Posterior pituitary gland secretes a number of hormones, out of which two are important:
Oxytocin
Vasopressin –anti diabetic
Previously it was thought that oxytocin and anti diabetic hormone resembled each other and had similar properties, but in 1953 it was discovered that oxytocin and ADH although had similar properties of uterine contractions, but differed in structure and properties.
They differ in structure at position 3 and 8, so labeled different groups of hormones.
Oxytocin
Biosynthesis of Oxytocin
Oxytocin is a cyclic peptide hormone, secreted from posterior pituitary.
It is synthesized in the cell bodies of para ventricular nucleus.
It goes down the axons, and is stored within neurohypophysis.
The precursor is rapidly converted by proteolysis to the active hormone and secreted from nerve endings.
Oxytocin is also synthesized in the luteal cells of the ovary, the endometrium and the placenta.
Stimuli include sensory stimuli from dilation of the cervix and vagina, suckling.
Structure
It is a nine amino acid peptide composed of 9 amino acid peptide, containing a six amino acid disulfide ring and a three membrane tail.
Pharmacokinetics
Orally not highly active, degraded when given orally.
Administered by I/V or IM route, at times intra nasal route may be used (to stimulate milk ejection)
Rapidly degraded by kidney and in liver.
Plasma half life is 6 min.
Not bound to plasma proteins.
Destroyed by Oxytocinase (present in kidneys).
Dosage
It is given I/V with fetal and maternal monitoring, so that fetal distress does not take place.
An infusion rate of 10mU/min is given and increased every 15-30 min.
Nasal puff in each nostril is sprayed for lactation, one puff in each nostril is used before nursing, mother is placed in sitting position, thus milk ejection is enhanced.
Mechanism of Action
Oxytocin acts via G protein coupled receptors which activate Ca²+ -IP³ pathway and intracellular release of Ca²+ ions.
Intracellular calcium release alters transmembrane ionic currents in myometrial smooth muscle cells to produce sustained uterine contractions (stimulate and enhance).
Increased sensitivity of uterus to oxytocin, prostaglandins are also synthesized leading to further augmentation of effects.
As pregnancy advances, activity of uterus (uterine contractions) increase and so does the sensitivity to oxytocin.
Weak ADH like activity.
Also affects myometrial smooth muscles and initiates contractions of smooth muscles leading to milk ejection.
Beta agonists, magnesium sulfate and inhalational anesthetics antagonize the effects.
Pharmacological actions
Uterus:
Activity increases as reaches 3rd trimester, leading to force and frequency of uterine contractions.
Sensitivity is also enhanced and effects are mainly related to fundus and body of uterus.
Full relaxation may occur between contractions.
Breast
Cause contraction of myoepithelial cells of mammary alveoli surrounding collecting ducts, leading to milk ejection from mammary alvoli, one puff is given in each nostril.
CVS
Due to direct effect, oxytocin causes vasodilation and fall in blood pressure,
Increased heart rate and tachycardia,
Flushing might occur as well.
Kidney
Weak ADH like activity
May cause retention of fluids
Decreased urine output, if given in high doses
Pulmonary edema may occur
Clinical uses of Oxytocin
1. Induction of Labor
Normal labor is allowed to progress, manipulation is not advisable, only administered in certain conditions. (Rh incompatibility, DM, preeclampsia, ecclampsia, toxemia of pregnancy, rupture of membranes)
Initially 0.5-2 units/min administered, dose may be increased within 15-30 minutes till effective uterine contractions are achieved with maternal and fetal monitoring.
2. Augmentation of Labor
If labor is not progressing.
3. Third stage of Labor and puerperium
To decrease the post partal hemorrhage, usually administered at the time of delivery of placenta to decrease the chances of post partum hemorrhage.
10-40 units oxytocin in 1 litre of 5% dextrose is infused slowly. Ergot alkaloids (ergometrine) are also utilized for this purpose (o.2-0.3 mg are given). If ergometrine is contraindicated, oxytocin may be used.
4. Milk ejection
Enhances milk ejection.
Adverse Effects
Maternal and fetal deaths due to hypertensive episodes, uterine rupture, water intoxication if rapidly
Afibrinogenemia is also reported.
Prostaglandins
Prostaglandins are said to have similar effects, act as uterine analogs.
PGE2, PGF2α and 15 methyl PGF2α are potent uterine stimulants.
PG have been detected in maternal blood.
Also enhance uterine stimulant activity, may augment the contractions.
Ergometrine & Methylergometrine
Erogot alkaloids obtained from claviceps purpura.
They increase force, frequency and duration of uterine contractions.
Gravid uterus is more sensitive and involves the lower segment as well.
Partial agonist action on 5-HT2 and α adrenergic receptors.
Used to decrease post partum hemorrhage
Oxytocin Challenge Test
I/V oxytocin is given in a dose of 0.5 milli units/min, till three contractions are achieved in 10 minutes. Purpose of doing the test is to access fetal well being. We compare maternal blood flow with that of fetal heart rate. This is to try to access placental circulatory reserve.
Uterine Relaxants
Agents given to decrease the contractions of uterus to relax it, given in cases:
when there are chances of threatened abortion or prematurity
if we want to shift mother to better health facilities unit
in conditions where fetal lungs are not mature, glucocorticoids are given to allow maturation.
Labor may be slowed down for days or even weeks.
Ritodrine:
A β2 selective agonist.
It has a major uterine relaxant action.
Doses given as I/V infusion of 50 mcg/min, dose may be increased after every 10 minutes till tone is decreased.
Causes postponement of delivery in 70% cases.
Side Effects;
Hypertension,
hyperinsulinemia ,
hypokalemia,
anxiety,
arrhythmias,
pulmonary edema,
hyperglycemia,
restlessness,
headache
Salbutamol and terbutaline may also be used.
Contraindications
Diabetes
Severe hypertension
Ca+ Channel blockers
Ca+ influx causes uterine contractions while Ca channel blockers have opposing effects.
Nifedipine given orally every 20-30 min till uterine contractions subside.
Magnesium Sulphate
Previously used, now uses are declining
Used to control convulsions and to reduce BP in toxemia of pregnancy.
Different agents are used to avoid unplanned pregnancy, for better family planning. These are agents which mainly contain hormone components within preparations and may be administered orally, in form of injectables or implant preparations.
These are the most widely used agents throughout the world, as are very affordable, convenient and easy to use.
Sex hormones
Estrogen
Progesterone
Other sex hormones
During reproductive years, radical changes occur under the influence of these hormones in ovaries and female sexual organs. This rhythmical pattern of menstrual cycle usually consists of 28 days. On around 14th day, under influence of follicle stimulating hormones and lutenizing hormones, ovulation occurs.
Contraceptives were designed to resemble FSH and LH, causing inhibition of ovulation so that fertilization and pregnancy do not occur.
Types of Oral Contraceptives
Combination Oral Contraceptives
It contains an estrogen & progestin
Estrogens Used:
Ethinyl – Estradiol
Mestranol
Progestins Used:
Levonorgestrel
Desogestrel
Norgestimate
Norethindrone
All preparations come as 28 day packs. Pill is taken daily for 21 days starting on the 5th day of menstruation.
Phased Regimens
a. Monophasic
b. Biphasic
c. Triphasic
Contain a fixed amount of estrogen and are very effective available as 28 day calendar packing, 1 tablet is taken daily for 21 days without interruption, whereas the next 7 tablets are placebo (pill free period). After 28 day intake, prompt bleeding occurs. Ideally started at 5th day of menstruation.
Biphasic/triphasic preparations
Preparations in which estrogens are present in fixed dose, progestins may vary with the type of preparation. 235 mcg estrogens are present in biphasic and triphasic preparations given for fixed interval during 28 day cycle. One tablet daily for 28 days, last 7 days placebo.
In biphasic preparations, one tablet is taken initially for 10 days, another type for 11 days, followed by 7 tablets.
In triphasic preparations, depending on type of preparation, one regiment tablet is taken for first 7 days, another for 8-15th day/16-21 day, followed by 7 placebo tablets.
