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Introduction to Autacoids:Histamine and 5-HT
Autacoids
Autacoids - locally acting mediators, with important roles in mediating Inflammation, pain and allergies Smooth muscle tone and blood pressure GI functions Hemostasis Many others
Types of autacoids we will study: Amines: Histamine and 5-HT Vasoactive peptides: Angiotensin and Bradykinin Eicosanoids: Prostaglandins and Leukotrienes
Structure and synthesis of Histamine
Synthesized by decarboxylation of histidine
Important role in Allergic reactions Regulation of Gastric acidity
HN N
CH2CH2NH2
HistamineHistidine
HN N
CH2CH-NH2
COOH
L-histidine decarboxylase
Physiologic effects of Histamine
Effects of intradermal injection of histamine
Symptom Time frame
Red spot, few secs to 1 min
Flare slower
Wheal 1-2 minutes
“Triple response”:
Effects of intradermal injection of histamine
“Triple response”:
Symptom Time frame Cause
Red spot, few secs to 1 min vasodilation
Flare slower axon reflex =>vasodilation
Wheal 1-2 minutes increased permeability of
post-capillary venules
Often accompanied by itching
The involvement of Histamine in Local Inflammation
Local vasodilation and leakage of inflammatory mediators into the tissue
Chemoattractant for some types of inflammatory cells
May modulate release of inflammatory peptides
A burning, itching sensation, especially in the palms of the hands, face scalp and ears
A feeling of intense warmth
Reddening of the skin (flushing)
Drop in blood pressure (hypotension)
Acceleration of heart (tachycardia)
Headache
After a few minutes, blood pressure recovers and hives appear on the skin (wheals)
Colic, nausea and hypersecretion of gastric acid
Moderate bronchospasm
Intravenous injection of a histamine liberator induces a dramatic response known as anaphylaxis:
Effects of Histamine poisoning
Injestion results in: severe nausea vomiting headache flushing sweating
Spoiled scombroid fish, such as mackerel or tuna contains a high content of histamine
Production and Metabolism of Histamine
Sites of production and storage of histamine
Mast cells
BasophilsHistamine stored in secretory granules – slow turnover
Mast cells are found in nearly all tissues of the body, especially in tissues prone to injury:nose, mouth, skin, feet, and exposed internal surfaces (lungs and GI tract)
Basophils are found in the blood
Sites of production and storage of histamine
Continuous release of histamine – rapid turnover
Enterochromaffin-like cells in the Gastric mucosa
Histaminergic neurons in the CNS
Regenerating or rapidly growing tissues
Histamine is metabolized by methylation and oxidation and secreted in the urine
HN N
CH2CH2NH2
Histamine
CH3N N
CH2CH2NH2
N-Methylhistamine
N-Methyltransferase
Monoamine Oxidase BN-Methylimidazole
Acetic Acid
CH3N N
CH2COOH
CH3N N
CH2CH2NH2
N-Methylhistamine
The level of N-Methylhistamine in the urine provides a reliablemeasure endogenous histamine production
What conditions might be reflected by high levels of N-Methylhistamine in the urine?
Why not just measure the level of histamine in the urine?
Control of Histamine Release
Histamine is released from mast cells during an allergic response
Receptor-induced exocytosis triggered by:-Antigen binding to cell-bound IgE( immediate or type I hypersensitivity)
Mast cell
FcRI
IgE
What clinical conditions result from type-1 hypersensitivity?
Hay fever
Initial phase of asthma
Urticaria
Anapylactic shock
Hypersensitivity responses to some drugs
Note: histamine mediates some, but not all of the immediate hypersensitivity responseOther mediators released by mast cells including Platelet activating factor (PAF) and leukotrienes contribute significantly to allergic brochospasm
Other stimuli that trigger release of histamine from mast cells
Complement C3a or C5a
Passive release may be induced by some drugs, usually organic bases:-Morphine-Tubocurarine-Radiocontrast media, etc.
