Week 12 - 13:

Chapter 16:
Histamine:
 From histidine
 Metabolized by the enzymes monoamine oxidase and diamine oxidase
 IgE= allergic reactions, this autacoid plays a pathophysiologic role in seasonal rhinitis
(hay fever), urticaria, and angioneurotic edema
o peptide bradykinin also plays an important role in angioneurotic edema
 Control of acid secretion in stomach & as a NT
 Fish stored badly= high H release= severe histamine toxicity (“scombroid poisoning”)
 Excess= imidazole acetic in urine
(A) Receptors & effects:
 H1 & 2= most peripheral action
 Triple response= on skin by H1, 2= small red spot @ center of intradermal injection of
H= surrounded by edematous wheal= surrounded by red flare
 (1) H1 receptor:
 Gq= increase IP3 & DAG
 smooth m.
 IgE mediated
 IP3 & DAG
 Pain, itching on skin, bronchoconstriction & vasodilation (due to NO)
 Contract, opening gaps in permeable barrier= local edema
 Allergic rxns & mastocytosis
 (2) H2 receptor:
 Gs= increases cAMP
 Gastric acid secretion by parietal cells
 Cardiac stimulant
 Reduce H release from mast cells= negative feedback effect
 (3) H3 receptor:
 Gi= lowers cAMP
 Presynaptic modulation of H= NT in CNS
 Food intake & body weight increase in H3- receptor knockout
 (4) H4 receptor:
 Gi= lowered cAMP
 Leukocytes= esp. eosinophils & mast cells
 Chemotactic response
(B) Clinical use:
 No therapeutic
 But drugs that block H1, 2= important
 No antagonist of H3, 4 available
Histamine H1 antagonists:

(A) Classification & prototypes:

 1st gen= diphenhydramine= highly sedating w/ autonomic receptor blocking effects
 2nd gen= cetirizine, fexofenadine, and loratadine= far less lipid sol. Than 1st gen. &
have less sedating & autonomic effects
 All H1 blockers= oral
 Extensively metabolized by liver
 Half life=
o 1st gen. H1= 4 – 12 hrs
o 2nd gen. = 12 0 24 hrs

(B) Mechanism & effects:

 H1 blocker= competitive or inverse agonist
 No effect on H release sites
 More effective if given before H release
 Most 1st gen= similar to M-blockers & alpha adrenoceptor blockers= potent antagonists
@ these
 Few also block 5HT receptors
 Some not all 1st gen are anti-motion sickness effects
 Many are local anesthetics
 H1 blocking= negligible effects @ H2

(C) Clinical use:

 Good for allergies= hay fever, urticaria
 Diphenhydramine, dimenhydrinate, cyclizine, meclizine, and promethazine are used
as anti-motion sickness drugs
 Diphenhydramine= also used for chemotherapy induced vomiting
 Doxylamine w/ pyridoxine= prevent morning sickness in pregnant women
 Adverse effects f 1st gen= exploited= hypnotics in over counter sleep aids

(D) Toxicity & interactions:

 Sedation= common esp. w/ diphenhydramine and promethazine
o Not taken before surgery
o Antimuscarinic effects such as dry mouth and blurred vision
 Less common w/ 2nd gen.= don’t enter CNS readily
 Alpha-adrenoceptor blockade w/ phenothiazine derivatives such as promethazine, may
cause orthostatic hypotension
 1st gen w/ other sedative drugs like benzodiazepines and alcohol occur
 Drugs inhibiting hepatic metabolism= high levels of certain antihistamine= concurrently
 2nd gen w/ CYP3A4 inhibitors= lethal arrhythmias
H2 antagonists:
(A) Classification & porotypes:
 Cimetidine is the prototype
 Ranitidine, famotidine, and nizatidine differ only in having fewer adverse effects than
cimetidine
 Don’t resemble H blockers structurally
 Orally active
 Half life= 1-3 hrs
 Relatively nontoxic= given in large doses so duration can be 12-24 hrs
 All 4= oral & over the counter

(B) Mechanism & effects:

 Surmountable pharmacologic blockage of H2
 Selective & no effect @ H1
 Reduce gastric acid secretion
 Blockage of cardiac & mast cells= happen but no clinical significance

(C) Clinical use:

