen consumption, cardiac output, and
blood volume - Affect enzyme system activity
- Affect metabolism of carbohydrates, fats, and
proteins - Regulate growth and development
33Types of Thyroid Dysfunction
- Hypothyroidism
- Underactivity
- Hyperthyroidism
- Overactivity
34Causes of Hypothyroidism
- Absence of the thyroid gland
- Lack of sufficient iodine in the diet to produce
the needed level of thyroid hormone - Lack of sufficient functioning thyroid tissue due
to tumor or autoimmune disorders - Lack of TRH related to a tumor or disorder of the
hypothalamus
35Replacement Hormone Products for Treating
Hypothyroidism
- Levothyroxine (Synthroid, Levoxyl, Levo-T,
Levothroid) Synthetic salt of T4 - Thyroid desiccated (Armour Thyroid and others)
Prepared from dried animal thyroid glands and
contains both T3 and T4 - Liothyronine (Cytomel) Synthetic salt of T3
- Liotrix (Thyrolar) Synthetic preparation of T4
and T3 in a standard 41 ratio
36Drugs of thyroid hormones
Name Contents, origin Onset Duration of action Way of introduc-tion
Thyreoidine (Thyroxin threeiodthyronin) extract from thyroid gland 2-3 days 3-4 weeks Orally
Threeiodthyronin (liothyronin) Synthetic 4-8 hours 8-10 days Orally
Levothyroxin-sodium (L-thyroxin-sodium) Synthetic 3-4 days (max. 8-10 days) 2-4 weeks Orally
37Focus on the Replacement Hormone Prototype
Levothyroxine
- Indications Replacement therapy in
hypothyroidism pituitary TSH suppression in the
treatment of euthyroid goiters, management of
thyroid cancer thyrotoxicosis in conjunction
with other therapy myxedema coma - Actions Increases the metabolic rate of body
tissues, increasing oxygen consumption,
respiration, and heart rate the rate of fat,
protein, and carbohydrate metabolism and growth
and maturation - PO route Onset slow peak 13 weeks
- IV route Onset 68 h peak 2448 h
- T½ 67 days metabolized in the liver and
excreted in the bile
38L - thyroxin
39Thyreocomb(thyroxin threeiodthyronin)
40Thyreotom (thyroxin threeiodthyronin)
41Hyperthyroidism
- Definition
- Excessive amounts of thyroid hormones are
produced and released into the circulation - Cause
- Graves disease
- Signs and symptoms
- Increased body temperature, tachycardia, thin
skin, palpitations, hypertension, flushing,
intolerance to heat, amenorrhea, weight loss, and
goiter
42Antithyroid Agents
- Thioamides
- Propylthiouracil (PTU)
- Methimazole (Tapazole)
- Iodine solutions
43Adverse Effects of Iodine Solutions
- Hypothyroidism
- Iodism (metallic taste and burning in the mouth,
sore teeth and gums, diarrhea, cold symptoms, and
stomach upset) - Staining of teeth
- Skin rash
- Development of goiter
44Antithyroid drugs
- Depression of production of TTH
- - iodine
- - diiodithyrosine (dithyrine)
- Depression of synthesis of hormones in thyroid
gland - - mercasolil
- - propilthiouracyl
- Disturbance of absorption of ?2 by thyroid gland
- potassium perchlorate - Destroying cells of thyroid gland follicles
- - radioactive iodine (?131)
45Calcium Control in the Body
46Actions of Parathormone (PTH)
- Stimulation of osteoclasts or bone cells to
release calcium from the bone - Increased intestinal absorption of calcium
- Increased calcium resorption from the kidneys
- Stimulation of cells in the kidney to produce
calcitriol
47Parathyroid Dysfunction
- Hypoparathyroidism
- The absence of parathormone
- Most likely to occur with the accidental removal
of the parathyroid glands during thyroid surgery - Hyperparathyroidism
- The excessive production of parathormone
- Can occur as a result of parathyroid tumor or
certain genetic disorders
