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304 Cards in this Set

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What are preganglionic nerves?
-sympathetic and parasympathetic preganglionic fiber that release acetylcholine
-ACh has two receptors: muscarinic and nicotinic
-postgaglionic nerves have nicotinic receptors
What is acetylcholine? How is it released?
-a small molecule that acts as a chemical messenger to propagate nerve impulses across the neuromuscular junction between a nerve and a muscle
-when the nerve impulse from a motor neuron arrives at the tip of its axon, ACh molecules stored there in vesicles are released into the synaptic gap
-some of these moelcules bind to nicotinic receptors (large proteins embedded into muscle fiber)
What are nicotinic receptors?
-nicotine can also bind to them lieke acetylcholine
-cholinoreceptors that are activated by alkaloid nicotine
-receptor are localized at the myoneural junctions of somatic nerves and skeletal muscle, autonomic ganglia including the adrenal medulla, and certain areas of the brain
What are nicotinic receptors structurally?
-consists of 5 protein subunits in skeletal muscle and 2 protein subunit in ganglia that form ligand-gated (ie regulated) ion channel pores in the cell membranes
-causes depolarization
What drug is commonly used for nicotinic receptors?
-hexamethonium
What occurs during binding of acetycholine to nicotinic receptors in skeletal muscle?
-1 molecule of ACh per alpha subunit (2 total)
-binding of 2 ACh molecules causes a rapid opening of the channel that permits passage of ions, mostly sodium
-Na+ flows down gradient into cell causing depolarization and an excitatory postsynaptic potential through transverse tubules, resulting in release in calcium from sarcoplasmic reticulum and ultimately muscle contraction
What occurs during hydrolysis of acetylcholine in muscle cells?
-done by acetylcholine esterase
-results in muscle cell repolarization
Where are N1-nicotinic receptors located?
-found in both sympathetic and parasympathetic autonomic ganglia and in the adrenal medulla
Where are N2-nicotinic receptors located?
-found at the neuromuscular junction of skeletal muscle
-similar to N1-nicotinic receptors
What do N1-nicotinic receptors do for autonomic ganglia? Adrenal medulla?
-automatic firing of postsynaptic connection for both sympathetic and parasympathetic neurons
-secretion of epinephrine
What can result due to continued presence of nicotinic agonists at nicotinic receptors?
-excessive cholinergic stimulation
-can lead to a "depolarizing blockade" (phase I block) in which normal depolarization is followed by persistant depolarization
-skeletal muscle is unresponsive to either neuronal stimulation or direct stimulation
What selective nicotinic receptor antagonists can block the effect of ACh at skeletal muscle and autonomic ganglia respectively?
-tubocurarine and trimethaphan
What are the five steps of ganglionic neurotransmission? What drugs can block at certain steps?
- primary event is rapid depolarization of postsynaptic nicotinic receptors by ACh (duration is milliseconds and blocked by hexamethonium)
-thene development of inhibitory postsynaptic potential also lasting milliseconds (blocked by atropine and alpha adrenergic blockers)
-then devlopement of late excitatory post synaptic potential (which lasts for 30-60 seconds and blocked by atropine due to activation of M1 receptors)
-then late slow EPSP for several minutes
-then secondary events of ganglionic transmission modulate the primary depolarization, by making it more or less likely to occur.
-conventional nicotinic receptor antagonists can inhibit ganglionic transmission completely
-muscarinic antagonists,alpha adrenergic antagonists and peptidergic antagonists can no do so
What are the mechanisms of drugs that mimic acetylcholine?
-by directly activating cholinoreceptors/ nicotinic receptors
-or inhibiting acetyltransferase, thus blocking the termination of action of endogenous acetylcholine
What are direct-acting cholinomimetics?
-direect-acting cholinomimetics may have affinity for both muscarinic and nicotinic receptors, or they may be more selective and activate only one of the two.
What are indirect-acting cholinomimetics?
-amplifiers which act only where acetylcholine is released from endogenous storage
-have little or no effect at innervated cholinoreceptors that are present on endothelium of blood cells
What drugs are direct and nicotinic only?
-nicotine and succinylcholine
What occurs during nicotinic cholinomimetics of autonomic ganglia?
-both sympathetic and parasympathetic ganglia have to be activated
-actions on dually innervated organs (pupil, sinoatrial node of heart) are unpredictable
What occurs during nicotinic cholinomimetics of skeletal muscle neuromuscular junctions?
-opening of the Na/K channels on the end plate results in depolarization and intially contractions of the muscle units
What occurs during maintained depolarization caused by a long-lasting nicotinic agonist such as succinylcholine?
-results in block of impulse propagation from the end plate to the skeletal membrane and leads to paralysis
What is nicotine? mechanism of action?
-a constituent of tobacco
-nicotine mimics the action of acetylcholine at the cholinergic nicotinic receptors of ganglia in skeletal muscle and in the CNS
-decreases MAO activity in the brain and other organs resulting in increased levels of dopamine
What are pharmacologic properties of nicotine?