Biphasic and triphasic preparations are ideal for females over 35 years of age, having pre-disposing factors. In 2003, FDA approved other preparations, these are:
SEASONALE:
Norgestrel-ethinyl estradiol
1 tab for 84 days without interruption followed by 7 placebo, menstrual bleeding occurs every 13th week
Only progestin is present, no estrogen, in order to discard side effects of estrogen to make more tolerable. A low dose progestin only pill is taken daily continuously without any gap (mostly oral)
Norethindrone (350µg) or
Norgestrel (75µg).
Taken without any interruption.
Implants
Norgestrel subdermal implants 216mg
I/M only preparations
Medroxyprogesterone acetate IM 150mg
Slow release contraceptive, effective for 5 years subdermally. I/M as long as 3 months.
Intrauterine Device
Contain progestin component, 2 preparations are available:
PROGESTASERT:
Progesterone
MIRENA:
Levonorgestrel
Available for yearly basis, effective as long as 5 years.
Efficacy of estrogens only preparations is very high (99%), intrauterine devices have an efficacy of 70-80%. Progestin only preparations cause inhibition of ovulation for as long as 14 weeks, long acting ones may inhibit for 18 months.
Those who plan pregnancy soon after taking off pill, may fail to get pregnant. Minipill is not advisable for early pregnancy on discontinuation, may be inhibited for weeks or months (up to 18 months)
Adverse Drug Reactions
Irregular bleeding
Spotting
Amenorrhea
Besides nausea, vomiting, headache, dizziness, restlessness, leg cramps, abdominal cramps
Injectables
Long acting progestin alone
Depot medroxyprogesterone acetate (DMPA) 150mg at 3 months interval.
Norethindrone enanthate (NEE) 200mg at 2 month intervals.
Progestin Implant Method
Progestin capsule (Etonogestrel)
Long acting progestin + long acting estrogen
MPA + estradiol cypionate IM every month.
Potential adverse effects of implants
Surgical insertion/surgical removal with irregular bleeding
Headache
Dizziness
Weight gain
Decreased host tolerance
Intracranial hypertension
Post coital Contraceptives
Also popularly known as morning after contraceptives, used in emergency situations like rape victims or if want to avoid pregnancy. Said to be effective 72 hours, 2 doses are ideally taken 12 hours apart.
Two doses of Minipill at an interval of 12 hours (0.75mg Levonorgestril per pill).
Two pills of a high dose oral contraceptives at an interval of 12 hours( 0.25mg of Levonogestrel + 0.5mg of Ethinylestradiol per pill ).
Ethinyl estradiol: 2.5mg BD x 5 days
Diethylstilestrol: 50mg daily x 5 days
Mifepristone: 600mg OD+Misoprostol 400µg OD
40% of females have nausea and vomiting with these drugs, so antiemetic must be administered with them. Other side effects include leg cramps and breast tenderness.
Mechanism of action
Inhibition of gonadotropin release from pituitary by reinforcement of negative feedback inhibition, thus FSH, LH synthesis and release is controlled.
Progestin is decreased and ovulation is inhibited
Secretion of thick cervical mucus secretion which becomes hostile for sperm, and is inhibited
Failure of blastocyst to implant.
Uterine and tubule contraction.
Dislodgment of just implanted blastocyst.
Adverse Effects
Mild adverse effects:
1. Nausea, edema, break through bleeding –due to estrogen component, switch to less estrogen more progesterone
2. Headache
3. Migraine –stops after use for some time
4. Breast discomfort –progestin only more common
5. Changes in serum proteins –estrogen type prep, alpha 2 globulin, fibrinogen levels increase
6. Failure of withdrawal bleeding –seen in combination preparations, progestin only and some other, this effect may be inhibited
7. Confusion
Moderate Effects:
1. Break through bleeding –biphasic, triphasic decrease chances
2. Weight gain, with combination preparations and and progestin type
3. Hyper pigmentation –common, highly sensitive to UV light or dark skinned, vitamin B deficiency, reversible process
4. Acne
5. Hirsutism –those preparations having 19 nortestosterone
6. Uretral dilation –usually at time of labor
7. Vaginal infection –very difficult to treat
8. Amenorrhea –may be seen in irregular menstrual cycle, if does occur, prolactin levels are assessed.
Severe adverse effects
1. Venous thromboembolic disease –increased chances of altered clotting factors, genetic alteration of homocysteine, decreased venous blood flow, endothelial preparations
2. Myocardial infarction –incidence is increased in females above 35 years, obese, diabetic, HTN, cardiac disease or smokers having higher chances of erythrogenesis
3. Cerebrovascular disease –esp. migraine history
4. GIT
a. cholestatic jaundice
b. cholangitis
c. cholilithiasis
d. hepatocellular carcinoma
e. hepatic adenoma
Chronic adverse effects are seen due to increased levels of cholic acid with bile acids.
5. Depression -reversible
6. Cancer –decreased incidence of ovarian and endometrial cancer
In breat cancer, beneficial effects are not achieved.
7. Alopecia, skin lesions –erythema nodosa and other manifestations
Contraindications
Hypertension & Hyperlipedemia
Thromboembolism
Diabetes mellitus
Heart disease/ failure
Liver disease
Migraine/ headache
Cerebrovascular disease
Optic neuritis
Drug Interactions
1. Enzyme Inducers
Phenytoin
Primidone
Carbamezipine
Rifampin
2. Suppression of intestinal microflora
Tetracyclins
Ampicillins
Noncontraceptive Uses
Regular Menstration
Less iron deficiency anemia & rheumatoid arthritis
Reduced menstrual blood flow
Reduced incidence of pelvic inflammatory disease & ectopic pregnancies, endometriosis
Normally sequence of events start from hypothalamus with gonadotropic releasing hormones acting on gonadotropic cells of pituitary to cause release of gonadotropins, which move downwards to ovary and tetes to stimulate them, causing secretion of estrogen and progesterone. Thus hypothalamus hypophyseal axis is formed.
Any disturbance can lead to infertility, drugs act at different levels:
Drugs Affecting Gonadotropic Releasing Hormones
GnRH analogs/agonists
GnRH antagonists
GnRH & its analogs
Pulsatile release occurs which can suppress release of gonadotropins
Gonadorelin
Goserelin
Leuprolide
Nafarelin
When need for stimulation given by special pumps every 90 mins in pulses
Female Infertility
Stimulation of gonadotropins – LH surge, given in pulses
Suppression of gonadotropins
Suppress premature LH surge, administered in continuous manner
Mainly by Leydig cells of testis (95% by leydig cells, 5% by adrenals)
In females, both ovaries and adrenals convert estradiol.
Same biosynthesis pathway as estrogen.
Classification
A. Natural
Testosterone
Dihydrotestosterone
Dehydroepiandrosterone
Androstenedione
B. Synthetic
Testosterone Esters
Testosterone cypionate
Testosterone enanthate
Alkylated Androgens
Methyltestosterone
Fluoxymesterone
Anabolic Androgens
Oxymetholone
Oxandrolone
Nandrolone decanoate
Mechanism of action
Steroidal receptors, androgenic receptors intracellularly present, binding leads to changes in pattern of synthesis of estrogen.
Pharmacokinetics
Routes of administration –oral, sublingual, transderma, topical
Protein binding – bind sex hormone binding globulin SHBG
5α-reductase – converts testosterone into dihydrotestosterone
Conjugation occurs and excreted in form of urates
Physiological & Pharmacological Effects
Development of primary sex characteristics
Development in utero and whole life.
Development of secondary sex characteristics
Like changes in growth of hair patterns, change in skin thickness, which becomes oilier, deepness of voice due to growth of larynx and vocal cords, muscular, skeletal growth.
Effect on growth & Ca+2 metabolism
Increased deposition, thickness of bones is increased
Epiphyseal closure is accelerated
Increase in muscular mass esp. shoulder girdle.
Metabolic effects
Androgens increase synthesis of hepatic proteins, clotting factors, triglyceride lipase, alpha 1 antitrypsin and other proteins.
Effect on water & electrolytes
Increased resorption of sodium from distal convulated tubules leading to edema in susceptible patients.
