Brenner/Stevens Pharmacology 3Ed. Chap. 5 & 26

Affects Acetylcholine Neurotransmission

Inhibits synthesis of neurotransmitter.
blocks choline transport into the neuron and thereby inhibits the synthesis of acetylcholine

Prevent vesicular storage of neurotransmitter

substance in black widow spider venom

markedly stimulate vesicular release of acetylcholine producing excessive activation of acetylcholine receptors

severe contraction and pain in local muscles, which then spreads to regional muscles and throughout the body. Abdominal pains are usually the most severe, mimicking appendicitis or food poisoning. Salivation, lacrimation, sweating, changes in heart rate, high blood pressure, shock, and coma may occur, though death from black widow spider bite is rare.

Clostridium botulinum

blocks the exocytotic release of acetylcholine and inhibits neuromuscular transmission

It is used to treat localized spasms of various muscles, including those of the eyes, face, and hands, and it is employed in treating tremor, dystonia, excessive salivation, and other symptoms of Parkinson's disease.

Injections of a preparation of this toxin known as Botox have been shown to reduce facial wrinkles and have been widely utilized for cosmetic purposes.

to treat excessive sweating (hyperhidrosis) of the palms and soles, and botulinum toxin is being studied as an alternative to acetylcholine receptor antagonists in the treatment of overactive urinary bladder.

dry mouth and dysphagia

choline ester

mimic the effect of acetylcholine

choline ester

mimic the effect of acetylcholine. direct-acting acetylcholine receptor agonists because they directly bind and activate acetylcholine receptors.

cholinesterase inhibitor (indirect-acting acetylcholine receptor agonist)

prevent the breakdown of acetylcholine and thereby increase the synaptic concentration of acetylcholine

acetylcholine receptor antagonists

muscarinic receptor antagonists and nicotinic receptor antagonists

ganglionic blocking agent (subcategory of nicotinic receptor antagonists)

neuromuscular blocking drugs (subcategory of nicotinic receptor antagonists)

tyrosine → dopa → dopamine → norepinephrine

calcium-mediated exocytosis in response to nerve stimulation

postjunctional α- and β-adrenoceptors. It also activates prejunctional autoreceptors that exert negative feedback and inhibit further release of norepinephrine

by neuronal reuptake via a transport protein known as the catecholamine transporter that is localized in the presynaptic neuronal membrane

inactivate norepinephrine that is not sequestered by presynaptic neurons. These enzymes are found in many tissues, including the liver and gut.

a drug that is a competitive inhibitor of tyrosine hydroxylase. Metyrosine can be used to inhibit norepinephrine and epinephrine synthesis in persons with an adrenal medullary tumor (pheochromocytoma) that secretes large amounts of these substances and thereby causes severe hypertension. The drug has also been studied as a treatment for dystonia or dyskinesia in persons being treated with neuroleptic (antipsychotic) drugs.

demser

inhibits the transporter for amines located in the vesicular membrane

blocks the release of norepinephrine in response to nerve stimulation

Drugs that block the synthesis, storage, or release of norepinephrine

endogenous substances and synthetic compounds that directly activate α- or β-adrenoceptors

albuterol, dobutamine, and epinephrine

indirectly increase the activation of adrenoceptors by increasing the synaptic concentration of norepinephrine

amphetamine and cocaine

the presence of a functional postganglionic neuron

Cocaine binds to and competitively inhibits the catecholamine transporter located in the presynaptic nerve terminal, thereby increasing the duration of action of norepinephrine at the synapse.

Amphetamine and related drugs are substrates for the transporter, which transports the drugs into the presynaptic neuron where they inhibit the storage of norepinephrine by synaptic vesicles, leading to reverse transport of norepinephrine into the synapse by the catecholamine transporter. These actions serve to increase the synaptic concentration of norepinephrine and its activation of adrenoceptors.

act by inhibiting the breakdown of norepinephrine. primarily exert their effects on the central nervous system.