-volatile liquid alkaloid that is readily absorbed from the respriatory tract, oral membranes, skin and is rapidly distributed
-metabolized primarily in the liver (rapid witha plasma half-life of apporximatly 1 hour), but also in the lung and kidney (rapid excretion of nicotine and its metabolites)
-a strong base and is highly ionized in the stomach and hence poorly absorbed from the stomach
-nicotine is excreted in the milk of lactating mothers who smoke
What is the relationship between tobacco smoke and nicotine?
-nicotine "rides" on small particles of tar
-when smoke gets to lungs, nicotine is absorbed quickly and reaches the brain in about eight seconds after the smoke is inhaled
-american cigarettes cotnain about 9 mg of nicotine, but because much of the nicotine is burned off, a smoker gets about 1 mg of nicotine in every cigarette
-reaches the central nervous system in about 3-5 minutes when chewed
What are the effects of nicotine on the nervous system?
-may cause nausea and vomiting in the early stages of smoking
-increases psychomotor activity and cognitive function
-increases release of adrneal catecholamines and antidiuretic hormone (ADH)
-increases blood pressure and heart rate
-increases tone and secretions of the GI tract
-faster respiration
-cnstriction of arteries
-cna be stimulating or relaxing based on dosage and the person's mood
-acts on central and peripheral nervous system
What are adverse effects of nicotine?
-contributes to cancer (lungs, oral cavity, bladder and pancreas, obstructive lung disease, coronary artery disease and peripheral vascular disease
-poisoning occurs from exposure to insecticides cotnainign nicotine, or in children by accidental ingestion of tobacco products
-death may result within afew minutes from respiratory failure.
-for therapy, vomiting or gastric lavage (followed by activated charcoal)
What is the tolerance in nicotine?
-developes rapidly
-primarily cellular, some metabolic
What is the dependence of nicotine?
-produces strong psychologic dependence
-activates the "brain reward system" (increased activity of dopamine in the nucleus accumbens)
-withdrawlal-like symptoms indicative of physical dependence occurs within 24 hrs and persists for weeks or months
-dizziness, tremor, increased blood pressure, drug craving, irritability, anxiety, restlessness, difficulty in concentration, drowsiness, headache, sleep distrubances, increased appetite, GI complaints, nausea, and vomiting may occur
What are the various medications and replacement therapies for nicotine dependence? How does overdsose occur?
-Nicotine polacrilex
-transdermal patch
-nasal spray
-cna casue overdose if person also smokes cigarettes
What is nicotine polacrilex as replacement therapy for nicotine? trasdermal patch? nasal spray? problems with each?
-a nicotine resin contained ina chewing gum and has therpeutic value for diminishing withdrawal symptoms with behavioral midification to overcome psychologic dependence
-has objectional tase and may casue stomach discomfort, mouth sores, and dyspepsia
-patch can cause local skin irritation
-nasal spray can casue nasal irritations and irirtatons in nmouth and throat if used as inhaler
What is the theory for why long-term exposure to cigarettes cause dependence and addiction?
-limbic pathways that use dopamine are affected
What are common withdrawal symptoms of nicotine?
-anxiety, depression, headaches, and fatigue
What is the dopamine reward pathway?
-drugs usually increase dopamine so interesty is in the dopaminergic system
-increased levels of dopamine lead to rewarding effects or positive reinforcement of drugs of misuse
What are some available pharacologic therapies with some reported success that affects acetylcholine and cholinoergic receptor metabolism?
-Clonidine (alpha adrenoreceptor agonist)
-nortripyline (Antidepressant)
-bupropion (antidepressant)
-selegilline (MAO-B inhibitor)
-vareicline (partial nicotine receptor agonists)
WHat are nicotinic receptor blockers?
-include separate groups of drugs that selectivly block ganglia and the neuromuscular junction in skeletal muscle
-ganglion blockers are rarely used but neuromuscular blockers are very important in modern anesthesiology
What are avaiiable ganglionic blockers of nicotinic receptors? How are they administered? Excreted?
-trimethaphan and mecamylamine
-competitive antagonists
-trimethaphan has positive charge and is given intraveonously and acts peripherally, excreted by kidney
-mecaamylamine is given orally and does not cross the blood-brain barrier, excreted more slowly by the kidney
How do ganglionic blockers of nicotinic receptors work?
-have little or no effect at neuromuscular junction
-block both sypathetic and parasympathetic ganglia and therefore have widespread autnomic actions
-work by interfering with the postsynaptic action of acetylcholine
What medical uses are ganglionic blockers of nicotinic receptors for?
-primary use is for hypertension
-for intial control of blood pressur ein patients with acute dissecting aortic aneurism
-rarly used due to very poorly tolerated autonomic toxicities
What are the properties of atropine as a cholinoreceptor blocking agent?