Tissue Injury or mechanical injury to mast cells
Heat or cold
Agents that inhibit the release of histamine from mast cells
Agents that increase cAMP 2-adrenoreceptor agonists H2 receptor agonists
(Histamine may down-modulate its own release,to limit the intensity of allergic reactionsespecially in mast cells in skin and basophils, but not in lungs)
Mast cell “stabilizers” Cromolyn Sodium Nedocromil Sodium
Nedocromil Sodium/Cromolyn Sodium
Inhibits antigen-induced bronchospasm and mast cell degranulation
Used prophylactically to treat mild to moderate asthmaWith regular use reduces airway hyperreactivityBut ineffective in the case of ongoing bronchoconstriction
Mechanism of action unclear but includes:inhibition of mast cell degranulationinhibition of leukocyte activationinhibition of chemokine-induced recruitment of neutrophils, eosinophils, and monocytes
Delivered by inhalation several times daily (since only 1% of oral dose is absorbed)drug excreted with half life of 45-100 min
Histamine Receptors and Antagonists
Four types of histamine receptors All are G-protein coupled
Receptor Distribution Signaling Mechanism
H1 Smooth muscleEndotheliumBrain
IP3, DAG
H2 Gastric MucosaCardiac muscleMast cellsBrain
cAMP
H3 Presynaptic in: Brain Myenteric plexus others
cAMP Ca2+
H4 EosinophilsNeutrophilsCD4 T cells
cAMP Ca2+
Pharmacology of histamine receptors
Very small changes the ligand structure can have a dramatic effect on receptor specificity:
2-methylhistamine
HN N
CH2CH2NH2
CH3
4(5)-methylhistamine
HN N
CH2CH2NH2CH3
(R)--methylhistamine
HN N
CH2CHNH2
CH3
CH3
H1 agonist
H1:H2
8:1
H2 agonist
H2:H1
170:1
H3 agonist
H3:H1
15:1
Histamine receptors and the effects they mediate in various peripheral organs
Receptor Physiologic Response Result
H1
Endothelium
Smooth muscle
Brain
Nerve Endings
-Vasodilation of small blood vessels(rapid response to low concentrations of histamine)
-Increased permeability of post-capillary venules
-Stimulation of sensory neuronal receptors
-contraction of smooth muscle of the ileum, bronchi, bronchioles and uterus
Redness, flushing,Hypotension
Edema, urticaria
Itching, pain, flare
Bronchoconstric-tion, especially in asthmatics
Histamine receptors and the effects they mediate in various organs
Receptor Physiologic Response Result
H2
Gastric mucosa
Cardiac muscle
Vascular smooth muscle
Mast cells
Brain
-Secretion of gastric acid
-Direct Cardiac stimulation
-Vasodilation (slower, prolonged response to high concentrations of histamine)
Contribute to peptic ulcer
less important than baroreceptor reflex
Hypotension
Histamine receptors and the effects they mediate in various organs
Receptor Physiologic Response Result
H3
Presynaptic
-Presynaptic inhibition of the release of neurotransmitters
unknown
Many drugs familiar from everyday life are histamine antagonists:
First generation H1 antagonists:Diphenhydramine (Benadryl)Dimenhydrinate (Dramamine, Travamine)
Second generation (nonsedating) H1 antagonists:Loratadine (Clarintin, Lorastin)Fexofenadine (Allegra, Telfast)
H2 antagonists:Cimetidine (Tagamet, Cimi)Ranitidine (Zantac, Zanidex)Famotidine (Pepcid, Gastro)
H1 receptor antagonists
Reversible, competitive inhibitors of the general structure:
X-C-C-N
Ar1
Ar2
HN N
CH2CH2NH2
Histamine
H1 Antagonists
C CH2O N
H
CH2
CH3
CH3
Diphenhydramine
1st generation
N
N CO
OC2H5
Cl
Loratadine
2nd generation
First Generation H1 Antagonists(Diphenhydramine, Mepyramine)
Well absorbed from GI tract, generally effective for 4-6 hours, but may persist longer in skinHave many side effectsCross the blood brain barrier -> CNS effects, especially sedation, but sometimes excitationMany have activity as muscarinic antagonists-may explain their usefulness as antiemetics(dimenhydrinate, diphenhydramine, promethazine)-atropine-like side effectsSome drugs may have other side effects: -adrenoreceptor antagonists Serotonin blocking Local anesthesia
Drug allergy may develop
Many first generation H1 Antagonists have anti-muscarinic effects
C CH2O N
H
CH2
CH3
CH3
Diphenhydramine
1st generation
Muscarine
CH CH2
ONCH
CH3
CH3
CH3+
CH CH2HO
H3C
Second Generation H1 Antagonists(Cetirizine, Loratadine Fexofenadine)
Well absorbed
Fewer side effects
Do not cross the blood brain barrier - nonsedating
No antimuscarinic activity - no atropine-like effects
Older drugs (Astemizole, Terfenadine) sometimes induced fatal arrhythmia, and were withdrawn from the market
The newer drugs (Loratadine, Fexofenadine) do not have this side effect.
