Flashcards in Drugs With Important Actions On Smooth Muscle Deck (187):
What is an autacoid?
Endogenous molecules with powerful pharmacologic effects that do not fall in the traditional autonomic groups.
What are the two most important amine autacoids?
Histamine and serotonin (5-hydroxytryptamine)
What are the ergot alkaloids (not autacoids)?
An heterogeneous group of drugs that interact with serotonin receptors, dopamine receptors, and α receptors.
Where is histamine stored?
In vesicles :
1. Mast cells
2. Enterochromaffin cells in the gut
3. Some neurons
How is histamine metabolized?
By the enzymes :
1. Monoamine oxidase
2. Diamine oxidase
How can excess of histamine in the body be detected?
By measurement of its major metabolite :
Imidazole acetic acid, in the urine.
What is the pathophysiologic role of histamine?
IgE mediated responses :
1. Seasonal rhinitis (hay fever)
3. Angioneurotic edema
What are the receptors for histamine?
4 receptors :
1. H1 and H2 mediate most of the peripheral actions.
2. H3 and H4 have also been identified.
What is the triple response?
Mediated mainly by H1 and H2 :
1. Small red spot at the center of an intradermal injection of histamine.
2. Surrounded by a red edematous wheal.
What G protein does the H1 receptor utilize?
Gq coupled - important in smooth muscle effects - IgE mediated responses.
What G protein does H2 receptor utilize?
Gs coupled - mediates gastric acid secretion by parietal cells in the stomach.
What G protein does the H3 receptor utilize?
Gi coupled - presynaptic modulation of histaminergic neurotransmission in the CNS.
What G protein does the H4 receptor utilize?
Gi coupled - it is located on the leukocytes (especially eosinophils) and mast cells : chemotactic responses by these cells.
Is there any clinical application of histamine ?
No - only for the H1 and H2 blockers.
What are the first generation H1 blockers?
1. Diphenhydramine (prototype)
What are the major second generation H1 blockers?
How are the H1 administered ?
What is the half life of the older H1 blockers ?
What is the half life of second generation H1 blockers?
What is the mechanism of action of H1 blockers?
Competitive antagonists at the H1 receptor - no effect on histamine release from storage sites. (More effective if given before histamine release occurs)
What resembles the structure of many of the first generation H1 blockers?
The structure of M blockers and α blockers - so the first generation H1 blockers are potent antagonists at these ANS sites.
What is the major application of H1 blockers?
In allergies (type I) (hay fever, urticaria etc.)
What H1 blockers are used as anti motion sickness drugs?
What H1 blocker is also used for the management of chemotherapy-induced vomiting?
With what H1 blockers is sedation common?
What antimuscarinic effects may the old H1 blockers have?
1. Dry mouth
2. Blurred vision
Which H1 blocker can cause orthostatic hypotension?
Promethazine - through α-adrenoceptor blockade.
What are the 4 major H2 blockers that are available?
1. Cimetidine (prototype)
How are the H2 blockers administered?
What is the half life of H2 blockers?
Why can H2 blockers be given in large doses?
Because they all are relatively nontoxic.
What is the mechanism of action of H2 blockers?
Surmountable pharmacologic blockade of H2 receptors. Relative selective.
What is the main therapeutic effect of H2 blockers ?
The reduction of gastric acid secretion.
What is the clinical use of H2 blockers?
1. In acid-peptic disease.
2. In gastric peptic ulcers.
3. IV H2 blockers are useful in preventing gastric erosions and hemorrhage that occur in stressed patients in IC units.
4. In Zollinger-Ellison syndrome/GERD : but proton pump inhibitors are preferred.
What is the toxicity of cimetidine?
1. Potent inhibitor of hepatic drug metabolizing enzymes.
2. May also reduce hepatic blood flow.
3. Significant antiandrogen effects in high doses.
What is the "root" of serotonin?
Where is serotonin stored?
In vesicles :
1. Enterochromaffin cells of gut.
2. Neurons of the CNS (neurotransmitter).
3. Neurons of enteric nervous system (as a local hormone).
How is serotonin metabolized?
How can excess of serotonin be detected?
By measuring its major metabolite : 5-HIAA in the urine.
How many serotonin receptors have been identified?
In clinical use, where do most of the serotonin agonists act?
At 5-HT(1D) receptor.
What G protein does the 5-HT1 receptor utilize?