Drugs that inhibit sympathetic stimulation of target organs

phentolamine, propranolol, labetalol

selectively blocks α-adrenoceptors

selectively blocks β-adrenoceptors

blocks both receptor types

(Fig. 5-4). (A). Increased arterial pressure activates stretch receptors in the aortic arch and carotid sinus. (B) Receptor activation initiates afferent impulses to the brain stem vasomotor center (VMC). (C) Via solitary tract fibers, the VMC activates the vagal motor nucleus, which increases vagal (parasympathetic) outflow and slows the heart. At the same time, the VMC reduces stimulation of spinal intermediolateral neurons that activate sympathetic preganglionic fibers, and this decreases sympathetic stimulation of the heart and blood vessels. By this mechanism, drugs that increase blood pressure produce reflex bradycardia. Drugs that reduce blood pressure attenuate this response and cause reflex tachycardia.

this activates stretch receptors (mechanoreceptors) located in the aortic arch and in the carotid sinus at the bifurcation of the carotid artery. Receptor activation initiates impulses that travel via afferent nerves to the brain stem vasomotor center. Stimulation of the vagal motor nucleus (via nerves from the solitary tract nucleus) leads to an increase in vagal (parasympathetic) outflow, a decrease in heart rate, and a decrease in the sympathetic nerve outflow from the vasomotor center. The effect on the heart rate is called reflex bradycardia.

If a drug lowers the blood pressure sufficiently, it may reduce the baroreceptor tone and thereby produce an acceleration of the heart rate and activation of sympathetic vasoconstriction.

Acetylcholine

norepinephrine

activate or block receptors for acetylcholine or norepinephrine in smooth muscle, cardiac tissue, and glands

smooth muscle contraction

smooth muscle relaxation and cardiac stimulation

drugs that have effects on neurotransmitter synthesis, storage, release, or metabolism

increase the concentration of a neurotransmitter at synapses, either by inhibiting transmitter inactivation (cholinesterase inhibitors), increasing transmitter release (amphetamine and tyramine), or blocking transmitter reuptake (cocaine).

Autacoids (also spelled autocoids) are substances produced by neural and non-neural tissues throughout the body and act locally to modulate the activity of smooth muscles, nerves, glands, platelets, and other tissues (Table 26-1). Several autacoids also serve as neurotransmitters in the central nervous system (CNS) or enteric nervous system.

Autacoids regulate certain aspects of gastrointestinal, uterine, and renal function, and they are involved in pain, fever, inflammation, allergic reactions, asthma, thromboembolic disorders, and other pathologic conditions. Drugs that inhibit autacoid synthesis or block autacoid receptors are helpful in treating these conditions, whereas drugs that activate autacoid receptors are useful for inducing labor, alleviating migraine headaches, counteracting drug-induced peptic ulcers, and other purposes.

Autacoids include monoamines, such as histamine and serotonin, as well as fatty acid derivatives, including prostaglandins and leukotrienes.

Autacoids activate specific membrane receptors in target tissues, mostly of the G protein-coupled receptor type.

Their effects are usually restricted to the tissue in which they are formed, but under pathologic conditions, extraordinarily large amounts of autacoids can be released into the systemic circulation.

These disorders cause the release of copious amounts of serotonin and histamine, respectively, and exert systemic effects including CNS effects.

Most autacoids are rapidly metabolized to inactive compounds, as seen with prostaglandins, and some autacoids undergo tissue reuptake, as evidenced by 5-hydroxytryptamine (5-HT) reuptake transporter proteins in neurons and peripheral cells.

Histamine is a biogenic amine produced primarily by mast cells and basophils, which are particularly abundant in the skin, gastrointestinal tract, and respiratory tract. Histamine is also produced by paracrine cells in the gastric fundus, where it stimulates acid secretion by parietal cells. Histamine also functions as a neurotransmitter in the CNS

Histamine is formed when the amino acid histidine is decarboxylated in a reaction catalyzed by the enzyme, l-histidine decarboxylase.

Histamine is stored in granules (vesicles) in mast cells and basophils until it is released.

It is released from mast cells when membrane-bound immunoglobulin E (IgE) interacts with an IgE antigen to cause mast cell degranulation.

respiratory drug that blocks histamine reaction.

Stimuli that increase cyclic guanosine monophosphate increase histamine release, whereas those that increase cyclic adenosine monophosphate oppose this action.