Fexofenadine is the safer, active metabolite of Terfenadine
CHO NCH2CH2CH2CHOH
C(CH3) 3
Terfenadine
CHO N CH2CH2CH2CHOH
CCH3
CH3
COOH
Fexofenadine
Cyp3A4
KetoconazoleMacrolide antibiotics
Grapefruit juice
Therapeutic uses of H1 antagonists
Suppress many of the effects of histamine:edema and whealflare and itchallergic rhinitis, urticaria, conjunctivitis,
Not useful for: the common coldallergic bronchoconstriction asthmasystemic anaphylaxis
a. Antihistamine
b. Adrenaline
Adrenaline is a physiologic antagonist of histamine It acts on different receptors, so is not a true antagonistBut it has opposing physiologic effects:
1. Vasoconstriction and increased cardiac output => increased bp2. Bronchorelaxation
What is the best way to treat an anaphylactic response?
Regulation of gastric acid secretion: the basis for therapy of peptic ulcer disease
Acid secreted by parietal cells in the lining of the stomachRegulated by multiple factors:neuronal (Ach, Vagal nerve)paracrine (histamine)endocrine (gastrin)Prostaglandins play a protective role -promote secretion of mucus and bicarbonate-inhibit acid secretion by parietal cells-enhance mucosal blood flow
Regulation of gastric acid secretion
Diseases Associated with Excessive Gastric Acid
Gastroesophageal reflux disease
Peptic ulcers of the stomach and duodenum(Generally results from Heliobacter pylori infection)
Ulcers secondary to NSAID use
Ulcers due to Zollinger-Ellison syndrome(a tumor of gastrin-secreting cells, or gastrinoma)
Regulation of gastric acid secretion: the basis for therapy of peptic ulcer disease
Structure and relative potency of H2 receptor antagonists
Cimetidine
Nizatidine
Famotidine
Ranitidine
1
4-10x
20-50x
4-10x
Relative potency
H2 Receptor Antagonists
H2 Receptor Antagonists
Competitive inhibitors at H2 receptors
Reduce acid secretion by 60-70% for about 10 hours
Basal secretion of gastric acid reduced more than stimulated secretion >90% of nocturnal acid secretion (basal) 60-70% of daytime acid secretion (meal stimulated)
Drug and its metabolites are excreted by kidney by glomerular filtration and renal tubular secretion=>important to reduce dose in patients with renal insufficiency
Generally few side effects, though Cimetidine is more problamatic than others, since it inhibits cytochrome P450 (potential for drug interactions)
H2 Antagonists, therapeutic uses
First line treatment for frequent GERD, that does not respond to lifestyle changes,Treatment of persistent heartburn requires twice daily dosage.