Effect on blood
Increased secretion of erythrocytes, increased RBCs
Anabolic effects
Increased activity, increased protein anabolism decreased catabolism
Increased Na, K, Ca, N
Increased tolerance in athletes.
Therapeutic Uses
Replacement therapy in male
Primary hypogonadism
Castration
Gynaecological disorders in female
Male contraception
Catabolic & wasting states –anabolic effects
Anemia –refractory cases, now replaced by recombinant erythropoietin
Osteoporosis
Growth stimulators
In those young boys having delayed puberty and growth but used with caution. Also cause closure of epiphysis and can retard growth.
Aging
Used to slow down aging process.
Anabolic steroids in sports
Not therapeutic use but misuse, to increase performance because of anabolic effects.
Adverse Effects
In females
Acne
Hirsuitism
In infants
Affects CNS
Growth
Sexual functions
In males
Hepatic dysfunction
a. Increased bilirubin b. Cholestasis c. Jaundice d. Increased incidence of adenoma and carcinoma of liver e. Some reports of hepatic failure with use
Urogenital system
Prostate hyperplasia –benign prostatic hyperplasia, urinary retention especially in older patients
Also increase incidence of prostatic cancer
Suppress sperm production -azospermia
CNS
Aggression
Psychotic behavior
Psychological dependence
CVS
Na retention
hypertension
Blood
Erythrocytosis
Polycythemia
Other effects
Acne
Gynecomastia
Contraindications & Cautions
Pregnant females causing masculinization of female fetus or under masculinization of male fetus.
Infants
Hepatic / CVS / Renal / Cancer patients (prostatic, breast)
Anti-androgens
Anti androgens are the inhibitors of testosterone secretion
They are released in non pulsatile nature,
GnRH analogs – Goserelin / Nafarelin are used in Prostate Cancer
Steroid synthesis inhibitors – Ketoconazole antifungal, inhibits many enzymes of steroid synthesis
5α-reductase inhibitors – Finasteride inhibits conversion of testosterone into dihydrotestosterone.
Uses BPH / Male pattern baldness / Hirsutism
Androgen receptor inhibitors
Flutamide / Bicalutamide
Cyproterone
Spironolactone –inhibition of androgen and aldosterone receptor
Uses Hirsutism / androgenic activity / Prostate Ca
Danazol
Drug having Progestational / Androgenic / Glucocorticoid activity
Weak glucocorticoid activity, Suppression of ovarian functions
21 carbon compounds to which non-phenolic ring and different groups are attached.
Source & Biosynthesis
Natural and synthetic
Classification
Natural
Progestrone
Synthetic
1. Progestrone derivatives
Hydroxyprogestrone caproate
Medroxyprogestrone acetate
2. 17-Ethinyl testosterone derivatives
Dimethisterone
3. 19-Nortestosterone derivatives
Norethindrone
Desogestrel
Norgestimate
Pharmacokinetics
Routes of administration –oral, i/M, implants, transdermal, form of depo preparations
Hydroxylation & conjugation occurs in the body, excreted in urine
Mechanism of action
Two isoforms of progesterone receptors are present – A & B –these are intracellular receptors, mechanism is same as estrogen.
Physiological & Pharmacological Effects
Neuroendocrine effects
Because of feedback on releasing hormones regulate release of different gonadotropins and gonadal hormones
Reproductive system
Development of uterus and endometrial lining responsible for glandular growth. In secretory phase, responsible for start of menstrual bleeding.
Mammary glands
Glandular/acinar growth
Metabolic effects
Increased basal levels
Produced in response to carbohydrate diet.
Lipid metabolism increase in lipoprotein lipase activity, increase in LDL and cholesterol. Effect is opposite to estrogens.
Decreased amino acids in plasma leading to decreased nitrogen excretion.
CNS effects
Depressant effect hypnotic –given bedtime
Body temperature increased during mid cycle time increased if used as predictor of ovulation, exact mechanism is not known.
Effect on respiration
Increased ventilator response to carbon dioxide
Decreased blood carbon dioxide during luteal phase
Maintains pregnancy, changes responsible for placenta formation
Suppress uterine contractions
Adverse effects
a. Hypertension b. Decreased HDL increased atherosclerosis c. Increased chances of breast cancer
Therapeutic Uses
Contraception
Hormone replacement therapy
Abnormal / Dysfunctional Uterine Bleeding
Dysmenorrhea / Endometriosis
Diagnostic Uses
See whether estrogen, if on stoppage of progesterone withdrawal bleeding, if no estrogen no withdrawal bleeding
Endometrial carcinoma –decreased chances when given with estrogen
Luteal phase support –rise in temperature
Premature labor
Habitual abortions –controversial use
Anti-progestins
Mifepristone
Acts on progestrone & glucocorticoid receptors
Uses
Contraceptive 600 mg single dose post coital as emergency contraceptive
Abortifacient – PGE1
In early pregnancy during 1st two months along with PGE1 pessaries used (4-6 mg given for 4 days or 800 mg for 2 days along with 1 mg PGE1 pessary as abortifacient
Steroids having phenol ring, many groups are attached, responsible for different pharmacokinetics and pharmacodynamics of different preparations
Source
Natural/Synthetic
Plants (fungi)
Present in animals and humans, main source is Stallion horse urine for clinical use
Synthetic are made from plastics, pesticides and many other industrial chemicals
Biosynthesis
Androstenedione has affinity for alpha receptors, action is different in different parts of body.
Classification
A. Natural Estrogens
– Estradiol
– Estrone
– Estriol
– Equilin
B. Synthetic Estrogens
I. Steroidal
– Ethinyl Estradiol
– Mestranol
– Quinestrol
II. Non-steroidal
– Diethylstilbestrol
– Chlorotrianisene
– Methallenestril
Pharmacokinetics
Routes of administration –can be given by oral/I/V/transdermal/topical applications/vaginal creams, gels
In body bind hormone binding globulin
Hydroxylation & conjugation occurs in liver to inactive metabolites
Enterohepatic circulation –pass to intestine and hydrolyzed, reabsorbed and reach liver again where conjugation occurs
If given through transdermal patch or topically, less liver effects are seen.
Mechanism of action
In body two forms of estrogen receptors are present:
α & ß
When estrogen binds these isoforms, stabilizing proteins, heat shock proteins, dissociate from receptor, estrogen receptor complex is formed. These receptors then form homo & Hetro-dimers.
Bind estrogen receptor elementpresent on promotor region of gene to modify transcription.
Enzymes, growth factors, cytokines are involved. Transcription not only involves binding with response element, but also co-regulators – co-activators are required.
It takes longer for non-genomic effects to appear, e.g. change in blood supply of uterus, increased calcium uptake by granulosa cells.
Physiological & Pharmacological Effects
Developmental Effects
Female maturation
Development of essential internal genital organs, growth, primary and secondary sexual characteristics, development of mammary glands
Male maturation
Endometrial Effects
Required for both growth and development of endometrial lining, smooth muscles, stroma and ductal region of uterus.
Metabolic & Cardiovascular Effects
Bones / Skin / Blood vessels- suppress osteoclastic activity, inhibiting resorption of bone, required for stimulation and formation of blood vessels. In vessels cause formation of nitric oxide, nitric oxide synthetase, responsible for vasodilatation.
Proteins / Lipids –increased protein synthesis, increased plasma proteins like binding proteins, globulins (corticosteroid binding, etc.), increased formation of fibrinogen, renin substrate.
Decreased LDL and cholesterol, increased HDL and triglycerides
Facilitate movement of intravascular fluid into extravascular space leading to edema. Decrease intravascular volume responsible for stimulation of aldosterone secretion and retention of sodium and water.
Therapeutic Uses
1. Replacement Therapy
a. Primary Hypogonadism – Turner’s syndrome
Estrogen is given to facilitate pubertal changes.
b. Castration / Oophorectomy
c. Postmenopausal Hormone Therapy
Given for different reasons:
i. Vasomotor symptoms
Hot flushes alternating with chills, very troublesome. As estrogen increases the chances of cancer, in high risk individuals, Clonidine can be given.
ii. Osteoporosis
Besides measures include:
Physical activity
Intake of calcium and vitamin D
Bone density at time of menopause determines.
iii. Vaginal & urogenital atrophy
Topical gels are used
iv. Cardiovascular disease
Beneficial effects on lipid profile.
v. Breast & endometrial cancers
Endometrial chances are decreased, breast cancer chances are increased if combination of estrogen and progesterone is given.