Gi coupled :
In the brain : mediate synaptic inhibiton via increased K conductance.
Peripheral : excitatory/inhibitory effects in various smooth muscle tissues.
What is the main action mediated by 5-HT2 receptors?
Synaptic excitation in the CNS and smooth muscle contraction (gut, bronchi, uterus, some vessels) or relaxation (other vessels).
Where are 5-HT3 mainly found?
1. In the CNS : chemoreceptive area and vomiting center.
2. In the peripheral sensory and enteric nerves.
What category of drugs act at 5-HT3 receptors ?
Where are the 5-HT4 receptors found?
In the GI tract - role in intestinal motility.
Has serotonin a clinical application?
What is the prototype 5-HT(1D) agonist?
For what conditions are 5-HT(1D) the first line of treatment?
1. Acute migraine
2. Cluster headache attacks
How are 5-HT(1D) agonists administered?
Orally - yet sumatriptan is also available for nasal and parenteral administration.
What is the major 5-HT4 partial agonist?
What is the main clinical use of Tegaserod?
It was approved for use in chronic constipation (restricted because of CVS toxicity).
With what syndromes are sometimes serotonin agonists associated ?
Hyperpyrexic syndromes :
1. High fever
2. Skeletal muscle effects
3. CVS abnormalities
Mention 3 effective 5-HT2 blockers?
Mention 4 effective 5-HT3 blockers.
What is the mechanism of action of ketanserin and cyproheptadine?
Competitive 5-HT2 blockers
What is the mechanism of action of phenoxybenzamine?
Irreversible 5-HT2 blocker
Are ketanserin, cyproheptadine, and phenoxybenzamine selective agents?
No, they are poorly selective.
Other actions include α-blockade (ketanserin, phenoxybenzamine) or H1-blockade (cyproheptadine).
What is the mechanism of action of ondasetron, granisetron, and dolasetron?
Selective 5-HT3 blockers.
Important antiemetic effects.
(Alosetron appears to lack these antiemetic effects.)
What is the clinical use of ketanserin outside the USA?
As a hypertensive drug.
What can ketanserin, cyproheptadine, and phenoxybenzamine help to treat?
Carcinoid tumor :
Neoplasm that secretes large amounts of serotonin - diarrhea, bronchoconstriction and flushing.
What is the clinical use of ondasetron and its congeners?
Useful in the control of vomiting with cancer chemotherapy and post operative vomiting.
What is the clinical use of alosetron?
Used in the treatment of women with irritable bowel syndrome associated with diarrhea.
What are the main adverse effects of ketanserin?
1. α blockade
2. H1 blockade
What are the main toxicities of ondasetron, granisetron, and dolasetron?
What other toxicity has dolasetron been associated with?
QRS and QTc prolongation - contraindicated in patients with heart disease.
What is the toxic effects of alosetron?
1. Significant constipation
2. Fatal bowel movement complications
What is the mechanism of action of most ergot alkaloids?
Partial agonists at :
1. α receptors
2. 5-HT receptors
Some are also potent dopamine agonists.
What is the main classification of ergot alkaloids?
Into 3 subgroups based on the organ or tissue in which they have their primary effects. (Vessels, uterus, brain)
What is the action of ergot alkaloids on vessels?
They can produce marked and prolonged α-receptor mediated vasoconstriction.
What is the prototype ergot alkaloid that acts on vessels?
In what else can ergotamine be used?
In epinephrine reversal, because it acts as a partial agonist (α-receptor).
What do the ergot alkaloids cause on uterus?
What is the prototype ergot alkaloid that causes uterine contraction?
What can LSD (lysergic acid diethylamide) cause on the brain?
What is the mechanism of action of LSD?
1. It is a potent 5-HT2 blocker in peripheral tissues.
2. Actions in the CNS thought to be due to agonists at dopamine receptors.
What can some ergot alkaloids cause in the pituitary?
Inhibition of prolactin (dopaminergic effect) - bromocriptine and pergolide.
What is the clinical use of ergotamine?
In migraines : acute attacks with caffeine.
What ergot alkaloids have been used for migraine prophylaxis?
What other clinical use do ergotamine/ ergonovine have (besides migraine prophylaxis)?
Reduction of postpartum bleeding.
What other clinical uses do bromocriptine and pergolide have?