No longer recommended for treatment of peptic ulcers, PPIs are preferable
May heal NSAID-induced ulcers, if NSAID use is discontinued
If NSAID use is continued, PPI is required to prevent recurrence
Activation of proton pump inhibitors at acid pH and covalent modification of the proton pump
Omeprazole: mechanism of action
Pro-drug is converted to the active compound at acid pH
Delivered in enteric coated pill so it may pass through acid environment of stomach unharmed
Pills dissolve in small intestine and drug is rapidly absorbed into the blood stream
Great specificity attained since the prodrug is inactive, and only the portion of the drug that accumulates in the acid canaliculi of the parietal cells is activated
Once activated it binds covalently to the extracellular domain of the proton pump, thereby irreversibly inactivating the pump
Characteristics of Omeprazole (brand name- Prilosec):
Plasma half life of 1-2 hours, but duration of action is 24-48 hours Once a day dosage takes 3-4 days to reach steady state level of inhibitionAcid required to activate drug=> Drug should be taken on an empty stomach, one hour before a meal, so peak serum concentration coincides with peak acid production=> Co-administration of H2 antagonist will decrease efficacy
Characteristics of Omeprazole (brand name- Prilosec):
Decrease both basal and meal-stimulated acid productionPreferred treatment for healing peptic ulcers GERD with complications (esophageal erosions, Barrett’s esophagus,
etc.) NSAID-induced ulcer if NSAID must be continued Gastrinoma, if cannot be surgically removed
Side effects:-hypergastrinemeia (risk of hyperplasia of enterochromaffin-like cells?)-reduced absorption of vitamin B12
-increased risk of enteric infections
5-HT
Functions both as neurotransmitter and as local hormone
“Involved in everything, but responsible for nothing”
5-HT = 5-Hydroxytryptamine = Serotonin
CH2 NH2CH2OH
NH
5-hydroxytryptamine
Powerful vasoconstrictor substance found in the serum, after blood has clotted
Functions Regulated by 5-HT
In PeripheryPeristalsis
Vomiting
Functions Regulated by 5-HT
In PeripheryPeristalsis
Vomiting
Platelet aggregation, haemostasis
Microvascular control
Functions Regulated by 5-HT
In PeripheryPeristalsis
Vomiting
Platelet aggregation, haemostasis
Microvascular control
Sensitization of nociceptors (pain, itch)
Inflammatory mediator
Functions Regulated by 5-HT
In Periphery In CNSPeristalsis Control of appetite
Vomiting Sleep
Platelet aggregation, haemostasis Mood
Microvascular control Hallucinations
Sensitization of nociceptors (pain, itch)
Stereotyped behavior
Inflammatory mediator Pain perception
Vomiting
Temperature regulation
Regulation of blood pressure
interspersed in mucosa of stomach and small intestine90% of 5-HT in body
in localized regions of the CNS - Raphe nuclei of the brain stem
in the Enteric Nervous System
don’t synthesize 5-HT but accumulate it from the plasma as they pass through the intestinal circulation
Distribution of 5-HT in body
Enterochromaffin cells
Neurons
Platelets
Plants, venoms and stings
Sites of synthesis an reuptake of 5-HT
Synthesis ReuptakeEnterochromaffin cells +Platelets +Neurons + +
5-HT Synthsized from tryptophan by a pathway analogous to catecholamine synthesis
NH
CH2CH
COOH
NH2
TryptophanOH
NH
CH2CH
COOH
NH2
5-hydroxytryptophanCH2 NH2CH2
OH
NH
5-hydroxytryptamine
Tryptophan
hydroxylase L-aromatic acid
decarboxylase
5-HT is degraded by oxidative deamination -analogous to Noradrenaline metabolism
CH2 NH2CH2OH
NH
5-hydroxytryptamine
CH2CHOOH
NH
CH2COOHOH
NH
5-hydroxyindoleacetic acid(5-HIAA)
MonoamineOxidase
Aldehyde
dehydrogenase
CH2COOHOH
NH
5-hydroxyindoleacetic acid(5-HIAA)
The level of 5-HIAA in urine is an indicator of the rate of 5-HT production in body
What disease is characterized by a high level of 5HIAA in the urine?
Carcinoid syndrome
Malignant tumor of enterochromafin cells, arising in the small intestine and metastasizing to the liverTumor may secrete mediators such as 5-HTSymptoms include flushing, diarrhoea bronchoconstrictions, and hypotension, and sometimes stenosis of heart valves.
Treated with 5-HT2A antagonists
5-HT Receptors -a complex picture
1A
7
6
54
3
2C
2B2A
1D1B
??????!
5-HT Receptors
5-HT Receptors
More 5-HT Receptors
Still more 5-HT Receptors
Roles of 5-HT in GI tract
GI tract Increased gastrointestinal motility and contraction -via direct excitation of smooth muscle (5-HT2) -via indirect activation of enteric neurons (5-HT3 and 5-HT4)
Vomiting Stimulates vomiting -via 5-HT3 receptors in GI tract on vagal nerve
(5HT released in mucosa upon irritation by chemotherapy, radiation therapy, distention, etc)
-via 5-HT3 receptors in the chemoreceptor trigger zone and vomiting center of brain
Ondansetron
5-HT3 antagonist
Used to prevent:-chemotherapy-induced nausea and emesis -radiotherapy-induced nausea and emesis-postoperative nausea and emesis
Not known whether it acts centrally or peripherally, but serotonin is released from enterochromaffin cells upon chemotherapy
5-HT4 Agonists and their use in gastrointestinal disorders
5-HT4 agonists promote GI motility - stimulate coordinated peristaltic activity
Tegaserod – Newer and more specific 5-HT4 agonist.