-competitive antagonists
-action on muscarinic recptors
-prototype
How have cholinoreceptor drugs changed from atropine used as an agent?
-agents have become more depolarizing
-actions on more nicotinic receptors
-and act more on neurmuscualr junctions
Whata drugs are cholinoreceptor blockign agents?
-atropine
-scopolamine
-propantheline
-trimethaphan
-cisatracurium
-succinylcholine
WHart are the two groups of drugs that affect skeletal muscle function and where do they primarily act?
-neuromuscular blockers: interfere with the transmission at the neuromuscular end plate, lack CNS Activity, peripherally acting
-spasmolytics: centrally acting
What are the general properties of tubocuranne as a skeletal muscle relaxant?
-long action
-non-depolarizing
-neuromuscular blocker
-skeletal muscle relaxant
What are the general properties of mivacurium as a skeletal muscle relaxant?
-short acting
-non-depolarizing
-neuromuscualr blocker
-skeletal muscle relaxant
What are the general properties of succinylcholine as a skeletal muscle relaxant?
-depolarizing
-neuromuscular blocker
What are the general properties of baclofen, diazepam, and tizanidine as skeletal muscle blockers?
-CNS acting
-chronic use
-spasmolytics
What are the general properties of dantrolene as a skeletal muscle blocker'?
-muscle action
-chronic use
-spasmolytics
What are the general properties of of cyclobenzaprine as a muscle relaxant?
-actue use
-spasmolytic
What are the prototypes for non-depolarizing neuromuscular blockers?
-tubocurarine
-vescuronium
-atracurium
What are prototypes for depolarizing neuromuscular blockers?
-succinylcholine
What are prototypes for spasmolytic neuromusucalr blockers?
-diazepam, baclofen, cyclobenzaprine, dantrolene, tizanidine, and botulinum toxin
Where do neuromusucular drugs bind?
-bind to all nicotinic receptors (at neuromuscualr junction and autonomic ganglia) and some actually bind muscarinic receptors to a small extent.
WHat do neuromusucal blockers induce during their mechanism of action?
-block skeltal muscle transmission, inducing paralysis
WHat is the mode of action of non depolarizing blocking agents of neuromusuclar blockers?
-majority of the clinically-relevant neuromuscualar blockers
-act by blocking the binding of ACh to its receptors, and in some cases, they also directly block the ionotropic activity of the ACh receptors
What is the mode of action of depolarizing blockign agents of neuromuscualar blockers?
-agents act by depolarizing the plasma membrane of the skeltal muscle fiber
-persistant depolarization makes the muscle fiber resistant to further stimulation by ACh (succinylcholine)
How do neuromusucular blockers work?
-act as competitive antagonists against6 acetylcholine at the site of postsynaptic acetylcholine receptors
-depolarizing blocker binds to the receptor and opens the ion channel, resulting in depolarization of the end plate
-non-depoalrizing blocker binds to the receptor but does not open the channel
-effects of these drugs can be reversed by adminstration of a cholinesterase inhibitor
What is neuromuscular transmission at the end plate?
-arrival of electrical impulse at the motor nerve terminal
-influx of calcium and release of acetylcholine
-acetylcholine diffuses across the synaptic cleft to the nicotinic receptor located on the motor end plate
-casues influx of calcium into muscle cell
At what locations can skeletal muscle relaxation and paralysis can occur from interruption of function at several sites along the pathway from the CNS?
-myelinaed somatic nerves
-unmyelinated motor nerve terminals
-nicotinic acetylcholine terminals
-motor end plate
-muscle membrane
-intracellular contractile apparatus
What are the modes of action of neuromuscular blockers?
-competitive pharmcologic antagonism of ACh presynaptically via inhibition of ACh synthesis or release
-and prolonged ACh-like agonist action at the postsynaptically receptor
What is the mode of action of tubocurarine as a non-depolarizing neuromuscular blocking agent? Toxicities?
-prototype
-competitive antagonism prevents depolarization by ACh at the skeletal muscle and end plate
-respiratory and autonomic effects
What is succinylcholine (agonist) as a depolarizing neuromuscular blocking agent? MODe of action? Toxicities?
-agonist
-has short action (3-6 min) fiollowing a single dose due to rapid metabolism via plasma cholinesterases
-some patients experiance prolonged duration of action due to enzymatic deficency (genotypic variation)
-end plate is depolarized causing brief defasciculations followed by flaccid paralysis (phase 1), which is not reversed by AChE inhibitors
-muscle end plate repoalrizes (phase II) with continuous infusion but remains blocked
-toxicities include GI distress, emesis, muscle pain, and hyperkalemia
What is the role of antagonistic non-depolarizing neuromuscular blockers? toxicities?
