Page 307 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 293

TABLE 16–7 Major ergoline derivatives (ergot alkaloids).

Amine alkaloids Peptide alkaloids
H R 8
8 O O
9 7 R ′
D 2 N
6 2′
5 N H C NH
12 10 CH 3
13 11 N 5′
A C 9 O O
14 16 4 H R ′
15 N 5
B 3 10 CH 3
1 2
R 1 N
1 2
HN R 2
R 2 ′ R 5 ′
R 1 R 8 R 2
6-Methylergoline H H
Ergotamine 1 H CH 3 CH 2
Lysergic acid H COOH

Lysergic acid H O
diethylamide α-Ergocryptine H CH(CH ) CH 2 CH(CH )
3 2
3 2
(LSD) C N(CH 2 CH )
3 2
Ergonovine H O CH OH Bromocriptine Br CH(CH ) CH 2 CH(CH )
2
3 2
3 2
(ergometrine)
C NHCHCH 3
1 Dihydroergotamine lacks the double bond between carbons 9 and 10.
administration by aerosol inhaler. Absorption after intramuscular catecholamines (phenylethylamine, left panel) and 5-HT (indole-
injection is slow but usually reliable. Semisynthetic analogs such thylamine, right panel) can be discerned in the ergoline nucleus.
as bromocriptine and cabergoline are well absorbed from the Their effects include agonist, partial agonist, and antagonist
gastrointestinal tract. actions at α adrenoceptors and serotonin receptors (especially
The ergot alkaloids are extensively metabolized in the body. 5-HT and 5-HT ; less for 5-HT and 5-HT ); and agonist
2
3
1D
1A
The primary metabolites are hydroxylated in the A ring, and or partial agonist actions at central nervous system dopamine
peptide alkaloids are also modified in the peptide moiety. receptors (Table 16–8). Furthermore, some members of the ergot
family have a high affinity for presynaptic receptors, whereas
Pharmacodynamics others are more selective for postjunctional receptors. There is
a powerful stimulant effect on the uterus that seems to be most
A. Mechanism of Action closely associated with agonist or partial agonist effects at 5-HT
2
The ergot alkaloids act on several types of receptors. As receptors. Structural variations increase the selectivity of certain
shown by the color outlines in Table 16–7, the nuclei of both members of the family for specific receptor types.

TABLE 16–8 Effects of ergot alkaloids at several receptors. 1

Serotonin Receptor Uterine Smooth
Ergot Alkaloid α Adrenoceptor Dopamine Receptor (5-HT 2 ) Muscle Stimulation
Bromocriptine − +++ − 0
Ergonovine ++ − (PA) +++ ++
Ergotamine − − (PA) 0 +(PA) +++
Lysergic acid diethylamide (LSD) 0 +++ − − (++ in CNS) +
Methysergide +/0 +/0 − − − (PA) +/0
1 Agonist effects are indicated by +, antagonist by −, no effect by 0. Relative affinity for the receptor is indicated by the number of + or − signs. PA means partial agonist
(both agonist and antagonist effects can be detected).