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Khurram Mahmood Assistant Professor PharmacologySlide 2: Ergot alkaloids… Compounds that incorporate the tetra cyclic ergoline nucleus First adrenergic blocking agents to be discovered Exhibit a complex variety of pharmacological properties Complexity of their actions limits their therapeutic uses Act on several types of receptors, α -adrenoceptor, serotonin receptor, dopamine receptor – partial antagonists or antagonists Spectrum of effect depends on the agent, dosage, species, tissue, physiological and endocrinological state, and experimental conditionsHistory and Source : History and Source Ergot - derived from an old French word argot, meaning cock’s spur Recognized for over 2000 years First used as a uterine-stimulating agent by physicians 400 years ago. Ergot is the product of a fungus Claviceps purpurea that grows on rye and other grains. This infected grain is a major source of ergot alkaloidsHistory and Source….: History and Source…. Ergot poisoning was recognized after consumption of infected grain, known as Holy fire or St Anthony’s fire Ergotamine – first pure ergot alkaloid obtained in 1920 Ergonovine in 1932 Numerous semisynthetic der by catalytic hydrogenation of natural alkaloidsClassification: Classification A. NATURAL Derivative of lysergic acid Two isoforms - only the levo form is pharmacologically active a. Amine alkaloids ( Upon hydrolysis yield lysergic acid and an amine; consequently they are called amine alkaloids) Ergometrine (ergonovine) Lysergic acid diethylamide (LSD) 6-methylergoline Lysergic acid b. Peptide alkaloids ( yield lysergic acid, ammonia, pyruvic acid, proline, and one other amino acid and so are known as amino acid alkaloids) Higher molecular weight Ergotamine, Ergotoxine, Ergosine and ErgostineClassification….: Classification…. B. SEMI-SYNTHETIC DERIVATIVES Methylergometrine Methysergide Bromocriptine Dihydroergotamine DihydrocristineSlide 8: Chemistry Derivative of tetracyclic compound 6-methyl ergolinePharmacokinetics: Pharmacokinetics Variable absorption from the gastrointestinal tract Ergotamine oral dose - ten times larger than the IM dose. Caffeine can improve its absorption and peak plasma levels (poor oral bioavailability i.e. less than 1% due to extensive 1 st pass effect) Amine alkaloids are also absorbed from the rectum, buccal cavity and after administration by aerosol inhaler Bromocriptine & Cabergoline - well absorbed from the GIT Extensively metabolized in the body 90 % excreted in the bile, traces of un-metabolized drug found in urine & faeces Effectively cross BBBPharmacodynamics - MOA: Pharmacodynamics - MOA Ergot alkaloids act on several types of receptors because of its chemical resemblance to the biogenic amines - Norepinephrine, Epinephrine, Dopamine and Serotonin Agonist, Antagonist or both simultaneously at these amine receptors Alpha –adrenergic receptors : agonist, partial agonist and antagonist actions Serotonin receptors : agonist, partial agonist and antagonist actions especially at 5 HT 1A and 5 HT 1D and less for 5 HT 2 and 5 HT 3 Dopamine receptors in the CNS : agonist or partial agonist actionsSlide 13: Organ System Effects (Pharmacological Actions) Organ System Effects…… CNS: Organ System Effects…… CNS CNS stimulants LSD (Lysergic acid diethylamide) a synthetic ergot compound - powerful hallucinogenic effect - agonist at CNS 5HT 2 receptors Bromocriptine, Cabergoline and Pergolide - highest selectivity for Dopamine receptors - agonist effects have important role in extrapyramidal motor control and suppress prolactin secretion from pituitary cells. Vagal centre stimulation - bradycardia CTZ stimulation - vomiting Organ System Effects… CVS: Organ System Effects… CVS Drug, Species and Vessel Dependent Ergotamine & similar compounds (ergonovine, methysergide) - constricts both arteries and veins and also reduces arterial pulsations by acting on both alpha and 5-HT receptors partially blocked by alpha adrenergic receptor blocking drugs Dihydroergotamine constricts veins more than arteries. Ergotoxine group produces hypotension due to it’s effects on the CNS Organ System Effects… Uterine smooth muscle : Organ System Effects… Uterine smooth muscle Stimulant action: involves serotonergic, alpha-adrenergic, and other effects Uterine sensitivity changes during pregnancy (possibly due to progressively increasing numbers of α 1 receptors Small doses: rhythmic uterine contraction and relaxation Larger doses: substantial, prolonged contractions Ergonovine: more