Mast cell degranulation can also be triggered by bacterial toxins and by drugs such as morphine and tubocurarine. Some of these stimuli result in the formation of inositol triphosphate (IP3) and diacylglycerol (DAG). As with neurons, this causes the release of intracellular calcium and the fusion of granule membranes with the plasma membrane, thereby releasing histamine and other compounds. The release of histamine that can occur with morphine administration does not appear to be mediated by opioid receptors because the opioid antagonist, naloxone, does not inhibit morphine-induced histamine release from mast cells.

Histamine is inactivated by methylation and oxidation reactions that are catalyzed by a methyltransferase enzyme and diamine oxidase, respectively.

H1, H2, and H3. All three types are typical, seven-transmembrane G protein-coupled receptor proteins.

allergic reactions that cause dermatitis, rhinitis, conjunctivitis, and other forms of allergy.

vasodilation; increases vascular permeability; and leads to erythema (heat and redness), congestion, edema, and inflammation

pruritus (itching), and in the lungs, it initiates the cough reflex

total peripheral resistance and blood pressure fall and the individual may progress to anaphylactic shock.

bronchoconstriction and contraction of most gastrointestinal smooth muscles.

increasing gastric acid secretion, but they are also involved in allergic reactions

H1 receptor antagonists

increases the heart rate and contractility, but the cardiac effects of histamine are not prominent under most conditions.

in various tissues in the periphery and on nerve terminals. Activation of these presynaptic receptors in the brain inhibits the release of histamine and other neurotransmitters.

their receptor selectivity as H1 receptor antagonists or H2 receptor antagonists.

Antihistamines

H1 receptor antagonists and H2 receptor antagonists.

first-generation H1 drugs

second-generation H1 drugs

orally or parenterally

first-generation antihistamines are distributed to the CNS and can cause sedation, whereas the second-generation antihistamines do not cross the blood-brain barrier significantly

an intranasal antihistamine

levocabastine, ketotifen, epinastine, and olopatadine

The H1 antihistamines contain an alkylamine group that resembles the side chain of histamine and permits them to bind to the H1 receptor and act as competitive receptor antagonists. The drugs can block most of the effects of histamine on vascular smooth muscles and nerves and thereby prevent or counteract allergic reactions.

they are rapidly absorbed and are widely distributed to tissues. Many of them are extensively metabolized in the liver by cytochrome P450 enzymes.

Hydroxyzine has an active metabolite that is also available as the drug, cetirizine, and this drug is excreted unchanged in the urine and feces.

an H1 antihistamine that is marketed as a nasal spray for the treatment of allergic rhinitis. It blocks H1 receptors and inhibits the release of histamine from mast cells, and it is much more potent than either sodium cromoglycate or theophylline in its inhibition.

about 40%, and the plasma half-life is about 22 hours

Azelastine is metabolized by cytochrome P450 enzymes to an active metabolite, desmethylazelastine, a substance whose plasma concentrations are 20% to 30% of azelastine concentrations. Azelastine and its principal metabolite are both H1 receptor antagonists. The unchanged drug and its active metabolite are excreted primarily in the feces.

First-generation antihistamine

6

Medium

none

Medium

First-generation Antihistamine

8

high

medium

high

First-generation Antihistamine

8

high

medium

high

First-generation Antihistamine

6

high

high

medium

First-generation Antihistamine

12

Medium

high

medium

First-generation Antihistamine

12

high

high

high

Second-generation Antihistamine

24

low

none

very low

Second-generation Antihistamine

12

very low

none

very low

Second-generation Antihistamine

24

Very low

none

very low

Intranasal Antihistamines

12

low

none

very low

second-generation antihistamines cause little or no sedation, so they are often preferred for the treatment of allergies

Antihistamines are usually more effective when administered before exposure to an allergen than afterward. Hence, persons with seasonal allergies, such as allergic rhinitis should take them on a regular basis throughout the allergy season.

Because the first-generation antihistamines have sedative effects, they are occasionally used to produce sedation. They are also used to treat nausea and vomiting, to prevent motion sickness in persons traveling by plane or boat, or to treat vertigo (an illusory sense that the environment or one's own body is revolving).

diphenhydramine, hydroxyzine, and promethazine. These drugs have been used to induce sleep or for preoperative sedation. Their sedating properties can also be useful in relieving distress caused by the severe pruritus associated with some allergic reactions. Persons taking these drugs should be cautioned against driving or operating machinery.