-prevent normal depoalrization of the end plate
-can be surmounted by increasing acetylcholine concentration in the synapse (Cholinoetserase inhibitors)
-competitive neuromuscular blockign drugs are used to produce skeletal muscle relaxation, which is used for surgical procedures of medium and long duration
-toxicities include hypotension and excessive neuromuscular vlock from requiring prolonged respiratory support
WHAT is the major use of succinylcholine clinically? toxicities?
-facilitate intubation and other procedures of very shrot duration
-increases abdominal pressure, arrythmias, and postoperative muscle pain
What is the difference between non-depolarizing and depolarizing drugs in autonomic effects on neuromuscular junction?
-non-depolarizing drugs have no effect on autonomic ganglia, except for tubocurarine (weak blocker)
-depolarizing drugs stimulate autonomic ganglia
-non-depolarizing drugs have from no effect to moderate ability to release histimine
-depolarizing drugs have slight ability to release histimine
-avoid pancuronium with cardiac patients since it's a moderate blocker of muscarinic receptors
What are the 2 types of deriviatives of neuromusuclar drugs?
-isoquinoline
-steroid
What drugs can be used for revrsal of non-depolarizing neuromuscular blockade? How do they work?
-neostigmine and pyridostigmine
-increase availabilty of acetylcholine at the motor end plate mainly by inhibition of acetylcholinesterase
-also increase neurotranmitter from the emotor nerve channel
-edorphonium inhibits acetylcholinesterase only
What is the main differance between depolarizing and non-depolarizing agents?
-non-depolarizing blockers are reversed by acetylcholinestrase inhibitor drugs. Since they are competitive antagonists at the ACh receptor, they cna also be reversed by increasesin ACh
-depolarizing blockers take longer to reverse due to their closly related propeertiees to acetylcholine. patient will experiance fasciculations before paralysis occurs and post-operative pain
WHAT is the major use of succinylcholine clinically? toxicities?
-facilitate intubation and other procedures of very shrot duration
-increases abdominal pressure, arrythmias, and postoperative muscle pain
What is the difference between non-depolarizing and depolarizing drugs in autonomic effects on neuromuscular junction?
-non-depolarizing drugs have no effect on autonomic ganglia, except for tubocurarine (weak blocker)
-depolarizing drugs stimulate autonomic ganglia
-non-depolarizing drugs have from no effect to moderate ability to release histimine
-depolarizing drugs have slight ability to release histimine
-avoid pancuronium with cardiac patients since it's a moderate blocker of muscarinic receptors
What are the 2 types of deriviatives of neuromusuclar drugs?
-isoquinoline
-steroid
What drugs can be used for revrsal of non-depolarizing neuromuscular blockade? How do they work?
-neostigmine and pyridostigmine
-increase availabilty of acetylcholine at the motor end plate mainly by inhibition of acetylcholinesterase
-also increase neurotranmitter from the emotor nerve channel
-edorphonium inhibits acetylcholinesterase only
What is the main differance between depolarizing and non-depolarizing agents?
-non-depolarizing blockers are reversed by acetylcholinestrase inhibitor drugs. Since they are competitive antagonists at the ACh receptor, they cna also be reversed by increasesin ACh
-depolarizing blockers take longer to reverse due to their closly related propeertiees to acetylcholine. patient will experiance fasciculations before paralysis occurs and post-operative pain
Why are muscular antagonists often administered at the same time as cholinesterase inhibitor?
-only want increase in ACh at neuromusucular junction which is nicotinic but cholinesterase inhibitor works everywhere
-it will decrease secretions
-such as atropine and or glycopyrolate
What is the mechanism of action diazepam as a neuromusuclar blocker?
-benzodiazepine that facilitates GABA mediated presynaptic inhibiton
-action in reducing spasticity is partly mediated in the spinal cord
-produces sedation at doses needed to reduce muscle tone (side effect)
-has an addicitive effect
What is the mechanism of action of baclofen as a neuromusuclar blocker? How is it metabolized? Eliminated? Side effects? administration?
-P-chlorophnenyl GABA
-was designed to be an orally active GABA-mimetic agent
-activates GABA(beta)-receptors in the spinal cord
-activation of receptors causes hyperpolarization (increasess potassium conductance)
-causes presynaptic inhibiton and reduces calcium influx
-can cross BBB
-acts both pre and postsynaptically to inhibit spinal reflexes
-metabolized by the liver and eliminated by renal excretion
-can cause ssedation, fatigue, dizziness, lowering of the seizure threshold, and cognitive dysfunction
-administered intrathecally or P.O
What is the mechanism of action of tizanidine as a neuromuscular blocker? metabolism? elimination? side effects?
-cogener of clonidine
-acts through agaonist effects on the alpha-2 adrenergic system at both the spinal and supraspinal levels to reduce spasm
-extensivly metabolized in the liver to inactivee compounds that are excreted by kidneys
-short-acting drug for the management of spasticity
-side effects include sedation, dizziness, hypotension, nausea, and dry mouth
What is the mechanism of action of cyclobenzaprine as a neuromusular blocker?