2. Colon cancer / Alzheimer’s
3. Contraception
4. Suppression of ovarian functions
5. Dysmenorrhea
Adverse Effects
1. Carcinogenic Effects
a. Breast cancer increased chances if progesterone is added
b. Endometrial cancer chances are decreased if given alone
c. Vagina –mothers treated with diethylstilbesterol if give birth to female child, increased chances of adenocarcinoma of vagina in child
Aminoglutethimide (inhibit conversion of cholesterol into pregnolone)
Aromatase inhibitors
Anastrozole
Letrozole
Exemestane
Breast / Prostate Cancers inhibitors
Estrogen receptor antagonists
Fulvestrant
SERMs
SERMs
Selective Estrogen Receptor Modulators
Tamoxifen (older used for treatment of infertility)
Raloxifene
Toremifene
Clomiphene
Competitive partial agonist inhibitors
Tissue-selective actions
In some areas estrogenic activity, others anti-estrogenic activity, estrogenic activity on bones, liver (protein metabolism), endometrium whereas anti-estrogenic activity on breast so used in breast cancers.
Uses
1. Breast cancer – chemoprevention
Treatment is given for around 5 years
2. Osteoporosis – Raloxifene has more effects on bones, advantage is that has antiestrogenic activity on breast, so chances of breast cancer are not there.
Thyroid is the largest endocrine gland in human body, situated in front of neck. Isthmus divides it into two parts. It is mandatory for body temperature, regulation, metabolism, growth, reproductive system, etc.
In absence of thyroid, hypothyroidism occurs. If hormones are deficient at birth, congenital abnormality occurs. Cretinism appears in children. Thyroid hormones, if deficient, are replaced at birth to avoid mental and growth retardation.
Hormones
Secretes three hormones:
Calcitonin, important in calcium homeostasis.
Triiodothyronine (T3) and thyroxine (T4), important in growth and metabolic function.
It is composed of large number of follicles filled with coli. Major constituent glycoprotein is thyroglobulin, secreted by the cells into coli.
Iodine:
Sources: Iodized table salt, dairy products, fish
Adult requirement: 150 mg, increased to 200 mg in pregnancy.
Iodized salt: 1 part sodium iodide added to 100,000 parts NaCl.
After ingestion, readily absorbed from small intestine
From extracellular pool, rapidly enters thyroid gland (trapping). After trapping, 30 times more iodine is present in gland than plasma.
Enters through basement membrane (NaI symporter), an apical membrane another symporter pendrin is present, which controls outflow of iodide from cell.
Transporter is also present in cochlea of inner ear à congenital absence leads to deafness and goiter.
Different enzymes are involved in three steps:
Oxidation in cells by peroxidase enzyme
Organification –binding of iodide with tyrosine in thyroid leading to formation of monoiodotyrosine and diiodotyrosine.
Coupling of MIT and DIT to form T4 and T3, which are stored in gland. When required, released in blood by proteolysis.
In periphery deiodination occurs (T4àT3), reused.
Thyroid Hormones
Cell membranes receptors: increase amino acid and glucose uptake.
Inner mitochondrial membrane receptors: regulate energy metabolism.
TSH
T4 & T3 are feed-back regulators of TSH
TSH is stimulated by α-adrenergic agonists
TSH secretion is inhibited by:
Dopamine
Bromocriptine
Somatostatin
Corticosteroids
Conversion of T4 to T3 is decreased by:
Acute & chronic illnesses
β-adrenergic receptor blockers
Starvation & severe protein energy malnutrition (PEM)
Corticosteroids
Propylthiouracil
High iodine intake (Wolff-Chaikoff effect)
Thyroxine (T4)
Total T4 level is decreased in:
Premature infants
Hypopituitarism
Nephrotic syndrome
Liver cirrhosis
PEM
Protein losing entropathy
Total T4 is decreased when the following drugs are used:
Steroids
Phenytoin
Salicylates
Sulfonamides
Testosterone
Maternal TBI (thyroid binding immunoglobulins)
Total T4 is increased with:
Acute thyroiditis
Acute hepatitis
Estrogen therapy
Clofibrate
Iodides
Pregnancy
Maternal TSI
Goitrogens
Food
Soybeans
Millet
Turnip,Mustard
Cabbage
Thyroid Hormones
99% of T3 and T4 are bound to plasma proteins (thyroid-binding globulin).
0.04% T4 and 0.4% T3 occur in free form.
They are excreted in the bile and urine.
T4 has a half-life of 6-7 days; T3 has a half-life of 1-2 days.
Oral absorption of T4 is 80% and T3 95%
Readily absorbed from GIT and excreted in bile and urine.
Some of the circulating T4 is deiodinated to T3, the more potent and rapidly acting form.
5:1 is the ratio of T4:T3 in thyroid.
Hyperthyroidism
Excess of thyroid hormones or over-production.
Common Signs and Symptoms of Hyperthyroidism
Nervousness
Irritability
Difficulty Sleeping
Bulging Eyes
Unblinking Stare
Goiter
Rapid Heartbeat
Increased Sweating
Heat Intolerance
Unexplained Weight Loss
Scant Menstrual Periods
Frequent Bowel Movements
Warm, Moist Palms
Fine Tremor of Fingers, clubbing
Emotional Symptoms of Hyperthyroidism
Nervousness
Restlessness
Anxiety
Irritability
Sleeplessness or insomnia
Exhaustion
Hypothyroidism
It is reversible in adults. Slowing down of all body functions occurs. It is irreversible in children, as creatinism may occur.
Detected by:
Low free thyroxine levels
Elevated TSH
Common Signs and Symptoms of Hypothyroidism
Tiredness
Loss of Interest and/or Pleasure
Forgetfulness
Dry, Coarse Hair
Loss of Lateral Eyebrow Hair
Puffy Face and Eyes
Goiter
Slow Heartbeat
Dry Skin
Cold Intolerance
Weight Gain
Heavy Menstrual Periods
Constipation
Brittle Nails
How to Remember Signs and Symptoms of Hypothyroidism
Sleepiness, Fatigue, Lethargy
Loss of Memory, Trouble Concentrating
Unusually Dry, Coarse Skin
Goiter (Enlarged Thyroid)
Gradual Personality Change, Depression
Increase in Weight, Bloating or Puffiness (Edema)
Sensitivity to Cold
Hair Loss, Sparseness of Hair
Thyroid Drugs
Replacement therapy.
Treatment for hypothyroidism.
Suppress TSH secretion.
Levo isomers are more potent in increasing basal metabolic rate.
Once absorbed, their pharmacokinetic and dynamic properties are identical to endogenous thyroid hormones.
Shelf life is 2 years.
Levothyroxine
Synthetic levo isomer of T4.
Oral and I/V preparations are available.
Low cost & content uniformity.
Better standardization & stability and long duration.
Long half-life of T4(7 days)
Facilitates maintenance of a steady physiologic replacement.
Liothyronine
Synthetic L-T3.
More difficult to monitor than T4.
More expensive.
Shorter half-life.
Treatment of choice for Myxedema coma.
Short term suppression of TSH.
Greater risk of cardiotoxicity.
Liotrix
Combination of levothyroxine and liothyronine.
Ratio of 4:1.
No advantage over levothyroxine so not frequently used.
Uses
Cretinism –congenital hypothyroidism
Adult Hypothyroidism
Myxoedema coma
Non-Toxic Goiter
Thyroid Nodule
Papillary Carcinoma of Thyroid
Adverse reactions
Hyperthyroidism (or symptoms of hyperthyroidism).
Cardiovascular toxicity (tachyarrhythmias, angina, and infarction)
CNS stimulation
Insomnia.