Pheniramine drugs (e.g., chlorpheniramine), are less sedating than other first-generation drugs and are used primarily in the treatment of allergic reactions to pollen, mold spores, and other environmental allergens.

Meclizine, diphenhydramine, hydroxyzine, and promethazine

Meclizine is less sedating than diphenhydramine, hydroxyzine, and promethazine, so it is frequently used to prevent motion sickness or treat vertigo.

Dimenhydrinate is a mixture of diphenhydramine and 8-chlorotheophylline and is used to prevent motion sickness or treat vertigo.

to relieve nausea and vomiting associated with various conditions

lack antiemetic activity, so their use is limited to the treatment of allergies

cetirizine

fexofenadine

primarily as the unchanged drug in the feces and urine, respectively

Loratadine and desloratadine

for the treatment of symptoms of allergic rhinitis, including sneezing, nasal itching, and nasal discharge. It is administered as two sprays per nostril twice daily. The drug can cause drowsiness so should be used cautiously when patients are driving or operating machinery

Levocabastine, epinastine, and olopatadine are selective H1 antagonists for topical ophthalmic use. They are indicated for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis. Ketotifen is a selective, noncompetitive H1 antagonist and mast cell stabilizer.

Ketotifen

The H1 antihistamines produce few serious side effects.

diphenhydramine, a first-generation antihistamine, but these preparations are known to cause drowsiness

they do not readily gain access into the CNS

beclomethasone, fluticasone, or triamcinolone

they may take a week or so to be maximally effective

Sedation

excitement

Diphenhydramine and promethazine

block cholinergic muscarinic receptors. As a result can cause dry mouth, blurred vision, tachycardia, urinary retention, and other atropine-like side effects.

Anticholinergic toxicity

a cholinesterase inhibitor that crosses the blood-brain barrier, that may be required to counteract the anticholinergic effects of antihistamines in the CNS.

Hismanal

caused prolongation of the QT interval

terfenadine (Seldane).

it prolonged the QT interval on the electrocardiogram, leading to a type of cardiac arrhythmia called torsades de pointes

Fexofenadine, Cetirizine and loratadine

Adverse effects of azelastine are rare and include dizziness, fatigue, headache, nasal irritation, dry mouth, and weight gain.

Adverse effects of levocabastine, epinastine, olopatadine, and ketotifen are usually limited to the eyes and include transient stinging and burning. These occur in less than 5% of patients.

peptic ulcer disease

5-hydroxytryptamine (5-HT),

an autacoid and a neurotransmitter that is produced primarily by platelets, enterochromaffin cells in the gut, and neurons.

in the enterochromaffin cells of the gastrointestinal tract.

tryptophan and is converted to 5-hydroxyindoleacetic acid (5-HIAA) by monoamine oxidase and aldehyde dehydrogenase

5-HT1 through 5-HT4

platelet aggregation, stimulation of gastrointestinal motility, and modulation of vascular smooth muscle contraction.

vasoconstriction in most vascular beds and contraction of most smooth muscles. In the CNS, serotonin is involved in the regulation of mood, appetite, sleep, emotional processing, and pain processing

serotonin agonists, serotonin antagonists, and serotonin reuptake inhibitors

a partial agonist that acts at the 5-HT1A receptor, is used to treat anxiety and depression

5-HT1D/1B receptor agonists that are used to treat migraine headaches

the first 5-HT4 receptor agonist used for the treatment of gastroesophageal reflux disease and gastrointestinal hypomotility. Activation of 5-HT4 receptors increases the peristaltic action of the gastrointestinal tract, which is helpful in the treatment of both gastroesophageal reflux disease and gastrointestinal hypomotility.

postmarketing surveillance revealed a risk of rare but sometimes fatal prolongation of the QT interval on electrocardiogram records ('long QT syndrome').