-acts centrally to decrease an acute spasm due to muscle injury, but is ineffective in cerebral palsy or spinal cord injury
-closely related to the tricyclic antidepressants (amitriptyline and imipramine)
What is the clinical use of dantrolene as a neuromuscular blocker? side effects? mechanism of action?
-hydantoin derivative
-site of action is the peripheral muscle rather than the central neurotransmitter systems
-dantrolene is the intial medication of choice for spasticity of cerebral origin because it acts at the level of the pereipheral muscle with minimal untoward central effects
-livere abnormalities can be seen with this agent thus liver enzymes must be monitored
-side effects also include weakness, nausea, diarrhea, and paresthesias
-inhibits release of calcium from sarcoplasmic reticulum durign muscle contraction
-onyl direct acting muscle releaxant
-affects excitation-contraction coupling mechanissm of skeletal muscle by depressing the release of ionic calcium from the sarcoplasmic reticulum to the myoplasma
What is botulinum toxin used for as a neuromuscular blocker? How does it work?
-used for denervation
-botox and myobloc available as drugs
-toxin exerts its effect by inhibiting the release of acetylcholine into the neuromuscular junction
-cost is major concern in usre, can cost thousands of dollars and is only temporary
What are common muscle relaxants used to relax striated muscles? What are they used for clinically?
-methocarbamol, carisprodol, chloroxazone, gabapentin, metaxalone, and orphenadrine
-relieef of spasticity in neuromuscular diseases such as multiple sclerosis as well as spinal injury and stroke
-may be also used for pain relief in minor strain injuries and control of the muscle symptomss of tetanus
-used primarily as an adjunct for rest in management of acute muscle spasms associated with sprains, to physical therapy in rehab following stroke, spinal cord injury, or othere musculoskeletal conditions
What is malignant hyperthermia? Symptoms? treatment?
-an inheritied disease that causes a rapid rise in body temperature (fever) and severe muscle contractions when the affected person receives general anesthesia
-often noted for the first time after patient is given anesthesia during surgical procedure
-rapid rise in temp., muscle rigidity and stiffness, dark brown urine mussclee ache without obvious excercise
-treat with acetaminophen and a cooling blanket, also with dantrolene to reduce death
-fluids given by IV and mouth as well as certain medications are essential for maintaining kidney function durign an acute episode
-succinylcholine sometmes asociated
What is histimine?
-small molecule produced by decarboxylation of the amino acid histidine
-catalyzed by the enzyme L-histidine decarboxylase ina reaction that requires pyridoxal phosphate
Where is histamine synthesized? What are mast cells?
-located in many tissues including the brain
-stored and found in highest amounts in mast cells and basophils
-mast cells are found in the respiratory tract, skin (hands and feet), GI tract, and blood vessels
-store histamine ina granule bound in a complex with heparin, adrenosine, ATP and acidic protein
How is histimine released?
-energy and calcium dependent degranulation reaction
-energy and calcium independent release (displacement)
How does energy and calcium dependeent degranulation reaction work in releasing histamine?
- induced by immunoglobulin E (IgE) fixation to mast cells (sensitization) and subsequent exposure to a specific antigen
-complement activation (mediated by immunoglobulin G or immunoglobulin M) may also induce deegranulation
How does energy and calcium independent release (displacement) work in releasing histamine?
-displacement is induced by drugs such as morphine, tubocurarine, guanethidine, and amine antibiotics
-in addition, mast cell damage caused by noxious agents such as veneom or mechanical trauma can release histamine
What drugs have a mechanism of action at H1 histamine receptors?
-benadryl and loradine
What drugs have a mechanism of action at H2 histamine receptors?
-ranitidine
Where are histamine H1 receptors found? What occurs when activated
-found in the brain, heart, bronchi, gastrointestinal tract, vascular smooth muscles, and leukocytes
-membrane bound and couples to G-proteins (Gq-H1)
-activation causs increase in phospholipase A2 and D activity
-increase in diacylglycerol and intracellular calcium and increased cGMP
-increases wakefullness in brain
-causes vasodilation and increae in permeability in blood vessels
-stimulates nonvacular smooth muscles
Where are histamine H2 receptors found? What occurs when activated?
-membrane bound, found in thee brain,, heart, vascular smooth muscles, leukocytes and parietal cells
-increases cAMP production
-increases gastric acid production in stomach
-causes vasodilation in blood vessels
-relaxes smooth muscles
Where are histamine H3 receptors located? What occurs when activated?
-found in central nervouss system and peripheral nervous system at presynaptic nerve
-membrane bounc and coupled to G-proteins
-activation increases intracellular calcium and decreases cAMP
-decreases histamine release in nerve cells
-modulates release of dopamine, acetylcholine, serotonin, and norepinephrine
-decreases ACh release from vagus nerve
Where are histamine H4 receptors located? What occurs when activated?