 Acid peptic disease, duodenal ulcer= reduce nocturnal acid secretion, accelerate healing
& prevent recurrence
 Acute ulcer is usually treated with 2 or more doses per day, whereas recurrence of
duodenal ulcers can often be prevented with a single bedtime dose
 IV H2 blockers= prevent gastric erosion & hemorrhage in stressed patients in intensive
care
 Zollinger-Ellison syndrome= helpful, but very large doses are required; proton pump
inhibitors are preferred
 Gastroesophageal reflux disease (GERD)= but not as effective as proton pump
inhibitors

(D) Toxicity:
 Cimetidine= potent inhibitor of hepatic drug metabolizing enzymes= reduce hepatic
blood flow
o Antiandrogen effects in patients getting high doses
 Ranitidine= weaker inhibitors on hepatic drugs metabolism= neither this or H2 blocker
have any endocrine effects
Serotonin (5HT) & related agonists:
 From tryptophan & stored in enterochromaffin in gut & neurons of CNS & enteric NS
 Metabolized by monoamide oxidase
 Excess like in carcinoid syndrome= using mjr metabolite 5-hydroxyindole acetic acid (5-
HIAA) in urine
 Partially taken back up into the nerve ending by a serotonin reuptake transporter (SERT)
 Stored mainly not made a lot in platelets
(A) Receptors & effects:
 (1) 5HT1 receptor:
 Brain & mediate synaptic inhibition via increased K conductance
 Peripheral = mediate both excitatory & inhibitory effects in various smooth m.
 Gi= low cAMP

 (2) 5HT2 receptor:

 Peripheral & brain
 Excitation in CNS & smooth ,. Contraction= gut, bronchi, uterus, some vessels or
relaxation= other vessels
 Gq= high IP3= low K conductance or low cAMP
 Mediate= vasodilation, diarrhea, bronchoconstriction= carcinoid tumor= release 5HT
 In CNS= reduce appetite in treating obesity

 (3) 5HT3 receptor:

 CNS esp. chemoreceptive area & vomiting center
 Peripheral sensory & enteric nerves
 Mediate excitation via 5HT gated cation channel
 Antagonists= useful antiemetic drugs

 (4) 5HT4 receptor:

 Gastrointestinal tract
 Role in intestinal motility
(B) Clinical uses:
 None= but selective agonist useful
 (1) 5HT 1D/1B agonists:
 Sumatriptan is the prototype
o Oral, nasal, parental
 Naratriptan and other “-triptans” are similar to sumatriptan
 For migraine, cluster headache attacks= headache syndromes
 Orally active
 Ergot= partial agonist @ 5HT receptors
  Calctonin gene related peprtide (CGRP)= assoc w/ migraine through non-5HT related
mech & recent studies of Ab against this peptide= promising
 (2) 5HT 2C agonist:
 Lorcaserin= for obesity
o Activates receptors in CNS= reduce appetite
 Older = fenfluramine and dexfenfluramine, appear to act directly and by releasing
neuronal 5-HT or inhibiting SERT, and thereby activating central 5-HT 2C receptors
o But pulled out since effects on pulm. Hypertension & damage cardiac valves
o These 2 combined w/ phentermine= amphetamine like anorexiant in weight loss=
products= “fen-phen” & “dex-phen” respectively

 (3) 5HT 4 partial agonist:

 Tegaserod= new= on colon= approved & briefly marketed for use in chronic
constipation = but pulled since cardiovascular toxicity

 (4) Selective serotonin reuptake inhibitors (SSRI):

 Antidepressants= increase activity @ central serotonergic synapses by inhibiting 5HT
reuptake transporter= SERT

(C) Hyperthermic syndromes:

 Assoc. w/ high fever, skeletal m. effects, cardiovascular abn. = can be life threatening

Serotonin antagonists:

(A) Classification & prototypes:

 Ketanserin, phenoxybenzamine, and cyproheptadine are effective 5-HT2 blockers.
 Ondansetron, granisetron, dolasetron, and alosetron are 5-HT3 blockers
 Ergot alkaloids are partial agonists (and therefore have some antagonist effects) at 5-HT
and other receptors

(B) Mechanisms & effects:

 Ketanserin and cyproheptadine= competitive
 Phenoxybenzamine= Irrev. Blocker
 All here= poorly selective
 Ondansetron, granisetron, and dolasetron= selective = antiemetic actions in the area
postrema of the medulla and also on peripheral sensory and enteric nerves.