Classification of Antithyroid drugs
Inhibit thyroid hormone synthesis (Thioamides)
Propylthiouracil,
Methimazole,
Carbimazole
Inhibit iodide trapping [Ionic inhibitors]
Thiocyanate,
Perchlorates,
Pertechnetate
Inhibit hormone release
Iodides,
Lithium
Destroy thyroid tissue
Radioactive Iodine
Inhibit peripheral conversion of T4 to T3
Amiodarone
β-blockers
Corticosteroids
Propylthiouracil
Ipodate
Thioamides
Propyithiouracil
methimazole,
carbimazole.
Inhibit the peroxidase enzymes catalyzing the oxidation of iodide, iodination of thyroglbulin
Inhibit coupling reaction
PTU also inhibits the peripheral deiodination of T4 to T3. Do not block uptake of iodine by gland.
Delay in absorption
Delay in onset 3-4 weeks, because formed T4 takes time to deplete, only further formation is stopped.
Pharmacokinetics
Propyl thiouracil
PTU is readily absorbed
Bioavailability is 50-80%
Volume of distribution is equal to total body water
Drug accumulates in thyroid gland
Secreted though kidneys, glucuronide form within 24 hours of administration.
Half life in plasma is 1.5 hours (90 minutes)
Methimazole,
Completely absorbed after oral administration
Accumulates in thyroid
Half life is 6 hours
Volume of distribution is equal to that of PTU, but excretion is slower.
Both drugs cross placenta. In pregnancy PTU is preferred, minimum dose required is given.
Methimazole causes congenital abnormality in fetus. Both drugs are excreted in breast milk in small quantity, but safe for nursing infants.
Uses
Used for control of hyperthyroidism until surgery.
Suppression of thyroid hormone synthesis until the effect of radioactive iodide begins.
Long-term therapy of mild-to-moderate hyperthyroidism.
The drugs are given orally.
Adverse effects
a. Mild maculopapular rash, b. joint pain, c. headache, d. nausea, e. loss of hair, f. altered sense of taste or smell, g. Hepatitis, h. Cholestatic jaundice i. Rare: agranulocytosis(0.1-0.5%) –most serious but not common, leading to leukopenia, sore throat, upper respiratory tract infection, immediately stop treatment.
j. Crosses the placenta and enters breast milk, which can lead to hypothyroidism in the fetus and nursing infant.
Differences
Propylthiouracil
Carbimazole
Less potent
10 times more potent
Highly PPB
Less bound
Less transfer across placenta & milk
Crosses the placenta
Half-life=1.5 hrs
6-10 hrs
DOA=6-8hrs
12-24hrs
No active metabolites
Active metabolites
Multiple doses
Once daily dose
Inhibits T3 conversion into T4
Does not effect
Iodides
Prepared in 1940s, now rarely used as sole agent.
Small amounts of iodine (75-100 ng/day) are required for hormone synthesis.
But high concentrations (+ 50 mg/day) produce autoinhibition.
lodides inhibit organification
Inhibit release of thyroid hormones.
Diminishes vascularity of the gland.
Uses
Used only preoperatively to shrink the gland. (prior to surgical removal of the gland).
Treatment of thyroid storm.
Prophylaxis of endemic goiter.
It is given as Lugol’s solution (iodine and potassium iodide).
Effects are visible within 24 hours. It is no longer used in long-term therapy.
Adverse reactions
Hypersensitivity reactions
Drug fevers,
Metallic taste,
Bleeding disordes,
Swollen salivary glands,
Conjunctivitis,
Rhinorrhea
Gastric irritation.
Long-term use can lead to sudden disinhibition of hormone synthesis, producing acute hyperthyroidism.
Radioactive Iodine
Given orally or I/V.
Rapidly taken,absorbed,,concentrated by thyroid,incorprated into storage follicles.
Leads to partial or total destruction of the gland by emission of beta particles.
Damage to surrounding tissue is minimal.
Metastatic carcinoma of thyroid
Advantages
simple
low cost,
effective,
easy administration,
absence of pain,
no surgical risk,
no genetic damage.
Disadvantages
Major: hypothyroidism.
Long latent period of response.
Not suitable for young patients.
Should be avoided during pregnancy.
Iodinated Contrast Media
Diatrizoate (PO), Iohexol (PO OR I/V).
Inhibit conversion of T4 to T3 in liver,kidney,pituitary gland & brain.
Useful adjunctive therapy in thyroid storm
Alternatives to iodides or thioamides
Beta Blockers
Excess thyroid hormones, upregulation of B-adrenergic receptors.
Tachycardia, tremors, anxiety.
Propranolol,metoprolol,atenolol.
Inhibits peripheral conversion of T4 to T3
Thyroid Storm
Acute exacerbation of symptoms of disease thyrotoxicosis, if not treated quickly, leads to death
Treatment:
1. Supportive
Fever controlled by antipyretics, I/V fluids, etc.
2. Drug treatment
Propanolol given I/V 1.2 mg after that orally 40-80 mg every 6 hours, if contraindicated, Diltiazem is used for CVS symptoms and severe tachycardia.
Potassium Iodide (10 drops orally daily] –retard release of thyroid hormones from gland.
Iodinated Contrast Media(1g orally)
Hydrocortisone to prevent shock
Antithyroid drugs to inhibit thyroid hormone synthesis.
Glucocorticoids Administered by Inhalation– used in bronchial asthma
Beclomethasone
Budesonide
Fluticasone
Triamcinolone
Mometasone
Steroids -Mechanism of Action
All steroids have the same mechanism of action, but differ in production of ultimate proteins.
Crossing cell membrane
All steroids enter cell passively.
Binding with cytosolic receptor
Mainly present intracellularly. Two types of receptors are involved:
GR –alpha
GR –beta
(GR = glucocorticoid receptor)
Receptors are distributed throughout the body. Mineralocorticoid receptors are present mainly in excretory organs like kidneys, colon and sweat glands, etc.
Receptors of glucocorticoids are present all over body.
Dissociation of receptor from Hsp 90 & 70
Normally receptors are covered by regulatory proteins, which are of two types:
HSP-90
HSP-70
These are the heat shock proteins, the regulatory and stabilizing proteins. When steroids bind the receptors, they cause displacement of stabilizing proteins from receptor sites.
Active transport of steroid-receptor complex into the nucleus
Binding of activated receptor with DNA
Receptor separates and steroid binds DNA
DNA transcripts the formation of specific mRNA
Formation of specific protein lipocortin (Annexin 1)
mRNA enters cytoplasm and goes to ribosomes to bind them causing formation of specific proteins by the power of translation.
Lipocortin (protein) inhibits phospholipase A2
Phospholipase is responsible for generation of arachidonic acid.
Inhibition of formation of arachidonic acid from phospholipid
Inhibition of formation of chemical mediators, including prostaglandins and leukotrines.
This is the anti-inflammatory mechanism of glucocorticoids.
Glucocorticoids Pharmacological Actions
Effects are divided into two main categories:
1. Metabolic Effects
a) Carbohydrate Metabolism
Steroids in carbohydrate metabolism cause and increase in blood levels of glucose.
Decrease utilization of glucose
Cause increase in gluconeogenesis
Cause increased breakdown of glycogen
All effects lead to increased glucose levels, producing diabetogenic effect.
b) Lipid Metabolism
Lipolysis occurs
In high doses, redistribution of fat to other parts of the body.
c) Protein Metabolism
Have catabolic effect
In high doses, cause loss of protein matrix from bones and cause thinning of skin and wasting of muscles
Atrophy of skin, if applied topically
Negative nitrogen balance
d) Water & Electrolyte Balance
Salt and water retention and excretion of potassium.
These effects are minor, in over dosage or prolonged use cause excretion of water
e) Excretion of urates
On prolonged administration, increase the chances of urine stone formation (urinary canaliculi)
f) Antivitamin D activity
Some anti-vitamin activity so cause increased excretion of calcium in urine.
g) Augment the action of growth hormone on adipocytes
(have specific lipase enzyme).
2. Non metabolic effects
a) Anti Inflammatory Action
Most important effect, causing reversal of all signs/symptoms of inflammation without removing cause. Thus have non-specific effect in inflammation.
b) Lympholytic action
Generalized decrease in lymphoid tissues in body occurs along with lymphocytopenia.
c) Immunosuppressive action
Cause a decrease in immunity by:
Causing decrease in lymphocytes (decreased antibodies formation)
Stabilization of mast cell membrane
Due to anti-inflammatory effect
Some anti-histaminic effect
d) Effects on Blood
Cause increase in RBCs, hemoglobulin, neutrophils and platelets.