-H4-receptors are found on hematopoietic cells and in the spleen, thymus, and colon
-increases chemotaxis of mast cells and leukocytes towards sites of inflammation
-inhibit production of cAMP and increasse intracellular calcium
What are the histamine agonists?
-betazole: 10x act. in H2 receptors that H1
-impromidine: 10000x H2 than H1
-methimepip: H3 agonist
What are the uses of histamine agonists? adverse effects?
-primarily diagnostic
-used in allergy testing assess histamine sensitivity ad in the test of gastric secretory function
-adverse effects include flushing, burning sensation, hypotension, tachycardia, and bronchoconstriction
What are first generation antagonists of histimine H1 receptors?
-alkylamins
-ethanolamines
-ethyleenediamines
-piperazines
-phenothiazines
-methylpiperidines
What are alkylamines as first generation antagonists of histimine H1 receptors?
-include chlorpheniramine and brompheniramine
-produce slight sedation
-antihistamines most frequently used in US
What are ethanolamines ass first generation antagonists of histamine H1 receptors?
-include diphenhydramine, doxylamine, and clemastine
-dimenhydrinate is a combo of diphendryamine and 8-chlorotheophylline
-producee marked sedation
-doxylamine marketed only as sleeping aid
-act as antiemetics
What are ethylenediamines as first generation histamine H1 receptor antagonists?
-include pyrilamine and antazoline
produce moderate sedation and can cause gastrointestinal upset
What are piperazines as firsst generation histamine H1 receptor antagonists?
-include mecliazine and cyclizine
-produce marked adveerse gastrointestinal effects and moderate sedation
-have antiemetic and antivertigo activities
What are phenothiazines as first generation histimine H1 receptor antagonists?
-include promethazine (nausea) and cyproheptadine (periactin)
-produce marked sedation
-have antiemetic activity
-also weak alpha-adrenoceptor antagonists
What are methylpiperidines as first generation histimine H1 receptor antagonists?
-include cyproheptadine
-have antihistamine, anticholinergic and antiserotonin activities
-will help increase appetites in pediatric patients
What are second generation agents in histamine H1 receptor antagonists?
-loratadine/deslortadine
-fexofenadine
-clemastine
-cetirizine
What are piperidines of second-generation Histamine H1 antagonists?
-includes loratadine and desloratadine (clarinex)and fexofenadinee
-has poor CNS penetration, little or no choliergic activity and greatly reduced sedation
-desloratadine is active metabolite of loratadine and has 15x more affinity for H1 receptor
-fexofenadine (allegra) is structually different but sedative activity is low but dose dependent
What are ethanolamines as a second-generation histamine H1 antagonist?
-includes clemastine
-much longer duration than dimenhydramine and some antiemetic activity
What are alkylamines as a second-generation histamine H1 antagonist?
-includes acrivastine and cetrizine (zyrtec)
-not associated with cardiac arrests or abnormalities
-poor penetrating of CNS
-less sedating and ineffective for motion sickness or antiemesis
What is the difference between 1st generation and second generation histamine H1 receptor antagonists?
-secondaries have marginal to no anticholirgic effect and has little to no sedative effect compared to 1st generation
What are the pharmacologic properties of histamine H1 receptor antagonists?
-well absorbed after oral administration
-effects seen within 30 minutes with 3-8 hrs with 1st gen. and 3-24 hours for second gen.
-lipid soluble
-1st gen can cross BBB, reduced in 2nd
-metabolized in liveer and induce microsomal enzymes
What are pharmacologic actions of histamine H1 receptor antagonists?
-ethanolamines, phenothiazines, and ehthylenediamines have muscarinic-cholinergic antagonist activity
-are effective local anesthetics due to blockade of sodium channels ine excitable tissues (dimenhydrinate and promethazine are potent)
-relax histamine-induced contraction of bronchial smooth muscle
-block vasodilator action of histamine
-inhibit histamine-induced increases in capillary permeability
-block mucus secretion and sensory nerve stimulation
-1st gen cause CNS depression but sometimes stimulation in children and some adults
What are therapeutic uses of histamine H1 receptor antagonists? Specific drug uses?
-treatment of allergic rhinitis and conjunctivitis
-clemastine approved for use with rhinorrhea
-used to treat common cold bases on anti-cholinergic properites
-diphenhydramine also has antitussive effect
-can treat urticaria (rash) and atopic dermatitis (hives)
-doxylamine and diphenhydramine used as sedatives/ sleep-aids
-also prevents motion sickness and suppresses appetite
What are adverse effects of histamine H1 receptor antagonists?
-produce sedation (synerstic with alcohol and othere depressants), dizziness, and loss of appetite
-can cause GI upset, nausea and constipation or diarrhea
-producee anticholinergic effects (dry mouth, blurred vision, and urine retention)
-astemizole and terfenadine (2nd gen) were taken off markeet due to Q-T prolongation and ventricular tachycardias
What are the histamine H2 receptor antagonists?