48Hormonal preparations of steroid structure
49Natural hormones of adrenal cortex
Mineral corticosteroids aldosterone desoxycortico
sterone 11-desoxy-17-oxy- corticosterone
Glucocorticosteroids hydrocortisone
(cortisole) corticosterone cortisone 11-dehydrocor
ticosterone
Hormones with sexual activity androsterone andro
stendione estrone progesterone
50 Hypothalamus-adrenal axis Hypothalamus-hypophys
is-epinephral system
- Hypothalamus
- CRH Somatostatin GRH TRH PRH PIH GnRH
- Anterior pituitary
- Growth hormone ACTH TSH FSH
- LH (male) LH (female) Prolactin
- Peripheral endocrine glands
- Adrenal cortex Thyroid Gonads Liver
- Feed-back mechanism
51Properties of glucocorticosteroides used in
clinics
- Anti-inflammatory
- Immune-suppressive
- Anti-allergic
- Anti-shock
- Anti-toxic
52Anti-inflammatory action of GCS
- Nonspecific inflammation
- Auto-immune component
- Hyperergic character
- Therapy of despair
53Mechanism of anti-inflammatory action of GCS
GCS
activation of lipomoduline
decreasing of activity of phospholipase ?2
slowing down of arachidonic acid metabolites
production (prostaglandins, leucotriens,
thromboxan ?2)
stabilization of cellular and lyzosomal membranes
decreasing of capillaries wall permeability
decreasing of leucocytes migration processes,
depression of phagocytes activity
depression of histamine, serotonin,
bradykinine releasing
54Administration of GCS
- Insufficiency of adrenal cortex
- Rheumatoid illnesses (rheumatoid arthritis,
rheumatism, system red lupus etc.) - Chronic active hepatitis
- Bronchial asthma
- Ulcerative colitis
- Nephritic syndrome
- Auto-immune hemolytic anemia
- Shock and collapse of any etiology
- Brain, lungs, larynx edema
- Acute allergic reactions
- Transfusion reactions
- Heavy infections (hiding behind the etiotropic
drugs!) - Liver diseases
55Doses and terms of GCS therapy
Situation Daily dose Terms of treatment
Acute cases (shock, collapse, brain, lungs edema, septic shock, asthmatic condition etc.) 200-500- 800-1000 mg i.v. 1-3 days
Subacute and acute attacks of chronic processes (rheumatoid diseases, ulcerative colitis, bronchial asthma etc.) 20-50 mg (rarely till 200 mg) 4-6 weeks- several months
Primary and secondary insufficiency of adrenal cortex 2,5-10 mg life-long
56Hydrocortisone acetate
57Prednisolone
58Prednisolone
59Prednisolone
60Becotide Beclometh(beclomethasone dipropionate)
61Kenalog(triamcinolone acetonide)
62Kenalog(triamcinolone acetonide)
63Fluocinar Sinaflan Sinalar(Fluocinole
acetonide)
64Dexamethasone
65Dexamethasone
66Dexamethasone
67Lorinden A flumethasone pivalate (locacorten)
neomycin
68Complications of GCS-therapy
Steroid diabetes immune-suppression depression of
resistance towards any infections atrophy of
muscles hypopotassiumemia peptic
ulcers disturbance of regeneration osteoporosis,
delay of growth matronism (buffalo hump,
moonlike face etc.) retention of Na , H2o
edema hypertension hypercoagulation of
blood changes of psychical conditions
disturbance of menstrual cycle hypothalamus-pitui
tary-epinephral insuffciency
Izenko-Cushings syndrome
69Controls and Actions of the Adrenal Glands
70MINERALOCORTICOIDSDesoxycorticosterone acetate -
DOXA
- Mode of action
- Acts on kidney tubules causes the
reabsorption of sodium and water, decreases the
reabsorption of potassium, - regulates fluid-electrolyte metabolism,
increases AP, enhances muscle work - Administration
- For chronic adrenal insufficiency (Addisons
disease), myasthenia, adynamia - Side effects
- edema, AP increasing, pulmonary edema,
cardiac insufficiency
71Drugs of female sex hormones