Most important is that they cause decrease in eosinophils, decrease in basophils and monocytes, leading to anti-allergic effects
e) CNS
When patient starts taking steroids (in therapeutic doses):
Elation occurs
Increased appetite
Euphoria
If taken in high doses, lead to:
Insomnia
Even psychotic behaviour
f) Decrease production of TSH & increased growth hormone production
Pharmacokinetics
Natural steroids,
After release bind specific proteins known as CBG (corticosteroid binding globulins)
Metabolized in liver and excreted in urine
Synthetic steroids can be given by various routes of administration:
Oral route
Topically
Inhalation –bronchial asthma
Parenteral
Intra-articularly –rheumatoid arthritis
Therapeutic uses of Glucocorticoids
1. Replacement therapy in adrenal disorders
Very important logical use in
a. Acute adrenal insufficiency
Usually occurs when steroids are given in high doses for long periods and then abruptly stopped, due to negative feedback (availability of hormones), atrophy of adrenal gland occurs.
Treatment is to give hydrocortisone or cortisol 100-200 mg 6 hourly, until condition is controlled.
When giving steroids for long periods, dose is gradually tapered off.
b. Chronic adrenal insufficiency (Addison’s disease)
Due to tumor of adrenal cortex, infections (tuberculosis of adrenal gland) or removal, chronic insufficiency occurs.
Treatment is to give replacement therapy including glucocorticoids along with mineralocorticoids.
Cortisol in a dose of 20-30 mg, synthetic ones are given in equivalent doses.
Once patient is stabilized, two-thirds of the dose is given in the morning, while one-third in evening.
c. Congenital adrenal hyperplasia
Very rare congenital defect in synthesis of glucocorticoids, leading to excessive formation of androgens. This may be:
Congenital
Defect in last step of corticosteroid because of excessive enzyme responsible for synthesis
Androgens are formed one step earlier, especially in pregnant females virulization of female fetus occurs.
Treated by administering glucocorticoids.
2. Non-adrenal disorders (Empirical Uses)
Ist Line uses
SLE and other Collagen disorder
Autoimmune disorders, very effective and live saving.
Acute leukemias and lymphomas
In combination with anti-neoplastic drugs
Status asthmaticus/Bronchial asthma
Hydrocortisone is given I/V 100-200 mg 6 hourly, until acute attack is controlled
Gram negative septicemia
Life threatening condition, death may occur, given in combination with anti-microbial drugs.
Cerebral edema
Medical emergency, may occur after head injury.
Dexamethasone is given for cerebral edema.
Glomerulonephritis/Nephrotic syndrome
Affect especially membranous type of glomerulonephritis.
Idiopathic thrombocytopenic purpura –sometimes repond to steroids
Aplastic anemia
Hemolytic anemia (acquired) –respond in emergency
Immunosuppression
Used as immunosuppressive in:
Rheumatoid arthritis
Prevent transplant graft rejection
Prevent graft vs. host reaction
Auto immune thyroiditis
Acute mountain sickness
In combination with acetazolamide and carbonic anhydrase inhibitors
Advantage of combination is that acetazolamide is that these have rapid action, while acetazolamide has delayed effects.
Allergies
Especially seasonal (pollen)
Acceleration of lung maturation in premature babies
Cortisol causes maturation of lungs and in premature infants, there is decreased release of cortisol so given to mother before delivery esp.
Beclomethasone 48 hourly before delivery I/M.
Again before 24 hours of delivery
15. Dermatologic conditions
Contact dermatitis
Lichen planus
Pemphigus
Seborrhoeic dermatitis
In most skin conditions steroids are used, esp. non-infective skin conditions.
16. Ocular conditions
Acute conjunctivitis
Choroiditis
Uveitis
17. Diagnostic purpose
To access primary and secondary caused of Cushing disease (ACTH excess) give potent steroid, dexamethasone, if after administration decreased levels occur, patient has Cushing disease due to primary dysfunction of adrenal cortex.
If no effect is observed, ACTH excess is due to secondary causes (hyperpituitarism or ectopic production)
2nd/3rd Line uses
Anaphylactic shock -1st line is adrenaline
Ulcerative colitis
Crohn’s disease
Rheumatoid arthritis
Osteoarthritis –non-responding
Acute gout –when excessive swelling and pain occurs, along with NSAIDS and Colchicine
Myasthenia gravis –along with neostigmine and physostigmine
Aspiration syndrome –to avoid aspiration of gastric contents
Bronchial asthma –along with other anti-asthmatics oral/inhalational
10. Acute spinal cord injury –to avoid inflammation and edema
Untoward effects of Glucocorticoids
1. Suppression of adrenal –pituitary axis
Prolonged administration caused negative feedback leading to atrophy of adrenal cortex. Steroids are not withdrawn abruptly, otherwise Addisonians crisis occurs. Dose is gradually tapered, to allow recovery time. Once axis is depressed, it may take months or even years to recover, but when given for short period in low doses (25 mg prednisolone daily for 5-10 days) there is no need to taper off dose.
2. Iatrogenic Cushing’s syndrome –in high doses 3. Hyperglycemia
Due to increased plasma glucose, effect on carbohydrate metabolism
4. Muscle wasting/myopathy
Catabolic effect on proteins
5. CVS
May cause retention of salt and water leading to:
Edema
Hypertension
Even cardiac failure
6. Immunological
Anti-immunity effects, leading to decreased resistance to infections and delayed healing of wounds, making more prone to infections
7. Eye
When used topically cause glaucoma on prolonged administration
Posterior subcapsular cataract
Corneal ulceration
8. GIT
a. May cause peptic ulcer, due to secretion of HCl and pepsin when taken orally for prolonged periods. b. May aggravate ulceration, c. In patients of peptic ulcer, may cause painless perforation d. May cause increase in candidiasis of GIT 9. Bones
Due to loss of protein matrix may cause osteoporosis, leading to spontaneous fractures.
So patients taking steroids are advised to take calcium and vitamin D supplements to avoid.
10. CNS
In therapeutic doses:
Euphoria
Elation of mood
In excessive doses:
Insomnia
Psychotic behavior
Aggravate psychosis esp. schizophrenia
May cause increase in intracranial pressure on prolonged administration –although rare.
11. Growth suppression
Especially in children due to early closure of epiphysis
12. Hypokalemia
Due to retention of sodium and excretion of potassium. Danger is when patient is taking digoxin or diuretics.
13. Candidiasis
Usually in patients of bronchial asthma, taking steroids by inhalation, due to deposition of steroids in larynx, pharynx, leading to candidiasis.
In larynx ultimately laxity of vocal cords and hoarseness of voice.
Nystatin mouth washes
Azoles
Amphotericin B mouth washes are used
Acne & hirsutism
On prolonged administration, especially after topical use.
14. Striae and bruising –esp. when applied to skin
Drugs causing increased sodium and water retention along with increased elimination of potassium, acting on the late distal part and collecting tubules.
Natural are not used in therapeutics.
Aldosterone hormone cannot be given orally because:
1. Has short duration of action 2. In older days, when it was used, it had to be given 5-7 times a day by I/M injection
Synthetic
Fludrocortisone in only used nowadays.
Given about 5-7 times a week
Can also be given orally
Use
Treatment of adrenocortical insufficiency, replacement therapy in combination with glucocorticoids
Treatment of hypotension esp. when due to excessive loss of sodium.
Dose
50-300 mcg daily. In children dose of 5 mcg/kg body weight daily by oral route of administration.
Chemically derivatives of sulfonamides. Divided into two main groups:
1st generation
2nd generation
Older drugs
Newer drugs
Less potent
100 times potent
Mechanism of action
Also known as insulin secretogoug.
Mainly act by causing increased secretion of insulin from beta cells of pancreas by binding receptors on surface of beta cells.
Also cause increased sensitivity of tissues to insulin
Also cause decrease in release of glucagon.