-includes cimetidine, ranitidine, famotidine, and nizatidine
-competitive antagonists at H2 receptor at gastric parietal cell
-used in treatment of gastrointestinal disorderss including heartburn and acid-induced indigestion
-promotee healing of gastric and duodenal ulcers and used to treat hypersecretory states such as zollinger-ellison syndrome
What is cimetidine as a histamine h2 receptor antagonist? adverse effecrs?
-usually given4 timess daily
-reduces acid secretion by approximatly 70% for 4-5 hours
-associates witha low incidence of mild GI upset, headache, and mental confusion esp. in the elderly
-can cause thrombocytopenia
-acts as a androgen-rceptor antagonist and can inducee dynecomastia adn impotence
-a competitve inhibitor of CYP 450 mixed-function oxidase system and can increase half-life of drugs
-decreasses aborption of ketoconazole
-decrease bioavailbilty by antacids
What is ranitidine as a histamine H2 receptor antagonist?
-5 to 10 times more potent than cimetidine and requires a less frequent dosing schedule, twice daily
-does not bind to the androgen receptor, it's effects on drug metabolism are less than those of cimetidine
-has low incidence of headache and cutaneous rash
What is famotidine as a histamine H2 receptor antagonist?
-appoximatly twice as potent as ranitidine and has a longer duration of action, given one daily
-produces adverse effects sismilar to those of ranitidine but does not bind to androgen receptor
-frequently used in its intravenous form for stress-relates gastritis
-mental status changes may occur esp in the elderly
Why does benedryl relieve itchy eyes and runny nose?
-shifts H1 receptor to inactivated site
Why doesn't loratadine cause drowsiness?
-ionized at physical pH and doesn't cross BBB
Cometidine is a selective H2 receptor antagonists used to inhbit histamine induced gastric acid secretion. What's the potential adverse effect?
-altered drug metabolism of CYP 450
What are the chromones? What are they used for? Adverse effects?
-include cromolyn and nedocromil sodium
-poorly absorbed salts that are administered by inhalation
-inhibit release of histamine and other autocoids from the mast cell
-each are used prophylactically in the treatment of asthma and do not reverse bronchospasm
-adverse effects include sore throat and dry mouth
-nedkcromil sodium appears to be more effective in reducing bronchospasm caused by exercise or cold air
How is serotonin synthesized? distribution? Storage?
-synthesized from amino acid 1-tryptophan by hydroxylation and decarboxylation
-apporximatly 90% of serotonin is found in the enterochromaffin cells of the gastrointestinal tract
-much of the remaining 10% is found in the platelets
-smaller amounts ar found in the othr tisues, including the brain
-platelets acquire serotonin from the circulation during passage through the intestine by a specific and highly active uptake mechanisms
-stored in granules as a complex with ATP
-major breakdown product is 5-hydroxyindoleacetic acid (5-HIAA)
What is the mechanism of action of serotonin type 1 receptors?
-coupled to an inhibiton in cAMP, stimulation contracts arterial smooth muscle, especially in carotid and cranial circulation
-at presynaptic sites, neuronal serotonin release is inhibited
What is the mechanism of action of serotonin type 2 receptors?
-coupled to an increase in phospholipase C activity
-stimulation causes contraction of vascular and intestinal smooth muscle and increases microciculation and vascular permeability
-stimulation of this receptor on platelet membranes causes platelet aggregation
-in the CNS, this receptor mediates hallucinogenic effects
What is the mechanism of action of serotonin type 3 receptors?
-coupled to a lignad-gated ion channel
-stimulation of this recpetor in the area postrema causes nausea and vomiting
-stimulation on peripheral sensory neurons causes pain
What is the mechanis m of action of serontonin type 4 receptors?
-increase cAMP
-in gastrointestinal tract, receptors mediate an increase in secretion and peristalsis
What is the mechanism of action serotonin type 5 receptors?
-expressed in the brain and are coupled to a decrease in cAMP
What is the mechanism of action of serotonin type 6 and 7 receptors?
-cloned and appear to be coupled to an increase in cAMP biosynthesis
-type 6 receptors appear to be involved in anxiety and cognitive function
-type 7 receptors are involved in thermoregulation, learning memory, and mood
What is buspirone as a serotonin agonist?
-relativly specific to type 1A receptor agonists
-useful for the management of anxiety disorders
What are the triptans as serotonin agonists? mechanism of action? specific drug effects and adverse effects?
-includes sumatriptan, rizatriptan, eletriptan, zolmitriptan, almotriptan, frovatriptan, and naratriptan
-class of type 1B, 1D, and 1F agonists
-!b agonist activity results in vasoconstriction of dilated cerebral vessels
-1D receptors inhibit vasodilation and inflammation of the meninges and pain transmission and the release of vasodilator substances such as calcitonin gene-related peptide (CGRP) in trigeminal neurons
-major use is the treatment of acute migraine
-about 50%-80% of patients report relief from pain within 2 hours
-may be useful to treat cluster headaches
-sumatriptan has 1B activity in coronary spasms and chest pain is an adverse effect of this
-adverse effects also include flushing, hypertension, nausea, and vomiting
-may also cause irritable bowel syndrome
-all available as oral agents
-sumatriptan and zolmitriptan also available as nasal sprays
-sumatriptan also available for subcutaneous injection
What is trazodone as a serontonin agonist?