A newer 5-HT4 agonist, tegaserod (Zelnorm), was approved for a narrower indication for women who have irritable bowel syndrome with constipation as their main symptom, but it was recently withdrawn from the market due to increased risk of heart attack or stroke.

serotonin antagonists

Serotonin Agonist, 5-HT1A, Anxiety; depression

Serotonin Agonists, 5-HT1D/1B, Migraine headaches

Serotonin Antagonists, 5-HT2, Schizophrenia

Serotonin Antagonists, 5-HT2, Carcinoid syndrome; pruritus; urticaria

Serotonin Antagonists, 5-HT2, Carcinoid syndrome; migraine head-aches

Serotonin Antagonists, 5-HT3, Nausea and vomiting

atypical antipsychotic that acts partly by blocking 5-HT2 receptors in the CNS. They are used in the treatment of schizophrenia

a 5-HT2 receptor antagonist that also has H1 antihistamine activity. This makes it useful in managing urticaria (hives) and other allergic reactions in which pruritus is a prominent feature. Cyproheptadine is administered orally every 8 to 12 hours and can cause slight to moderate drowsiness.

in the care of patients with carcinoid tumor. This tumor can produce huge quantities of serotonin, histamine, and other vasoactive substances that cause a constellation of clinical effects called the carcinoid syndrome. Affected patients suffer from malabsorption, violent attacks of watery diarrhea and cramping, and paroxysmal vasomotor attacks characterized by sudden red to purple flushing of the face and neck. The malabsorption and diarrhea can be managed by giving cyproheptadine or methysergide in combination with opioid antidiarrheal drugs.

the first selective 5-HT3 receptor antagonist used as an antiemetic agent in cancer chemotherapy as well as treating nausea and vomiting from other causes. It prevents nausea and vomiting by blocking the effects of serotonin in the chemoreceptor trigger zone and in vagal afferent nerves in the gastrointestinal tract

5-HT3 receptor antagonists used as an antiemetic agent in cancer chemotherapy as well as treating nausea and vomiting from other causes.

for treatment of women with irritable bowel syndrome whose predominant bowel symptom is diarrhea.

an injectable-only formulation for the prevention of acute or delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy.

the treatment of depression and other CNS disorders

arachidonic acid (eicosatetraenoic acid) and other 20-carbon fatty acids

They are freed from their esteric attachment to membrane phospholipids by phospholipase A2, an enzyme that is activated by numerous chemical stimuli and by physical stimuli such as cell damage.

prostaglandins and leukotrienes

smooth muscle, platelet aggregation, neurotransmission, glandular secretion, and other biologic activities by activating specific prostanoid receptors in target tissues

thromboxane A2 (TXA2)

prostacyclin (prostaglandin I2 [PGI2]).

primarily in inflammatory cells, including mast cells, basophils, eosinophils, macrophages, and polymorphonuclear leukocytes. Leukotrienes C4 and D4 (LTC4 and LTD4) are the main components of the slow-reacting substance of anaphylaxis. These two leukotrienes are secreted in the presence of asthma and anaphylaxis and play a major role in bronchospastic disease.

leukotriene inhibitors, NSAIDs, and corticosteroids

by inhibiting 5-lipoxygenase or by blocking leukotriene receptors. They are currently used in the management of asthma, but other therapeutic applications are being explored.

by inhibiting cyclooxygenase and are used primarily to alleviate pain and inflammation

Corticosteroids block the formation of all eicosanoids, partly by inhibiting phospholipase A2. They have anti-inflammatory, antiallergic, and antineoplastic effects and are used in the treatment of a wide variety of adrenal diseases and nonadrenal disorders.

PGE1

Vasodilation

Erectile dysfunction; patency of the ductus arteriosus

available in injectable, pellet, and cream formulations

Adverse effects in men treated with alprostadil include penile pain, penile fibrosis, priapism (persistent erection), flushing, diarrhea, headache, and fever.

PGF2α analogue

Contraction of uterine muscle

Abortifacient; postpartum bleeding

Carboprost is administered intramuscularly

It can cause flushing, diarrhea, vomiting, altered blood pressure, blurred vision, respiratory distress, and other adverse reactions.

PGE2

Contraction of uterine muscle

Abortifacient; cervical ripening

Dinoprostone is available as a vaginal insert, gel, or suppository.