1. Used to reduce prolactin secretion (pituitary tumors)
What are the toxic effects of ergot alkaloids in the vasculature?
Severe prolonged vasoconstriction :
When used for long periods, what ergot alkaloid toxicity can occur in the vessels?
Unusual hyperplasia of connective tissue (fibroplasia).
Retroperitoneal - retropleural - subendocardial.
What other toxic effects do the ergot alkaloids have, other than vascular effects?
1. GI upset
2. Marked uterine contractions
3. CNS effects : hallucinations resembling psychosis (LSD and methysergide)
What are the major effects of ANGII?
1. "Classic" effects
2. Facilitates the release of NE from the adrenergic nerve endings via presynaptic heteroreceptor action.
3. Also AT2 receptor : vasodilation via NO during fetal development.
4. Also mitogenic - role in cardiac remodeling.
What is the major vasopeptidase inhibitor?
Omapatrilat : block both neutral endopeptidase 24.11 and ACE.
How is bradykinin produced?
From kininogen by a family of enzymes, the kallikreins.
Rapidly degraded by various peptidases, including ACE.
How is the action of bradykinin mediated?
Through its 2 receptors : B1 and B2 - IP3 + DAG, cAMP, NO, PGs.
What are the main actions of bradykinin?
2. Inflammation : edema and pain.
3. Saliva : major role in stimulating secretion.
Where may bradykinin play an important role?
1. In the antihypertensive action of ACE inhibitors.
2. In hereditary angioedema
What anti-bradykinin drugs have been approved?
1. Ecallantide (kallikrein inhibitor)
2. Icatinant (B2 blocker)
Used in angioedema.
What are the two main natriuretic peptides?
3. C-type natriuretic peptide.
Where are the two natriuretic peptides synthesized and stored?
In the cardiac atria (BNP also from brain tissue).
What are the major effects of natriuretic peptides?
1. Vasodilators as well as natriuretic agents.
2. Increased GFR
3. Decreased Na reabsorption
4. Inhibitory effects on renin
5. Inhibition on ANGII and aldosterone
What is the serious condition in which BNP can be used as a diagnostic marker?
What is the "BNP drug" that is approved for acute HF?
Nesiritide (significant toxicity)
What are the endothelins?
Peptide vasoconstrictors formed in and released by endothelial cells in blood vessels.
How many endothelins have been identified?
ET1, ET2, and ET3.
How many endothelin RECEPTORS have been identified?
ETa and ETb (G-protein coupled).
What is the endothelin receptor responsible for the vasoconstriction produced by endothelin?
The ETa receptor.
What are the major effects of endothelins?
1. More vasoconstriction than NE.
2. Relatively long lasting effect.
3. Stimulate the heart + increase NP release.
4. Activate smooth muscle proliferation.
In what disorders may endothelins be involved?
1. Forms of hypertension
2. Other CVS disorders
Mention 2 major ETa blockers used in pulmonary hypertension?
What is the VIP?
Vasoactive instestinal peptide - extremely potent vasodilator : more important as a neurotransmitter. Found in CNS and GI tract.
What are the major neurokinins?
1. Substance P
2. Neurokinin A
3. Neurokinin B
What are the main neurokinin receptors?
NK1 and NK2 receptors in the CNS and periphery.
What are the vascular effects of substance P?
Mixed vascular effects :
1. Potent arteriolar dilator
2. Stimulant of veins/intestinal/airway smooth muscle.
Is substance P found in the GI tract?
Yes - local hormone.
Is substance P found in the CNS?
Yes - higher concentrations are found in neurons subserving pain.
What does Capsaicin? (Hot component of chili peppers)
Releases substance P from its stores in nerve endings and depletes the peptide.
Has been APPROVED for topical use on arthritic joints and post herpetic neuralgia.
What the action of aprepitant?
Oral NK1 blocker : approved for chemo induced vomiting and nausea.
Where is CGRP mainly found?
2. Most smooth muscle tissues
What is the major action of CGRP ?
Most potent hypotensive agent found to date. Causes reflex tachycardia.
What is the neuropeptide Y?
A potent vasoconstrictor peptide that also stimulates the heart.
What are the eicosanoids?
An important group of endogenous fatty acid autacoids that are produced from arachidonic acid.
What are the two major subgroups of eicosanoids?
