Download Hormonal preparations

HORMONAL DRUGS
Lector prof. Posokhova K.A.
Hormones
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
Hormones and hormonal drugs of
protein and polypeptide structure
Influence of insulin on
metabolism
Type
of Stimulation
metabolism
Depression
Carbohydrate
Synthesis of glycogen (in liver and Glycogenolysis
muscles)
Gluconeogenesis
Transport of glucose into a cell
Glycosylying of proteins
Glycolysis
Phosphorilation of glucose
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
Metabolic 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
Disorders 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
Classifications 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, non–insulin-dependent diabetes
mellitus (NIDDM)
– Usually occurs in mature adults
– Has a slow and progressive onset
Insulin 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, Insulrapid, Humalog,
Humalin R,
Actrapid
S.c., i.m.,
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-Znsuspension,
Ultratard n-m
S.c., i.m.
4. Standard
20-60 min
mixtures of drugs of
1st group with NPHinsulins
Till 18 hours
Insuman Comb:
30% / 70%, 25%
/ 75%, 20% /
80%, 10% / 90%
S.c., i.m.
i.v.
Types 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
Rules 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
aren’t combinable with NPH-insulins, and surphen –
insulins should not be combined with neutral drugs
with short action.
Indication for usage of insulin drugs:
Patients with diabetes mellitus:
1.
2.
3.
4.
Absolutely indicated in case of diabetic coma and precoma.
Diabetes mellitus of I type if diet therapy and other sugar
decreasing means aren’t enough effective.
Diabetes of any type if it is accompanied by complications
(ketoacidosis, infection, gangrene etc.)
Surgeries, pregnancy.
Other cases:
5.
6.
7.
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.
Shock therapy of schizophrenia.
Variants of insulin therapy
1. traditional
2. intensive
Traditional 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
Intensive (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
TREATMENT OF HYPERGLYCEMIC
KETOACIDIC COMA
1.
Introduction of insulin (only insulin of short action is used)
•
intravenously dropply counting 0,1 ОD/kg of body weight per hour. First two hours –
with the speed of 8 ОD/hour. If the initial glycemia is higher than 33,3 mmol/lл 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.
Elimination of dehydration and hypovolemia: intravenous dropping introduction of
liquids: during 1st hour 1 l of 0,9 % NaCl (better – Ringer’s 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
Acidosis correction – solution of sodium hydrocarbonate (if pH lower than 7,1)
•
2.
3.
4.
5.
Correction of electrolyte disorders: after 2 hours from beginning of treatment
intravenous dropping introduction of КСІ dosed 2 g/hour should be started under the
constant control of potassiumemia.
Symptomatic treatment: of correction of blood pressure only introduction of mesatone
is possible, since other adrenomimetics stimulate glycogenolysis and increase sugar
level in blood.
COMLICATIONS 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:
а) 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).
TREATMENT OF
HYPOGLYCEMIC COMA
• Intravenous bolus introduction of 20-50 ml of 40 %
glucose (dextrose) solution.
• If the condition doesn’t 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.
SYNTHETIC ANTIDIABETIC
PREPARATIONS
(taken orally)
Derivatives of sulfonilurea –
4 generations
І (appeared in the 50-s) – chlorpropamid,
butamid, bucarban;
ІІ (introduced after 1967) – glybenclamid
(maninil);
ІІІ – glymeperid (amaryl);
ІУ – repaglynid.
Possible mechanism of hypoglycemic action of derivatives of sulfonilurea
butamid, chlorpropamid
Block of ATP-dependent К+ -canals of -cells
Depolarization of membranes of -cells
Opening of potential-depending Са 2+ -canals of -cells
Entering of Са 2+ into -cells
Secretion of insulin
Mechanism of action of sulfonilurea
derivaties
• Blockade of ATP-depended К+ - canals of -cells of
Langergan’s isles – depolarization of -cells
membranes – opening of potential-depending Са2+canals – increasing of Са2+ 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 К +-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.
Indications for administration of
drugs – derivatives of
sulfonilurea
diabetes mellitus of ІІ type, if:
а) 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.
Classification of biguanids
1. Phenilethylbiguanids (phenphormin);
2. Buthylethylbiguanids (buphorminglibutid);
3. Dimethylbiguanids (methphormin –
glucophage).