Used to treat irritable bowel syndrome with constipation (abdominal pain, swelling and constipation)
Found effective in women only
CLINICAL STUDIESIn three multicenter,double-blind,placebo-controlled studies, 2,470 women (mean age 43 years [range 17-89 years]; 86%Caucasian, 10%Afri can American) with at least a 3-month history of IBS symptoms prior to the study baseline period that included abdominal pain, bloating and constipation received either Zelnorm™ (tegaserod maleate) 6 mg b.i.d.or placebo. In all patients, constipation was characterized by at least two of the following three symptoms each occurring >25% of the time over a 3-month period: <3 bowel movements/week, hard or lumpy stools, or straining with a bowel movement. Study design consisted of a 4-week placebo-free baseline period followed by a 12-week double-blind treatment period. Study 1 and 2 evaluated a fixed dose regimen of tegaserod 6 mg b.i.d. while Study 3 utilized a dose-titration design. Each week of the 4-week placebo-free baseline period and the 12-week double-blind treatment period, patients were asked the question, “Please consider how you felt this past week in regard to your IBS, in particular your overall well-being, and symptoms of abdominal discomfort, pain and altered bowel habit. Compared to the way you usually felt before entering the study ,how would you rate y our relief of symptoms during the past week?” The response variable consisted of the following 5 categories: completely relieved, considerably relieved, somewhat relieved, unchanged, or worse. Patients were classified as responders within a month if the y were considerably or completely relieved for a t least two of the four weeks, or if they were at least somewhat relieved for each of the four weeks.
Cardio-vascular system
Mixture of vasoconstriction of large peripheral blood vessels via 5-HT2A
-via direct effect on vascular smooth muscle of cranial blood vessels via 5-HT1
and vasodilation in skeletal muscle and heart -via indirect effect on vascular endothelium => production of NO
-via inhibition of NA release from sympathetic nerve terminals
Reflex Bradycardia (Chemoreceptor reflex) -via 5-HT3 on chemoreceptor nerve endings, triggering vagal output to the heart=>bradycardia
Venoconstriction leading to increased capilary filling and flushing
Physiologic effects of 5-HT
Opposing effects of 5-HT on vasculature
1. Initial decrease in heart rate, cardiac output and blood pressure, due to the chemoreceptor response (5-HT3 receptors on nerve endings)
2. Increase in blood pressure due to vasoconstriction
3. Decrease in blood pressure due to vasodilation in skeletal muscle
Triphasic response follows injection of 5-HT:
Platelets Platelet aggregation,
In the case of blood clotting there is release of 5T by the aggregating platelets => vasodilation if endothelium is intact => vasoconstriction if endothelium is damaged
Physiologic effects of 5-HT
Physiologic effects of 5-HT
Nerve Endings Stimulates nociceptive nerve endings (5HT3)
Inhibits transmitter release from peripheral adrenergic neurons
Stimulates autonomic chemoreceptor reflex in heart and lungs (bradycardia and hypotension)
Stimulates vomiting via 5-HT3 receptors in GI tract on vagal nerve via vomiting center of brain
Physiologic effects of 5-HT
CNS Excitation
Inhibition
Presynaptic inhibition of neurotransmitter release Sleep/Wake Cycle
Aggression and ImpulsivityAnxiety and DepressionCognitionSensory PerceptionMotor ActivityTemperature RegulationNociceptionAppetiteSexual BehaviorHormone Secretion
Today known to be involved in many disorders including:carcinoid syndromemood disorders (depression, mania, anxiety)digestive disorders (irritable bowel syndrome and acid reflux disorder)vascular disordersmigraine
5-HT = 5-Hydroxytryptamine = Serotonin
CH2 NH2CH2OH
NH
5-hydroxytryptamine
Depression -TCA (tricyclic antidepressants) -SSRI (selective serotonin reuptake inhibitors) (fluoxetine = prozac) -MAOI (monoamine oxidase inhibitors)Obesity(fenfluramine, dexfenfluramine) (inhibitors of 5-HT reuptake) Induce weight loss but can cause pulmonary hypertension and heart valve defectsMigraine
The complex (poorly understood, but convincing) role of 5-HT in many diseases