1. Leukotrienes (straight-chain derivatives).
2. Prostacyclin, prostaglandins, and thromboxane (cyclic derivatives).
Where do we find COX1?
In many tissues - PGs produced from COX1 appear to be important for a variety of physiologic processes.
Where do we find COX2?
In inflammatory cells (primarily).
Besides inflammatory functions, what other functions is COX2 responsible for?
1. Synthesis of prostacyclin.
2. Synthesis of PGs important in renal function.
Where is preferentially Tx and prostacyclin synthesized?
1. Tx : platelets.
2. Prostacyclin : endothelial cells.
What is the half life of eicosanoids?
Seconds to minutes - inactive when given orally.
What are the eicosanoids most directly involved in pathologic processes?
3. LTC4 and LTD4 (slow-reacting substance of anaphylaxis SRS-A).
What is the role of PGs on the renal function?
Important modulators of GFR :
Act on the afferent and efferent arterioles, and mesangial cells.
NSAIDs with diuretics = reduced efficacy of diuretics...
What is the clinical use of PGE2 (dinoprostone) and PGF2a?
In obstetrics :
Cause contraction of the uterus.
PGE2 : approved for use to soften the cervix before induction of labor by oxytocin.
Both have been used as abortifacients.
What are the possible adverse effects of PGE2 and PGF2a?
Describe an extremely effective and safe abortifacient combination.
PGE2 analog (misoprostol) + progesterone blocker (mifepristone)
What is the clinical use of PGs in pediatrics?
PGE1 : given to maintain patency of the ductus arteriosus in infants with transposition of the great arteries, till surgery.
What is the clinical use of PGs in pulmonary hypertension and dialysis?
Prostacyclin (PGI2) is approved for use (epoprostenol) in SEVERE pulmonary hypertension + to prevent platelet aggregation in dialysis machines.
What is the clinical use of PGs in peptic ulcer associated with NSAID use?
PGE1 analog (misoprostol) : prevention of peptic ulcers in patients taking high doses of NSAIDs for arthritis and have history of peptic ulcers.
What is the clinical use of PGs in ophthalmology ?
1. Latanoprost (PGF2a derivative) - used for glaucoma.
Increase the outflow of aqueous humor - reducing intraocular pressure.
What is the action of zileuton?
A selective inhibitor of lipoxygenase.
Mention two blockers of the LTD4 receptor used in the treatment of asthma.
What is the main inhibitory action of corticosteroids?
Inhibit the production of arachidonic acid by phospholipases in the membrane. Also inhibit the synthesis of COX2.
What is the main effect of NSAIDs?
Inhibition of cycloxygenase and the production of the thromboxane, prostaglandins, and prostacyclin. (Most inhibit inselectively both COX1 and COX2)
Mention some selective COX2 inhibitors.
2. Meloxicam (slightly selective)
Last 2 withdrawn due to CVS toxicity.
Where is aspirin allergy more common?
For unknown reasons, in people with nasal polyps.
Where does the antiplatelet action of aspirin stem from?
Permanent drug inhibition of TX synthesis. Platelets cannot produce new enzymes (in contrast to inhibition of PGI2 synthesis in the endothelium).
Where are zileuton, zafirlukast, and montelukast primarily used?
What is NO?
An autacoid produced by arginine in the body + the active metabolite of the drugs that release it (NO donors).
How is endogenous NO synthesized?
By a family of enzymes collectively called nitric oxide synthase (NOS).
How can NOS be inhibited?
By arginine analogs such as N(g)-monomethyl-L-arginine (L-NMMA)
Is NO stored ?
NO! Because it is a gas at body temperature, it very rapidly diffuses from its site of synthesis to the surrounding tissues.
What drugs stimulate the production of NO?
1. M agonists
3. Certain vasodilators (bradykinin, hydralazine).
Mention some important drugs that release NO.
How is NO released from nitroprusside?
Spontaneously in the blood in the presence of oxygen.
How is NO released from nitrites and nitrates?
Intrecellularly : requires the mitochondrial enzyme ALD2 and thiol compounds such as cysteine.
What is the second messenger induced by NO?
cGMP (Not cAMP)
What is the effect of NO in cell adhesion?
1. Reduced platelet aggregation
2. Reduced platelet adhesion
What is the effect of NO in inflammation?
Tissue injury causes NO synthesis and NO appears to facilitate inflammation both directly and through stimulation of PG synthesis by COX2.