Mechanism 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
Inhaled 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
Sites of Action of Drugs Used to Treat
Diabetes
Types 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
Hormonal preparations
of thyroid gland
Actions 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
Thyroid Control of Hormone Levels
Regulation of thyroid hormones synthesis
Functions 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
Types of Thyroid Dysfunction
• Hypothyroidism
– Underactivity
• Hyperthyroidism
– Overactivity
Causes 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
Replacement Hormone Products for
Treating Hypothyroidism
• Levothyroxine (Synthroid, Levoxyl, LevoT, 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 4:1 ratio
Drugs of thyroid hormones
Name
Contents, origin
Onset
Thyreoidine
(Thyroxin +
2-3 days
threeiodthyronin)
extract from
thyroid gland
Duration
of action
Way of
introduction
3-4 weeks
Orally
Threeiodthyronin Synthetic
(liothyronin)
4-8 hours
8-10 days
Orally
Synthetic
Levothyroxinsodium (Lthyroxin-sodium)
3-4 days
(max. 8-10
days)
2-4 weeks
Orally
Focus 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 1–3 weeks
• IV route: Onset 6–8 h; peak 24–48 h
• T½: 6–7 days; metabolized in the liver and excreted in
the bile
L - thyroxin
Thyreocomb
(thyroxin + threeiodthyronin)
Thyreotom
(thyroxin + threeiodthyronin)
Hyperthyroidism
• 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
Antithyroid Agents
• Thioamides
– Propylthiouracil (PTU)
– Methimazole (Tapazole)
• Iodine solutions
Adverse 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
Antithyroid drugs
1)
2)
3)
4)
Depression of production of TTH
- iodine
- diiodithyrosine (dithyrine)
Depression of synthesis of hormones in thyroid gland
- mercasolil
- propilthiouracyl
Disturbance of absorption of І2 by thyroid gland
- potassium perchlorate
Destroying cells of thyroid gland follicles
- radioactive iodine (І131)
Calcium Control in the Body
Actions 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
Parathyroid 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
Hormonal preparations
of steroid structure
Natural hormones of adrenal cortex
Mineral corticosteroids
Glucocorticosteroids
hydrocortisone (cortisole)
corticosterone
cortisone
11-dehydrocorticosterone
aldosterone
desoxycorticosterone
11-desoxy-17-oxycorticosterone
Hormones with sexual
activity
androsterone
androstendione
estrone
progesterone
Hypothalamus-adrenal axis
Hypothalamus-hypophysis-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
Properties of
glucocorticosteroides used in
clinics
• Anti-inflammatory
• Immune-suppressive
• Anti-allergic
• Anti-shock
• Anti-toxic
Anti-inflammatory action of
GCS
• Nonspecific inflammation
• Auto-immune component
• Hyperergic character
• Therapy of despair
Mechanism of anti-inflammatory action of
GCS
GCS
activation of lipomoduline
decreasing of activity of phospholipase А2
slowing down of arachidonic acid
metabolites production
(prostaglandins, leucotriens,
thromboxan А2)
stabilization
of cellular and
lyzosomal
membranes
depression of
histamine, serotonin,
bradykinine releasing
decreasing of
leucocytes’
migration processes,
depression of
phagocytes activity
decreasing of capillaries’
wall permeability
Administration 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
Doses and terms of GCS therapy
Situation
Acute cases (shock,
collapse, brain, lungs
edema, septic shock,
asthmatic condition etc.)
Daily dose
Terms of
treatment
200-5001-3 days
800-1000 mg
i.v.
Subacute and acute
20-50 mg
attacks of chronic
(rarely till
processes (rheumatoid
200 mg)
diseases, ulcerative colitis,
bronchial asthma etc.)
4-6 weeksseveral
months
Primary and secondary
insufficiency of adrenal
cortex
life-long
2,5-10 mg
Hydrocortisone acetate
Prednisolone
Prednisolone
Prednisolone
Becotide = Beclometh
(beclomethasone dipropionate)
Kenalog
(triamcinolone acetonide)
Kenalog
(triamcinolone acetonide)
Fluocinar – Sinaflan – Sinalar
(Fluocinole acetonide)
Dexamethasone
Dexamethasone
Dexamethasone
Lorinden A:
flumethasone pivalate
(locacorten) + neomycin
Complications 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-pituitary-epinephral insuffciency
Izenko-Cushing’s syndrome
Controls and Actions of the
Adrenal Glands
MINERALOCORTICOIDS
Desoxycorticosterone 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 (Addison’s disease),
myasthenia, adynamia
• Side effects
edema, AP increasing, pulmonary edema, cardiac
insufficiency
Drugs of female sex
hormones
Estrogens
estron
(oil solution
of folliculin)
estradiol
ethynilestradiol
(microfollin)
synestrol
Gestagens
progesterone
oxyprogesterone caproate
alilestrenol (turinal)
Estrogens
• 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
Sites of Action of the
Estrogens
Administration 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
Effects 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
Administration 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
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)
Complications in case of administration of
hormonal contraceptives
hypertension
thrombo-embolia
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
Focus 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 5–8 days; duration 6 weeks
• T½: 5 days, with hepatic metabolism and excretion
in the feces
Abortifacients
• Use
– Evacuate the uterus by stimulating
intense uterine contractions
• Types
– Carboprost (Hemabate)
– Dinoprostone (Cervidil, Prepidil Gel,
Prostin E2)
– Mifepristone (RU-486, Mifeprex)
Androgens 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
ANABOLIC STEROIDS
Phenobolinum, 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