Drugs Acting ON Uterus PDF

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DRUGS ACTING ON UTERUS & ERECTILE DYSFUNCTION : Drug Acting on Uterus Cause contraction or relaxation of uterus : Uterine contractility enhanced by  oxytocin ( ergometrine (ergonovine  prostaglandin analogues : Uterine relaxation enhanced by  B- adrenoceptor agonists  magnesium sulphate  prostaglandin synthetase inhibitors  calcium channel blockers Oxytocin : Pharmacological Actions : Synthesized in the ( supraoptic nucleus (SON  paraventricular nucleus (PVN) of hypothalamus By axonal transport arrive and stored in the posterior pituitary Sensory stimuli from cervix & vagina induce secretion of oxytocin from posterior pituitary Stimulation of breast leads to secretion of oxytocin  contraction of myoepithelium  milk ejection reflex : On Uterus Stimulates frequency & force of contraction Effect dependent on presence of estrogen Contributes to initiation of labor Sensitivity of uterus to oxytocin increase during pregnancy : Oxytocin induced myometrial contraction inhibited by  B- adrenoceptor agonists  magnesium sulphate  inhalational anesthetic agents : On CVS Large amounts   marked transient relaxation of vascular smooth muscle  reduction of blood pressure  flushing  reflex tachycardia : Other Effects Large amounts  antidiuretic effect -

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: Mechanism of Action Specific receptors in myometrium Elicits prostaglandin production in endometrial / decidual cells Alters transmembrane ionic currents in myometrial smooth muscle cells to produce sustained contraction : Pharmacokinetics Administration IV to induce labor Intra-nasal spray – postpartum use to induce lactation Inactive when administered orally T 1/2 5 – 12 minutes Metabolized by oxytocinase : Uses To induce labor or augment dysfunction Conditions requiring early vaginal delivery  Rh problems  maternal diabetes mellitus  pre-eclampsia Uterine inertia Third stage of labor To control post-partum bleeding Milk ejection : Toxicity When properly used toxicity is rare Uterine rupture Water intoxication Foetal death Maternal death from hypertensive episodes :Contraindications Foetal distress Prematurity Abnormal presentation Cephalo-pelvic disproportion Ergot Alkaloids : Ergometrine 

First used as uterine stimulating agent

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Ergot – product of fungus

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Derevative of 6-methy ergoline

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Pure Form – Ergotamine 2

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Ergometrine ( Ergonovine ) water soluble derivative

: Ergometrine Actions : Uterus - Increase motor activity of uterus  Dose related increase in frequency & force of contraction  Pregnant uterus is more sensitive  Uterus at term is more sensitive than early pregnancy Combines alpha-agonist , serotonin & other effects Ergometrine 

Ergonovine is more active and less toxic than ergotamine.

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Useful for the control of post partum or after labor bleeding.

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Should never be given before delivery.

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Given at the time of delivery of placenta.

: Pharmacokinetics : Routs of administration ∞ Parentally ∞ Orally ∞ Rectally - Extensive first-pass effect - T ½ is 2 hours but effect persist for 24 hours - Metabolized in liver - Excreted in bile : Side effects - GI upset : diarrhea, nausea, vomiting - Tingling of fingers and toes - Muscle pain - Overdosage  prolonged vasospasm  pallor, anginal pain, gangrene - Contraindicated in : ∞ Peripheral vascular disease ∞ Coronary heart disease ∞ Hypertension ∞ Impaired renal & hepatic disease

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Prostaglandins  Analogues found in uterus are PG-E & PG-F 2-alph : Actions :On Myometrium cause strong uterine contraction < sensitivity of uterus to prostaglandins increase as gestation progress < : On Cervix local instillation of PG induces ripening, softening and relaxation of cervix < PG-analogues : PG-E2 & PG-F2alpha : Toxicity  stimulates GIT >> nausea, vomiting, diarrhea.  Transient pyrexia  Hypertention by constricting vascular smooth muscle : Therapeutic uses    

Gemeprost (PG-E1): intravaginal persarry for termination of pregnancy Dinoprost (PG-F2alpha) intravaginal tablets for induction of labor Intra-amniotic route for therapeutic abortion Carboprost: Given deep IM or treatment of post-portum hemorrhage in patients who don’t respond to Oxytocin or Ergometrine.