Estrogens estron (oil solution of
folliculin) estradiol ethynilestradiol (microfolli
n) synestrol
Gestagens progesterone oxyprogesterone
caproate alilestrenol (turinal)
72Estrogens
- Uses
- Hormone replacement therapy (HRT)
- Palliative and preventive therapy during
menopause - Actions
- Protecting the heart from atherosclerosis
- Retaining calcium in the bones
- Maintaining the secondary female sex
characteristics
73Sites of Action of the Estrogens
74Administration of drugs of female sex
hormones estrogens 1) Genital hypoplasia,
primary and secondary amenorrhea 2) Sexual
underdevelopment of women 3) After
ovary-ectomia 4) Climacteric disorders 5)
Lactation depression 6) Weak labor
activity (estrogen background) 7) Prostate cancer
of men, breast cancer of women after the age of
60 8) A part of contraceptive agents
75Effects of Progesterone on the Body
- Decreased uterine motility
- Development of secretory endometrium
- Thickened cervical mucus
- Breast growth
- Increased body temperature
- Increased appetite
- Depressed T-cell function
- Anti-insulin effect
76Administration of gestagens 1) miscarriage,
habitual abortion 2) dysfunctional uterus
bleedings, algomenorrhea 3) as component of
contraceptives 4) Climacteric disorders 5) As
part of fertility programs 6) Treat specific
cancers with specific receptor site sensitivity
77 Hormonal contraceptives 1) combined
estrogen-gestagen a) monophased (bisecurin,
non-ovlon, rigevidon, marvelon, demulen) b)
double-phased (anteovin, neo-eunomin) c)
triple-phased (tri-regol, trisiston) 2)
monohormonal gestagen (mini-pilli) exluton,
ovret, continuin 3) postcoital hestagen
(postinor) 4) depot-contraceptives - of
prolonged action norplant (levonorgestrel)
depot-provera (medroxyprogesterone acetate)
78Complications in case of administration
of hormonal contraceptives
hypertension hypercoagulation dyspeptic
disorders (nausea, vomiting) migraine
depression obesity cholestatic jaundice breast
cancer, cancer of uterus cervix ischemic heart
disease myocardium infarction stroke embryotoxic
and teratogenic action
thrombo-embolia
79Focus on the Fertility Drug Prototype Clomiphene
- Indications Treat ovarian failure in patients
with normal liver function and normal endogenous
estrogens unlabeled use treat male sterility - Actions Binds to estrogen receptors, decreasing
the number of available estrogen receptors, which
gives the hypothalamus the false signal to
increase FSH and LH secretion, leading to ovarian
stimulation - PO route Onset 58 days duration 6 weeks
- T½ 5 days, with hepatic metabolism and excretion
in the feces
80Abortifacients
- Use
- Evacuate the uterus by stimulating intense
uterine contractions - Types
- Carboprost (Hemabate)
- Dinoprostone (Cervidil, Prepidil Gel, Prostin E2)
- Mifepristone (RU-486, Mifeprex)
81Androgens and Their Indications
- Testosterone (Duratest, Testoderm, others)
- Hypogonadism breast cancer
- Danazol (Danocrine)
- Block the release of FSH and LH in women
- Fluoxymesterone (Halotestin)
- Hypogonadism breast cancer
- Testolactone (Teslac)
- Breast cancers
82ANABOLIC STEROIDSPhenobolinum, Retabolil,
Methandrostenolonum
- PHARMACOLOGICAL EFFECTS
- Stimulation of protein synthesis
- Depression of phosphor and Ca excretion
- Increase of bones, muscles and parenchymatous
organs mass - Stimulation of regeneration
- ADMINISTRATION
- Aplastic anemia (bone marrow suppression)
- Osteoporosis, bone fractures
- Exhausted diseases
- Prolonged treatment with GCS
- COMPLICATIONS
- Hepatitis, sexual disorders (impotence),
edemas, masculinization, nausea, vomiting