The Ergot alkaloids

Pharmacology


The Ergot Alkaloids


Dr. Ahmed Al-Zohyri

Lec 8.




The Ergot alkaloids
They are produced by a fungus that infect grain under damp growing condition (c1aviceps purpurea)
The ergot fungus synthesize histamine ,Ach , tyramine & a number of other alkaloids.
Ergot alkaloid affect Alpha adrenocepters , dopamine & 5-HT receptors.
Pharmacology of ergot alkaloids
Kinetics: the ergot alkaloid are variably absorbed from the GIT.
The oral dose of ergotamine is about 10 times larger than the 1/m dose.
Speed of absorption & peak blood levels after oral administration can be improved by administration with caffeine.
The amine alkaloids also absorbed from rectum, buccal cavity & aerosol inhaler.
Absorption after 1/m inj. Is slow but reliable.
Bromocriptin is more completely absorbed from the GIT than ergotamine.
Dynamics:
Mechanism of action: ergot alkaloids act on several types of receptors.
They act as agonists, p.agonist & antagonists at Alpha adrenocepters & 5-HT receptors & agonist at CNS dopamine receptors.
They have a powerful stimulant effect on uterus & other smooth m. not associated with the above receptors.
Organ system effects
l-CNS: some naturally occurring alkaloids are powerful hallucinogens such as lysergic acid diethylamide (LSD25).
LSD25 is a semi synthetic compound demonstrates hallucinogenic action.
Bromocriptine ( lactation suppressant) suppress prolactin secretion from pit. cells by activation of regulatory dopamine receptors.
2-Vascular smooth m: ergotamine constricts most human blood vs. & the effect blocked by Alpha blocking agents.
Ergotamine, ergonovine and methysergide , all have partial agonist effect at 5HT2 vascular receptors.
The specific anti-migraine action of the above ergot derivatives is related to their action on vascular or neuronal 5-HT receptors.
Ergotamine and methysergide are the agents mostly used for the treatment of migraine.

3- Uterine smooth muscle: ergot alkaloids have a stimulant effect on uterus which varies with hormonal status.
The uterine smooth muscle at term is more sensitive than earlier in pregnancy and far more so than the non pregnant organ.
In small doses, ergot preparations can evoke rhythmic contractions and relaxation of the uterus.
At higher doses, ergot preparations can induce a powerful and prolonged contraction.
Ergonovine is more selective than other alkaloids and the agent of choice in obstetric applicants of these drugs.
Clinical uses of Ergot alkaloid:
a. Migraine: Ergotamine for oral, sublingual, rectal supp. and inhaler use. It’s often combined with caffeine (100 mg caffeine + 1 mg ergotamine) to facilitate absorption.
-  Due to accumulative toxicity of ergotamine, ergonovine, 0.2-0.4 mg 3 times / day is used.
b. Hyperprolactinemia : Increased serum level of prolactin, bromocriptine mesylate is extremely effective in reducing the high levels of prolactin ( dose of 2.5 mg, 2 or 3 times daily), some doses are used to suppress physiologic lactin .
c- postpartum hemorrhage: erg. alk. are useful only for control of late uterine bleeding(not to be used before delivery).Ergotamine 0.2mg I.M. effective within 1-5 mins.
Toxicity & contraindications of Erg. Alk.:
The most common toxic effects are:
1. GIT disturbances(diarrhea, nausea & vomiting)due to activation of the vomiting center &GIT 5-HT receptors.
2. Vasospasm:(due to overdose),it may cause gangrene.
3. Drowsiness: as in case of methysergide central stimulation & hallucinations.
Contra indications:
 Obstructive disease.
Collagen disease.
Pregnancy.
Kinins:
A group of vasodilator peptides formed by the action of kallikreins (enzymes) on protein substrates known as kininogens.

Action of Kinins:
1- Effect on C.V.S.:
a. Produce vasodilation in the vascular beds including heart, kidney, skeletal mm. & liver(10 times potent than hist.).
Vasodialtion may be due to:
I. A direct inhibitory effect of kinins on the arteriolar smooth m.
II. May be mediated by the release of vasodilator PGS(E2 & I2).
b. The predominant effect of kinins on veins is contraction & may be due to:
l-direct simulation of venous smooth m .. or
2- due to the release of vasoconstrictor PGs(F2 α).
2- Effects on the endocrine & exocrine glands:
I. Kinins may modulate the tone of salivary & pancreatic ducts & help to regulate GIT motility(due to effect on smooth m.).

II. They influence transepithelium transport of H2O,electrolytes, glucose & a.as & may regulate their transport in the GIT & kidney.
III. May play a role in the physiologic activation of various prohormones (proinsulin).
3- Role in inflammation: they can produce the basic symptoms of inflammation, also production of Kinins increased in the inflammatory lesions.
4- Effects on sensory nerves: they are potent activators of sensory pain endings in the skin & viscera.
Kinins receptors & Mechanisms of action:
Their biological effects are thought to be mediated by specific receptors( membrane receptors at target cells).
-Two types of receptors (ß1&ß2)-bradykinin recep.-
- Some of their actions mediated by generation of PGs, others may involve changes in intracellular conc. of Ca++.
-Metabolism of Kinins: rapid (t1/2 less than 15 seconds) by Kininases.


Angiotensin:
Biosynthesis:

Angiotensinogen                  Angiotensin I                 Angiotensin II
                  Angiotensin III                  Peptide fragments
       
Actions of Angiotensin II :
1- On blood pressure: angiotensin II is a potent pressor agent nearly 40 times more than Noradrenalin, It causes a direct contraction of vascular smooth m. (especially arteriolar) .
Angiotensin II can also increase blood pressure through action on brain and autonomic nervous system.
2- On adrenal cortex: Act directly to stimulate Aldosterone synthesis and release. In high doses, it stimulates the secretion of glucocorticoids.
3- On Kidney: Acts directly to cause renal vasoconstriction and increase proximal tubular sodium reabsorption.
On CNS : Stimulate drinking ( dipsogenic effect) and increase secretion of ACTH .
 Angtiotensin II have a surface receptors at the above sites.
Antagonists of Renin- Angiotensin System:
1- Drugs that block renin secretion are (Clonidin ,Propanolol and Methyldopa ).
2- Renin inhibitors ( Pepstatin ).
Vasopressin ( ADH):
Important in the long term control of blood pressure through its action on the kidney to increase water reabsorption.
In the short term regulation of arterial pressure .it is important as a vasoconstrictor that increase peripheral resistance.
Atrial natriuretic peptide: play an important role in Na excretion.
Vasoactive intestinal peptide: extracted from lung widely distributed in central and peripheral NS, produce vasodilation in most vascular beds, relax tracheobronchial and GIT smooth muscles, stimulates intestinal water and electrolyte secretion.
Substance P: a potent vasodilator, present in the CNS as neurotransmitter and as a local hormone in the GIT.
As a vasodilator, it produces marked hypotension by direct inhibitory action on arteriolar smooth muscle.
Neurotensin: present in the GIT and in the circulation when administered into peripheral circulation, it produces vasodilation, hypotension.
Calcitoningen-related peptide: present in the thyroid gland, CNS, CVS, GIT, Urogenital system.
When injected into the CNS, produce suppression of feeding and hypertension.
Neuropeptide Y:
Present in high concentration in brain and peripheral NS.
Produces a variety of CNS effects as increased feeding ,hypotension, respiratory depression and hyperthermia.peripheral effects include vasoconstriction of cerebral blood vessels and hypertension.