Some pathologic conditions may be treated with drugs that influence 5-HT levels or 5-HT function For Example:
Buspirone
5-HT1A partial agonist
Anti-anxiety drug
Anxiolytic, but not sedative
Effects take days or weeks to develop - not effective for panic attacks
Migraine - a poorly understood disorder
Affects 10-15% of population
Symptoms: Aura, followed by severe throbbing headache, starting unilaterally, often with photophobia, nausea, vomiting, prostration, and lasting for several hours
Or Migraine without aura (more common):episodic attacks of headache lasting 4-72 hrs with at least two of the following (unilateral pain, throbbing, aggravation on movement, moderate to severe intensity) and one of the following (nausea, vomiting, photophobia, phonophobia)
Migraine - a poorly understood disorder
Pathophysiology not well understood and hotly contested:Cause may be vascular, neural, inflammatory, or associated with platelet function
Strong evidence implicates 5-HT:
-sharp increase in urinary excretion of 5-HIAA during the attack with concomitant fall in blood concentration of 5-HT
-migraines may be precipitated by agents like reserpine and fenfluramine that release 5-HT from intracellular storage sites
-many effective drugs are 5-HT agonists or antagonists
Sumatriptan- an effective antimigraine drug
5-HT1D (and 5-HT1B) agonistlow or no affinity for other receptor subtypes
The clinical effect of triptans correlates with their affinity for 5-HT1D and 5-HT1B
Causes constriction of intracranial blood vessels
Used to treat acute attacks of migraine but not useful for prophylaxis
Reduces the nausea and vomiting associated with migraine
Sumatriptan- an effective antimigraine drug
For fast onset, can give subcutaneously (12 min) or as a nasal spray (15 min) rather than orally (1-2 hrs)
Short acting (half life of 2 hours)metabolized by MAO
Side effects:-rare but serious cardiac events, especially in patients at risk for coronary artery disease (causative relationship not clear)Tendency to cause chest pain due to coronary artery spasm
Contraindicated in patients with cardiovascular disease or uncontrolled hypertension or in patients who are taking MAO inhibitors
How does Sumatriptan work? - some hypotheses:
Clinical efficacy may be due to constriction of carotid arteriovenous anastomoses
According to one theory, migraine is associated with abnormal dilation of these anastomoses, located mainly in the cranial skin and ears, which may “shunt” as much as 80% of the carotid arterial blood flow, leading to cerebral ischemia and hypoxia
May activate presynaptic 5-HT1D and 5-HT1B receptors, blocking the release of proinflammatory neural peptides in the perivascular space
Ergot Alkaloids (Ergotamine, Methysergide)
Natural substances derived from the fungus Claviceps purpurea, which infects damp grains, esp. rye.
Complex tetracyclic alkaloids based on lysergic acid
Symptoms of Ergot poisoning (St. Anthony’s fire)-mental disturbances, hallucinations-intensely painful peripheral vasoconstriction, which may result in gangrene-uterine contraction, which may lead to abortion
Ergot Alkaloids (Ergotamine, Methysergide)
Act on: 5-HT receptorsadrenoreceptorsdopamine receptorstimulate smooth muscleno clear structure/function relationship
Some of the ergot alkaloids have been isolated and are clinically useful
Structure of ergot alkaloids
ErgotamineAntagonist/partial agonist at -adrenergic receptors and partial agonist at 5-HT1D receptors – also stimulates smooth muscle
Effective if given early during a migraine attack
Often combined with caffeine, to increase absorption when given orally
Side effects:When taken repeatedly, induces long lasting and cumulative vasoconstriction, which may result in gangrene=> patient must be well informed as to maxium dose per attack and per weekmay cause uterine contraction => contraindicated in pregnancy
Methysergide
Weak agonist at -adrenergic and dopamine receptors and antagonist/partial agonist at 5-HT2 receptors
Used for prophylaxis of migrainebut ineffective in the treatment of an impending or active migraine
Lacks cumulative vasospastic toxicity seen with ergotamine
Chronic use may induce retroperitoneal fibroplasiaand subendocardial fibrosis=> must go off the drug periodically
Side effects: nausea, vomiting and diarrhea