PGI2

Vasodilation

Pulmonary hypertension

The drug is administered by continuous intravenous infusion, and the dosage is titrated on the basis of clinical improvement and adverse effects. The most common adverse reactions include flushing, tachycardia, hypotension, diarrhea, nausea, vomiting, and flulike symptoms.

PGF2α analogue

Increase in aqueous humor outflow

Glaucoma

It can alter the color of the iris and cause a permanent eye color change by increasing the amount of melanin in melanocytes.

PGE1 analogue

Gastric cytoprotection

Gastric and duodenal ulcers induced by use of NSAIDs

available in an orally administered formulation

Diarrhea, one of the most common adverse effects of misoprostol use, can be minimized by starting patients on a low dose of the drug and then gradually increasing the dose. In pregnant women, misoprostol is absolutely contraindicated because it can stimulate uterine contractions and cause premature labor.

a stable analogue of prostacyclin which has a half-life of between 2 and 4 hours and can be safely administered by a continuous subcutaneous infusion, via a self-inserted subcutaneous catheter using a microinfusion pump designed specifically for subcutaneous drug delivery. It is approved to diminish the symptoms (e.g., shortness of breath) associated with physical activity in patients with pulmonary arterial hypertension.

a peptide autacoid produced by vascular endothelial cells. It activates ETA and ETB receptors in vascular smooth muscle and other tissues. The results of ETA receptor activation are vasoconstriction and cell proliferation, while ETB receptors mediate vasodilation, anti-proliferation, and increased ET-1 clearance. ET-1 may serve physiologically to counteract the vasodilation produced by the endothelin-relaxing factor (nitric oxide),

a dual ETA and ETB receptor antagonist that is approved for treating pulmonary arterial hypertension. Clinical trials have shown that bosentan significantly improves 6-minute walking distance in persons with class III or IV pulmonary arterial hypertension, while decreasing pulmonary vascular resistance and dyspnea.
Bosentan is administered orally and is generally well tolerated, but 11% of patients experienced elevated serum aminotransferase levels. For this reason, liver function tests should be monitored at baseline and then monthly in persons taking bosentan. Based on animal studies, bosentan is very likely to cause major birth defects if used by pregnant women, and it is contraindicated in pregnancy and in women of childbearing age who are not using hormonal contraceptives.

ET receptor antagonist, ambrisentan, was recently approved for the treatment of pulmonary arterial hypertension. Ambrisentan has much greater selectivity for ETA receptors compared to ETB receptors (>4000-fold), although the clinical impact of such high selectivity is not known. Like bosentan, similar warnings are made regarding hepatic function and enzyme level monitoring.

marketed under a new trade name, Revatio, for the treatment of pulmonary arterial hypertension. As sildenafil inhibits phosphodiesterase type 5, an increase of cyclic guanosine monophosphate within pulmonary vascular smooth muscle cells results in relaxation and vasodilation of the pulmonary vascular bed.

histamine, serotonin, prostaglandins, and leukotrienes

vasodilation, edema, congestion, and pruritus

gastric acid secretion

chlorpheniramine, diphenhydramine, meclizine, promethazine,

cetirizine, loratadine, fexofenadine, and desloratadine

allergies

prevent motion sickness

nausea and vomiting

terfenadine

prolong the QT interval or cause torsades de pointes

cardiac effects

serotonin agonists, serotonin antagonists, and serotonin reuptake inhibitors.

migraine headaches

migraine headaches

carcinoid syndrome, which is caused by excessive production of serotonin and other vasoactive substances in patients with carcinoid tumors from enterochromaffin tissue

5-HT3 receptor antagonists used in the treatment of nausea and vomiting.

arachidonic acid and other precursor 20-carbon fatty acids.

prostaglandins and leukotrienes. The ratio of omega-6 and omega-3 fatty acids in the diet plays an important role in the activity of eicosanoid end products.

patency of the ductus arteriosus in neonates awaiting surgery for heart defects. It is also used to treat erectile dysfunction in men.

gastric and duodenal ulcers in persons taking NSAIDs.

cervical ripening before induction of labor and for evacuation of the uterine contents.

PGF2α derivatives

control postpartum bleeding and to terminate pregnancy

glaucoma.