(C) Clinical uses:

 Ketanserin is used as an antihypertensive drug outside USA
 Ketanserin, cyproheptadine, and phenoxybenzamine= carcinoid tumor = secretes
large amounts of serotonin (and peptides) and causes diarrhea, bronchoconstriction, and
flushing
  Ondansetron= vomiting in chemotherapy & postoperative vomiting
 Alosetron = women with irritable bowel syndrome associated with diarrhea
(D) Toxicity:
 Adverse effects of ketanserin are those of α blockade and H1 blockade
 Ondansetron, granisetron, and dolasetron include diarrhea and headache
 Dolasetron has been associated with QRS and QTc prolongation in the ECG and should
not be used in patients with heart disease.
 Alosetron causes significant constipation in some patients and has been associated with
fatal bowel complications

Treatment of obesity:
 Only Lorcaserin= 5HT based
o Selective
o But significant pulmonary and cardiac toxicity may be associated with drugs
selective for this receptor subtype
 Amphetamine mimetics, eg, phentermine, are still in heavy use for appetite reduction
although clinical evidence shows that efficacy is limited and transient.

Ergot alkaloids:
 Made by fungus I wet spoiled grain
 Epidemics of “St. Anthony’s fire” (ergotism)
 Atleast 20 families naturally
 Some therapeutic
 Most ergot alkaloids are partial agonists at α adrenoceptors and 5-HT receptors, and
some are potent agonists at dopamine receptors

(A) Classification & effects:
 3 mjr subgroups= basis of organ/ tissue of primary efefcst
 (1) Vessels:
 Marked and prolonged α-adrenoceptor–mediated vasoconstriction
 Ergotamine= prototype
o overdose can cause ischemia and gangrene of the limbs or bowel
o may also block the α-agonist effects of sympathomimetics
o can cause epinephrine reversal

 (2) Uterus:
 Powerful contraction= esp. near term
 Ergonovine= prototype
 Can cause abortion or miscarriage
 Earlier in pregnancy & non preg. Uterus= much higher doses needed for contraction
  (3) Brain:
 Hallucination
 LSD= lysergic acid diethylamide= semisynthetic prototypical hallucinogenic ergot
derivative, but are uncommon with the therapeutic ergot derivatives
o potent 5-HT2 blocker in peripheral tissues, its actions in the CNS are thought to
be due to agonist actions at dopamine receptors
 In the pituitary, some ergot alkaloids are potent dopamine like agonists and inhibit
prolactin secretion
 Bromocriptine & pergolide= most potent semisynthetic ergot derivatives= D2 agonists
in pituitary & basal ganglia

(B) Clinical uses:

 (1) Migraine:
 Ergotamine= for acute attacks= still used w/ caffeine
 Methysergide, dihydroergotamine, and ergonovine have been used for prophylaxis
o but methysergide is no longer available in USA
 Triptan derivatives= sumatriptan, are now considered preferable to the ergots because of
lower toxicity

 (2) Obstetric bleeding:
 Ergonovine & ergotamine for postpartum bleeding
 Powerful & long lasting contraction that reduce bleeding but most given before delivery
of placenta

 (3) Hyperprolactinemia & parkinsonism:

 Bromocriptine, pergolide & cabergoline= reduce prolactin secretion
o dopamine is the physiologic prolactin release inhibitor
o pergolide= withdrawn from USA
o Bromocriptine= reduce size of pituitary tumors of the prolactin-secreting cells
 Bromocriptine and cabergoline are used in hyperprolactinemia and off label to treat
acromegaly
 These have been used in the treatment of Parkinson’s disease, but other drugs are
preferred
(C) Toxicity:
 public health standpoint (epidemics of ergotism from spoiled grain) and from the toxicity
resulting from overdose or abuse by individuals. Intoxication of grazing animals is
sometimes reported by farmers and veterinarians

 (1) Vascular effects:

 Severe prolonged vasoconstriction can result in ischemia and gangrene
 Most consistently effective antidote is nitroprusside
 When used for long time= unusual hyperplasia of connective tissue
o Maybe retroperitoneal, retropleural or subendocardial= can cause hydronephrosis
o Similar lesions= in carcinoid= siugegst that they are mediated by agonist effects
@ 5HT receptors

 (2) Gatsrointetsinal effects:

 cause gastrointestinal upset (nausea, vomiting, diarrhea) in many ppl

 (3) Uterine effects:

 Marked uterine contractions
 Uterus can be progressively more sensitive to ergot alkoids
 Abortion from it is rare when used for migraines
 But most docs say avoid ir or conservative use in pregnancy

 (4) CNS effects:

 Hallucinations resembling psychosis are common with LSD but less so with the other
ergot alkaloids.
 Methysergide was occasionally used in the past as an LSD substitute by users of
“recreational” drugs