Tocolytic Agents Agents that inhibit uterine contraction Used to delay or prevent premature parturition Slow or arrest delivery for brief periods in order to undertake other therapeutic measures : Agents  B2-adrenoceptor agonist ( Retodrine & Terbutaline )  Magnesium sulphate  Prostaglandins synthetase inhibitor ( Indomethacin )  Calcium Channel Blocker ( Nifedepine & Norcardipine) 4

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Retodrine   

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selective B2-adrenoceptor agonist developed specifically for use as a uterine relaxant relaxes smooth muscles of :  uterus  bronchial tree  arteries effective 20-36 weeks gestation

: Uses Mainly used for Rx of premature labor * Rx initiated with IV infusion and about 30 minutes before the end of IV infusion oral * therapy begins

: Adverse Effects Tachycardia * Increased cardiac output * Fluid overload  maternal pulmonary oedema ( esp. If combined with * ( corticosterioids Hyperglycemia * Hypocalcemia * Prostaglandin Synthetase Inhibitors Cyclooxygenase inhibitors (NSAIDS esp. Indomethacin) inhibit prostaglandin synthesis – can half pre-term labor Concers of foetal and neonatal side effects limit their use * Premature closure of ductus arteriosis Increased risk of pulmonary hypertension Oligo-hydraminios Post Maturity Used in gestation prior to 34 weeks *

Magnesium Sulphate Effective inhibitor of uterine contraction * 5

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Interferes with calcium uptake by myometrial cells which need it to contract * Generally given IV as an infusion *

:Adverse reaction GIT – nausea and vomiting Hot flushes Blurred vision :Toxicity Decreased respiratory rate Hypotension Extreme muscle Relaxation Caution Clost monitoring is required *

Erectile Dysfunction Persistend inability of male to attain or maintain penile erection of sufficient * rigidity to have satisfying sexual activity The term Erectile Dysfunction (ED) rather than Impotence, more accurately * .define the problem

N.B: There was a picture showing engorgement of cavernous spaces with blood in the . erect state Physiology of Erection Normal Erectile function requires a complex set of neural and vascular interactions * : Penile erection is elicited by at least 2 distinct mechanisms * Central Psychogenic Refelxogenic -

Physiology of Erection:

ON AR AROUSAL OUSAL

Parasympathetic activity triggers series of events starting by the release of NO . and ending with increase levels of cGMP Parasympathetic activity  Acetylcholine Release  Cavernosal Endothelial cells NO  Increase activity of Guanylate cyclase  Production of intracellular mediator cGMP 6 SMSO your access to success

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Erectile Dysfunction (ED) Classification : Two etiologic categories Organic  > 80% .1 Vasculogenice ( Arterial Inflow Disorder)  Most Common Neurogenic Hormonal % Psychogenic  40% of cases.  Scarring occurs only in 5% of the cases. Oral Preparations Phosphodiesterase inhibitors - Sildenafil (Viagra) - Tadalafil (Cialis) - Levitra Mechanism of Action :  Phosphodiesterase (PDE) inhibitors  PDEs  diverse family of enzymes which hydrolyze cAMP & cGMP  stops its effects in different body tissues (e.g. relaxation of SMs ) Mechanism of Action of Sildenafil NO-cGMP mechanism of penile erection & the NO-enhancing effect of the PDE5 inhibitor Sildenafil Penile/sexual stimulation NO

NANC & endothelial cells GTP

Guanylate cyclase Sildenafil

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GMP PDE5

cGMP

Corpus cavernosum Smooth muscle cell Penile Relax erection

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NO=nitric oxide. CGMP=cyclic guanosine monophosphate. PDE5=phosphodiesterase type 5. GTP=guanosine triphosphate. NANC=nonadrenergic noncholinergic neurons

Sildenafil: Pharmacokinetics Tablets  50mg Rapidly absorbed  bioavailability of 40% Peak plasma concentration 30 – 120 min. (median 60 min) in fasted state. Metabolized by cytochromes in the liver to an active N-desmethyl metabolite possess 50% potency of the parent drug for inhibiting PDE5.  Excreted in the feces (>80%) &...