uterine selective (agent of choice for obstetric uses) Ergometrine – not used due to AEs Organ System Effects… GIT : Organ System Effects… GIT Intestinal Serotonin Receptors - diarrhea and abdominal cramps. Central dopamine receptors & CTZ - N and V Ergotamine is more effective than ergometrine Other Smooth Muscle Has little or no effect on bronchiolar & urinary s. musclesTherapeutic / Clinical Uses: Therapeutic / Clinical Uses 1. Migraine Ergot der – highly specific Ergotamine : best results when administered prior to the attack (prodromal phase) -- less effective as attack progresses May be combined with caffeine; promotes absorption Vasoconstriction associated with excessive ergotamine use may be long-lasting, cumulative and potentially severe (no more than 6mg for each attack and no more than 10mg in a week) oral, SL, rectal, inhaler, IV or IM routes of administration Dihydroergotamine (IV administration mainly): may be appropriate for intractable migraine (nasal or oral formulations are being assessed) Methysergide – withdrawn because of toxicityTherapeutic / Clinical Uses…: Therapeutic / Clinical Uses… 2. Hyperprolactinemia Associated with pituitary tumor, use of centrally acting dopamine antagonist (antipsychotic) drugs Bromocriptine D 2 agonist-suppress prolactin secretion, 2.5 mg 2 -3 times daily & also for suppressing physiologic lactation (serious postpartum CVS toxicity-discouraged) Cabergoline similar but more potentTherapeutic / Clinical Uses…: Therapeutic / Clinical Uses… 3. Postpartum Hemorrhage Ergot Derivatives: used to control late uterine bleeding (NEVER given before delivery, increase in maternal and fetal mortality occur) Ergot alkaloids cause uterine contractions (prolonged, powerful spasms, unlike natural labor) Ergonovine maleate, 0.2 mg IMTherapeutic / Clinical Uses…: Therapeutic / Clinical Uses… 4. Diagnosis of Variant Angina Ergonovine IV 5- Senile cerebral insufficiency- DihydroergotoxineErgot poisoning (Ergotism, St. Anthony's fire) : Ergot poisoning (Ergotism, St. Anthony's fire) Symptoms burning sensations in the limbs due to vasoconstriction of blood vessels, gangrene and loss of limbs due to severely restricted blood circulation hallucinations, irrational behavior, convulsions, and even death. Other symptoms include strong uterine contractions, nausea, seizures, and unconsciousness. Ergot poisoning specific manifestations depend on the alkaloids mixtureAdverse effects: Adverse effects GIT disturbances: N, V, D, & abdominal cramps Spontaneous Abortion Methysergide –hallucination, drowsiness, convulsions. Overdosage of ergotamine & ergonovine causes vasospasm ------- gangrene Bowel infarction ---- mesenteric artery vasospasm Connective tissue proliferation in the retroperitoneal space, pleural cavity , endocardial tissue of heart with chronic therapy of methysergide.Contraindications : Contraindications Obstructive vascular diseases. Collagen diseases.Bromocriptine (parlodel) : Bromocriptine ( parlodel ) Semi-synthetic derivative of ergot alkaloid Bromocriptine… Pharmacokinetics: Bromocriptine… Pharmacokinetics Absorption : rapidly and partial from the GIT Extensive first pass effect PPCs: 1.5- 3 hours after oral administration Plasma half life: 3 hours Metabolites excreted in bileBromocriptine…: Bromocriptine … Pharmacological actions Potent dopamine receptor agonist Preference for D 2 receptors in the CNS, cardiovascular system, pituitary-hypothalamic axis and gastrointestinal tractPharmacological actions…: Pharmacological actions… Prolactin release (inhibitory) Growth hormone GH in normal individuals GH in acromegaly Extrapyramidal effects acts on dopamine receptors in nigrostriatal system – useful in parkinsonism Reticular formation stimulant action on CNS-induces non specific arousal of CNS, effective in treating comatose pts of hepatic encephalopathy CTZ – stimulates - vomitingTherapeutic uses: Therapeutic uses Parkinsonism For prevention & suppression of lactation Rx of hyperprolactinemia associated with hypogonadism, galactorrhea, infertility Benign breast diseases Mastalgia Menstrual disorders Acromegaly Hepatic encephalopathyAdverse effects: Adverse effects GIT – N, V, constipation, bleeding from peptic ulcer CNS – headache, dizziness, drowsiness CVS – postural hypotension, cardiac arrhythmias At higher doses Dry mouth Confusion Hallucination Pleural effusion Leg cramps, digital vasospasm Red painful swollen feet and hands You do not have the permission to view this presentation. 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