Cause decrease in gluconeogenesis
Increase in number of insulin receptors
Ineffective in type I diabetes mellitus, requiring up to 30% of beta cells to be intact for action.
Cause a decrease in conductance of ATP sensitive potassium channels à decreased conductance leads to increase in positivity inside cells à leading to depolarization resulting in à increased entry of calcium through calcium channels à increased release of insulin from beta cells.
Pharmacokinetics
Well absorbed after oral administration.
Extensively bound to plasma proteins, maximum is for Glibenclamide, while Chlorpropamide has the least.
Half life varies. 1st generation drugs have short half life (4-7 hours) and short duration of action. Chlorpropamide has long half life of 36 hours (longest in 1st generation). Acetohexamide has active metabolite having same half life (4-7 hours)
Second generation compounds have shorter half life of 1.5-5 hours, but have longer duration of action than 1st generation compounds, which may be due to active metabolites formed. Since more potent, usually given once daily.
Most drugs are metabolized in liver and excreted in urine. Chlorpropamide is 20% excreted unchanged in urine. Glipizide and Tolbutamide are mainly excreted through bile and less through urine.
Adverse Effects (4%)
Hypoglycemia
More with drugs with longer half life including Chlorpropamide and Glibenclamide, in renal insufficiency, especially in elderly. Treatment is same:
Glucose by mouth
I/V
Cholestatic jaundice
Since metabolized in liver, hepatotoxicity might occur.
Agranulocytosis
Blood dyscrasias
Anaemia (hemolytic and aplastic)
Alcohol intolerance
In presence of alcohol, there are more chances of hypoglycemia
Allergic reactions
Drugs Interaction Of Sulphonylureas
1. Alcohol
Hypoglycemia
Chlorpropamide can cause disulfiram like reaction with alcohol
2. Enzyme inducers 3. Enzyme inhibitors à hypoglycemia 4. Chlorpropamide potentiates the effects of ADH on collecting tubules, also used in treatment of diabetes insipidus.
Interacting drugs
Type of interaction
Result
Thiazides
Antagonism
Diminished effect of sulphonylureas
Rifampicin
Enhanced metabolism of sulphonylureas
Diminished effect of sulphonylureas
AspirinSulfonamides
Displacement of sulphonylureas from plasma proteins
Enhanced effect of suophonylureas
ChloramphenicolDicoumarol
Decreased metabolism of sulphonylureas
Enhanced effect of suophonylureas
Preparations and dosage of Sulphonylureas
Tolbutamide:
Initial dose is 500 mg while 3000 mg is max. effective dose.
Acetohexamide:
250 -1500 mg
Tolazamide and Chlorpropamide:
Initially 100-250 mg while 750 to 1000 mg is maximal.
Glyburide:
Initial daily dose 2.5 -5 mg. maximum range is 20 mg
Glipzide: Initially 5 mg. Max is 40 mg in divided doses
Gliclazide: Initially 40 – 80 mg and max is 320 mg
Meglitinide
Repaglinide
Nateglinide
Have same mechanism of action and effects as sulfonyl ureas, but differ from others in:
Rapid onset of action
Short duration
Are metabolized in liver, excreted in bile, thus can be given in renal insufficiency
Cause less incidence of hypoglycemia as compared with sulfonyl ureas (shorter duration of action).
Nateglinide may cause severe hypoglycemia.
Sulfonyl ureas are not given in obese patients as cause increased apetite, these drugs cause less increase in weight thus can be given
Dose
Ranges between 0.5-4 mg twice or thrice daily depending upon severity.
Biguanides
Chemically are guanidine derivative. Most of these are withdrawn due to adverse effects including lactic acidosis. Only one drug, Metformin is used.
Mechanism of action
Although does not cause release of insulin, but for action of oral antidiabetic should be so. Mainly act by:
Suppress hepatic gluconeogenesis, preventing hepatic outflow of glucose as liver is mostly responsible, especially during night time.
Stimulate glycolysis leading to breakdown of glucose
Mainly used in treatment of type II diabetes mellitus, in combination with sulfonyl ureas and insulin. Can also be used alone.
Also used in polycystic ovarian syndrome (drug causes decrease in insulin, resistance leading to ovulation in these women)
Adverse effects
Mainly GIT effects:
GIT upset
Diarrhea
Abdominal discomfort
Sometimes so severe that patient may leave drug
Lactic acidosis –more common in patients of renal insufficiency, in alcoholics.
Contraindications
Renal disease –as cause lactic acidosis
Pregnancy
Lactation
Severe infections
Cause increases in HDL and decrease in LDL, beneficial for patients of cardiac diseases. Effects are over after 4-6 weeks of treatment.
Dose: start at low dose of 0.5 g, can be increased to 0.85 g tid or 1 g thrice or twice daily.
Metformin does not cause hypoglycemia, as there is no release of insulin.
Alpha Glucoside Inhibitor
Acarbose
Mechanism of action
Inhibit alpha-glucosidase in intestinal brush border
Inhibit hydrolysis of oligosaccharides to glucose
Also inhibits pancreatic alpha-amylase, responsible for converting starch into oligosaccharides.
Ultimately causes decrease in conversion into glucose.
Pharmacokinetics
Not absorbed from intestine when given orally, only a small amount is absorbed, excreted unchanged in urine.
Most of drug is broken down by bacteria in intestines.
Duration of action 3-4 hrs
Dose:25-100mg bid or tid
Adverse effects
Does not cause hypoglycemia when given alone
GIT –as not absorbed, may cause:
GIT upsets
Flatulence
Diarrhea
Abdominal cramps
Contraindications
Mainly in patients suffering from GIT disease, may lead to ulceration or intestinal obstruction.
Drug interactions
Also inhibit or decrease absorption of metformine so not given in combination.
Thiazolidinediones or Glitazones
Rosiglitazone, Troglitazone withdrawn due to adverse effects. Only Pioglitazone is available.
Mechanism of action
Also known as insulin sensitizers as increase sensitivity of tissues to insulin.
Mainly act by binding peroxisome proliferator activated receptor-g (PPAR-g), which is a nuclear receptor mainly concerned with regulation of glucose of lipids.
bind receptors leading to increase utilization of glucose
Increased HDL levels, decrease in breakdown of fats
Expansion of S/C fat
Thus, increased insulin sensitivity to tissues.
Pharmacokinetics
Well absorbed after oral administration.
Have extensive PPB.
Mainly metabolized in liver
Pioglitazone also has active metabolites, which are excreted in urine.
Some parent drug is also excreted in bile, so drug can be given in renal insufficiency.
Duration of action 12-24 hrs
Used for polycystic ovarian syndrome
Adverse effects
All drugs are hepatotoxic, Troglitazone has been withdrawn due to hepatotoxic effects. Thus all patients should have regular LFTs.
Rosiglitazone causes increase in LDL levels so drug is withdrawn from market (cardiovascular disease)
Retention of sodium and water
Increase in subcutaneous fat (increase in weight), used carefully in cardiovascular diseases.
Dose: Pioglitazone: 15-30mg o.d
Dipeptidyl Peptidase Inhibitors
Pramlintide & Exenatide
GLIP stands for glucagon like peptide. Pfzmlintide and Exenatide act through GLIIP enzyme.
Mechanism of action
Normally when patient takes glucose by mouth, increase in release of insulin occurs. Release is more when taken orally than I/V. this effect is said to be due to GLIP.
In diabetics, decrease in release of insulin in response to glucose occurs.
These drugs cause increase in activity of GLIP, so improve insulin release in response to glucose.
Slow gastric emptying
Decrease food intake
Increase glucose suppression of glucagon secretion
Promote beta cell regeneration
Decrease apoptosis
Reduce weight gain, postprandial hyperglycemia & loss of beta cells
Drawbacks
Main drawback is that since they are peptides, they cannot be given orally. They are usually given parentally.
Have short duration of action
So not in practice, only long acting drugs may have some benefits.