What other effects is NO suspected to have?
1. Action as a neurotransmitter.
2. Involved in some types of apoptosis.
How is acute bronchospasm treated in asthma?
1. β2 agonists
2. M blockers
3. Theophylline and derivatives.
What requires the long term preventing treatment in asthma?
Anti-inflammatory drugs :
2. Long acting β2 agonists
3. Anti-IgE antibodies
What drugs have effects on both bronchoconstriction and inflammation but are used only for prophylaxis?
The leukotrienes blockers.
Mention some important short acting β2 agonists used in asthma.
Mention some important long acting β2 agonists used in asthma.
3. Indicaterol (only for COPD)
How are the β2 agonists administered in asthma?
What is the half life of the older and the new β2 agonists used in asthma?
Old : 6h or less.
New : 12-24h.
What is the mechanism of action of β2 agonists used in asthma?
Increase in cAMP in smooth muscle cells - powerful bronchodilator response.
What is the first line of treatment in acute asthma ?
Sympathomimetics (β2 agonists)
What happens when long lasting β2 agonists are used alone?
They increase asthma mortality - should be used in combination with corticosteroids.
What are the adverse effects of β2 agonists given in asthma?
1. Skeletal muscle tremor.
2. Even by inhalation, some cardiac effect if common (tachycardia - when given in high doses, there is also some β1 selectivity.)
What can increase the risk of arrhythmias in patients with asthma, when they being given β2 agonists?
COPD with concurrent cardiac disease.
What are the three most common methylxanthines that are found in plants?
1. Caffeine (in coffee)
2. Theophylline (in tea)
3. Theobromine (cocoa)
What is the only methylxanthine that is important in the treatment of asthma?
How is theophylline metabolized?
In the liver, by P450 drug metabolizing enzymes.
When is theophylline clearance higher?
1. In young adolescents
2. In smokers
3. Other drugs that induce hepatic enzymes.
What is the main mechanism of theophylline action?
1. Inhibition of phosphodiesterase (PDE), the enzyme that degrades cAMP to AMP. (High doses required)
2. Also block adenosine receptors in the CNS and elsewhere.
In asthma, what is the most important therapeutic action of theophylline?
Besides bronchodilaton, what other effects does theophylline have?
1. CNS stimulation
2. Cardiac stimulation
4. Slight increase in BP
6. Increased GI motility
What the main clinical use of methylxanthines?
In asthma and COPD.
What is the most commonly used methylxanthine in asthma?
Slow-release theophylline (for control of nocturnal asthma).
What salt of theophylline is usually prescribed for asthma?
Mention some important adverse effects of methylxanthines.
1. GI distress
4. Severe nausea
What is used to reverse the severe cardiovascular toxicity from theophylline OD?
What are the main muscarinic blockers that are used in asthma?
How is ipratropium administered?
Orally, in aerosol form - little systemic action.
What is the difference between ipratropium and tiotropium?
Tiotropium is a longer-lasting analog.
When given orally, what is the mechanism of action of ipratropium and tiotropium?
Competitively block muscarinic receptors in the airways and effectively prevent bronchoconstriction mediated by vagal discharge.
When given systemically (NOT APPROVED), what is the mechanism of action of ipratropium and tiotropium?
They are indistinguishable from other short acting M blockers.
What are the main effects of ipratropium and tiotropium?
1. Reverse bronchoconstriction in some asthma patients (especially children) and in many patients with COPD.
2. No effect on the chronic inflammatory aspects of asthma.
What percentage of the asthmatics responds to ipratropium and tiotropium? (For acute bronchospasm)
1/3-2/3. β2 agonists are effective in almost all.
What is the main difference between β2 agonists and antimuscarinic agents used in asthma regarding their toxicity?
In contrast to β2 agonists, M blockers do not cause tremor or arrhythmias.
What is the main characteristic of cromolyn and nedocromil?
They are unusually insoluble chemicals, so that even massive doses given orally or by aerosol result in minimal systemic levels.
Now rarely used for asthma in the USA.
When do we use corticosteroids in the treatment of asthma?
Because of their toxicity, only chronic use, when other therapies are unsuccessful (prednisone).
What is the first line therapy for patients with moderate to severe asthma?
Surface active corticosteroids via inhalation.
Mention some relatively safe surface active corticosteroids that are used as first line treatment in moderate to severe asthma?