Derived from Greek word diabainain: to pass through
It is a state of high glucose levels which may lead to complications including:
Atherosclerosis
Renal failure
Changes in eye
Retinopathy
Ischemic heart disease
Ultimately coma and death
Patient shows an increase in blood glucose levels due to decreased utilization of glucose, leading to increase in compensatory mechanisms, resulting in increased fat metabolism, leading to formation of ketone bodies (Acetone, Acetoacetic acid, alpha ketobutyric acid). This leads to ketoacidosis and death of patient.
Symptoms of Diabetes Mellitus
Main symptoms occur when absolute or relative deficiency is seen due to various factors:
polyuria
polydipsia
glycosuria
Treatment
To give insulin. Increase in glucose levels occur due to relative deficiency of insulin. The purpose is to increase glucose metabolism and decrease fat metabolism.
Types of Diabetes Mellitus
Two types:
Type-I (IDDM)
Absolute deficiency of insulin due to degeneration of pancreas, usually occurring in young age. It may be due to:
Viral infections
Autoimmunity
Insulin is required for treatment, so known as IDDM.
Type-II (NIDDM)
Occurs in middle age, relative deficiency of insulin occurs. Although production may be normal but insulin antagonists may be present in blood. It is a less severe disease than type 1. Type II may lead to ketoacidosis. Insulin may not be required for treatment, it is usually due to increased activity of pancreas (overactiivty). Also has genetic basis.
Causes of insulin lack:
1. Lack of secretion –degradation of beta cells of pancreas
2. Tissues insensitivity to insulin mainly due to excessive secretion from pancreas (esp. type II occurring due to overeating)
3. Excess of insulin antagonists
a. Glucocorticoids
b. catecholamines
c. GH
d. oral contraceptives
4. Depressed release of insulin and transport
Increased blood glucose levels especially after meal is the main stimulus for the release of insulin.
It is mainly synthesized in beta cells of pancreas from pro-insulin, which comes from pre-proinsulin.
Insulin structure
It has a molecular weight of 5808. Chemically consists of 2 polypeptide chains:
a chains –consisting of 21 amino acids
b chains –consisting of 30 amino acids
linked together by disulfide bonds.
Mechanism of action
When insulin is released by beta cells on pancreas, it goes to target tissues present mainly in:
liver,
fat (adipose tissue)
muscles
These contain insulin receptors. Concentration of receptors varies with the amount of insulin in blood. It is inversely proportional to the levels of insulin in blood.
If insulin is increased, downregulation of receptors occurs, leading to decrease in receptors.
After insulin release, it binds insulin receptors present on cell membrane of tissues. There are 2 parts of these receptors:
alpha part –outside cell membrane
beta part –transmembrane
Insulin binds alpha part. Due to binding, autophosporylation of beta part takes place.
Beta part is a kinase enzyme. When autophosphorylated, it also causes phosphorylation of other cell constituents in cell membrane, ultimately leading to translocation of glucose transporters from storage sites to cell membrane.
When these glucose transporters are transported, they cause increased utilization of glucose.
Pharmacokinetics
Polypeptide hormone, thus it cannot be given orally.
Routes Of Administration Of Insulin
S/C, I/V, I/M but mostly given subcutaneously. In emergency I/V given.
Implantable pumps
Insulin pens containing catridges filled with insulin
Metabolized by insulinase enzyme in liver and kidney.
Most of insulin secreted by pancreas enters portal veins and goes to liver, only 15% reaches systemic circulation.
When given subcutaneously, entry into liver and other organs is same, thus this route is preferred.
Addition of certain metals to prolong duration of action e.g. zinc is added to increase duration.
Protamine zinc insulin is a type of long acting insulin.
InsulinsTypes: (According To Source)
Bovine
Porcine
Human (recombinant DNA)
a) Bovine differs from human insulin in 3 amino acids.
b) Porcine differs from human insulin in 1 amino acid
c) Human insulin is pure form –formed by recombinant DNA technique
Disadvantage of bovine and porcine form is although having same effect but increased chances of hypersensitivity reactions.
Human insulin
Has rapid onset of action
Has short duration of action
Is less immunogenic –no or less hypersensitivity reactions
But human insulin is very expensive, so as there is no difference in action, we always use bovine and porcine forms, being cost effective. Human form is resorted to only when patient is not responding or when hypersensitivity reactions are seen.
Bovine and porcine in pure form are mono component, causing less hypersensitivity reactions as compared to older preparations. Human insulin is in pure form, so has no reactions.
Classification (According To Duration Of Action)
Ultra short acting
Short acting
Intermediate acting
Long acting
Preparation
Onset of Action
Peak Effect
Duration of action
Ultra – short acting
Insulin lisproInsulin aspartGlulisine
20min
½ hour
3-4 hrs
Short acting
Soluble insulin
½ – 1 hour
4-6 hrs
8-10 hrs
Insulin zn suspensionSemilente
Intermediate acting
NPH (isophane)
Insulin zn suspension lente
2hrs
6-10 hrs
24 hrs
Long acting
Protamine zn insulin (pzi)
4 hrs
10-8 hrs
36 hrs
Insulin zn suspensionUltralente
Glargine
2-5 hrs
5-24 hrs
18-24 hrs
Insulin mixtures
Humulin 70/30 mix (30% soluble Insulin with 70% isophane)Mixtard 30 HM (30% soluble Insulin with 70% isophane)
Variable actions Depending on Predetermined Proportions of Short/intermediate or Intermediate/long acting Insulin
Doses Of Insulin
Preparations of insulin are available in the form of units. One unit of insulin is defined as:
“amount of insulin required to lower blood glucose level of a 2 kg normal rabbit from 120 – 45 mg/dl”
Normal amount secreted by pancreas daily is 30 -50 units/d (0.5 -0.8 units/kg) of soluble (regular) insulin
In IDDM, dose normally ranges between 30-50 units of insulin daily, depending on:
Levels of blood glucose
Physical activity of patient
Diet of patient
When blood levels are more than 300mg/dl, start with 20 units of regular short acting insulin.
If blood levels are less than 200-300/dl, start with 10 units of regular insulin, with 4 units daily increments until blood levels are controlled.
Long acting insulins given 10-14 units/day: dose increment 4 units on alternate days
Ideally a combination of regular and long acting insulins is used twice daily. (regular –rapid onset, long acting –sufficient for delayed action)
Once dose is adjusted, two-third dose is given in morning before breakfast and one-third before evening meal.
Adverse effects of insulin
Hypoglycemia
When there is change in requirement of insulin, e.g.
patient misses a meal,
increased physical activity
he may go into hypoglycemia. Due to release of catecholamines, certain symptoms appear:
tachycardia
sweating
anxiety
apprehension
insomnia
headache
in severe cases coma ‘hypoglycemic coma’ or even death may occur
Treatment
give (if conscious) sugar, glucose or meal
if unconscious, glucose given I/V, usually 30% glucose given by I/V drip or infusion
most important is to educate the patient, as there may be damage to brain:
not to miss meals
always keep sugar, glucose to avoid
no increase in physical activity or excessive physical activity
whenever feels sympotms, take sugar to avoid hypoglycemia
Lipodystrophy
Repeated injection at same site. Advised not to take injection at same site.
Allergy
Animal origin –skin rash, articaria, localized or generalized
Obesity (increased appetite)
May cause weight gain of patient
Treatment Of Diabetic Ketoacidosis
When treatment is not given, breakdown of fats cause diabetic ketoacidosis, which may be serious enough to cause death of patient.
1. Soluble/short acting Insulin:
Severe Ketoacidosis: 0.1 unit/kg/hr or 7 unit/hr
Less severe: 3 unit/hr
I/V drip: 40 units/l
Rapidly acting in medical emergency.
2. I/V fluids and electrolytes: Isotonic saline 5 L total fluid deficit: 500 ml Ist 20 min 2 L 90 min 1 L 90 min 1 L 120 min
3. Potassium: KCl I/V infusion 15mmol/hr by slow infusion, carefully monitored, given in hypokalemia.
4. Bicarbonate: If plasma PH< 7.0
Forms of human insulin (depending on source recombinant DNA technique)
emp (enzyme modified porcine)
prb (proinsulin recombinant in bacteria)
pyr (precursor insulin yeast recombinant)
Mostly used for type II diabetes –all are taken 30 minutes before meal.