-parent drug is metabolized to m-chlorophenylpiperazine, an activator of serotonin recepto type 1B and type 2 receptors
-also blocks the reuptake of serotonin
-used to treat depression
What is tegaserod and cisapride as serotonin agonists?
-tegaserod is a specific type 4 agonist used to treat irritable bowel syndrome and constipation
-tegaserod increases the release of acetylcholine in the gut and increase motility (speeds gastric emptying and reduces gastrointestinal sensitivity)
-valube in conditions by inadequate peristalsis
-major toxicity of tegaserod is diarrhea
-cisapride has the same mechansism of action as tegaserod but is available only for compassionate use because of toxicity (torsades de pointe arrythmia)
How is cyproheptadine as a serotonin antagonist?
-a potent histamine antagonist and also blocks serotonin type 1 and 2 receptors
-used most frequently to limit diarrhea and intestinal spasms produced by serotonin-secreting carcinoid tumors and postgastrectomy dumping syndrome
-produces sedation and anticholinergic actions
What is ondasetron, granisetron, dolasetron, and palonosetron as serotonin antagonists?
-highly effective in treating the nausea and vomiting associated with chemotherapy and radiation therapy and have become the primary agents used in this circumstance
-administered intravenously or orally
-intravenous administration 20 min prior to anticancer treatment is the most effective
What is risperidone as a serotonin antagonist?
-antagonist for type 2A-2C and dopamine (D2) receptors
-atypical antischizophrenic agent with reduced extrapyramidal activity
What is clozapine as a serotonin antagonist?
-mainly blocks dopamine D1 and D4 receptors
-also blocks serotonin type2A and 2C receptors and has mixed muscarinic antagonist/agonist activities
-a atypical antipsychotic with reduced extrapyrimidal effects
What is fluoxetine and other SSRI's effects on serotonin receptors?
-actions of this class of antidepressants are presumed to be due to decreased serotonin uptake into neurons
What is the structure of ergot alkaloids? What are the 2 classes?
-include a variety of compounds sahring the tetracyclic ergoline nucleus that are produced by the fungus claviceps pupurea
-these agents have strong structural similarity to the neurotransmitters norepinephrine, dopamine, and serotonin
-includes amine ergot alkaloids
-includes peptide ergot alkaloids
What are the amine ergot alkaloids?
-include ergonovine, methysergide, lysergic acid and LSD, and methylergonovine
What are the peptide ergot alkaloids?
-includes ergotamine, dihydroerotamine, ergocristine, ergonovine, bromocriptine, and pergolide
What is the mechanism of action of ergot alkaloids?
-display varyign degrees of agonist or antagonist activity in three receptor sites:
-alpha-adrenoceptors, dopamine receptors, and serotonin receptors
-pharmacologic application is determined by relative affinity and efficiacy of the individual agents for these receptor systems
-many agents exhibit partial agonist acitivites and thus can cause either stimulatory or inhibitory effects
What are the pharmacologic properties of ergot alkaloids?
-may be administered parenterally, rectally, sublingually, as inhalents, or orally and vary widely in theri absorption
-amine alkaloids are slowly and relativly poorly abosrbed
-peptide alkaloids are completely absorbed
What ergot alkaloids are used therapeutically for postpartem hemorrhage?
-ergonovine and methylergonovine
-most uterine-selective agents, cause prolonged and forceful contraction of uterine smooth muscles
-should not be used to induce labor
What ergot alakloids are used therapeutically for acute migraines? How does it work?
-ergotamine
-for acute migraine attacks
-major effect is cerebral vasoconstricition, reverses rebound vasodilation that is the probable cause of pain
-acts as a central serotonin receptor and alpha-adrenoceptor agonist
-most effective if administered early
-frequently combined with caffeiene which increases absorption
-produces lond-lasting and cumulative effects
-weekly dosage must be strictly limited
What ergot alkaloids is used for prophylaxis of migraine? How does it work?
-methysergide
-acts as a serotonin-receptor antagonist and it inhibits initial vasoconstriction in the early stages of a migraine
-effective in 60% of aptients for the prophylaxis of migraine
-it is effective after the onset of an attack
-cumulative toxicity of methysergide requires drug-free periods 3-4 weeks every 6 months
-also propanolol and other beta-adrenergic antagonist are also effective aganets for the prophylaxis of migraine
What is used therapeutically for hyperprolactinemia? How does it work?
-Bromocriptine mesylate and pergolide
-dopaminergic agonists and cause specific inhibition of prolactin secretion (elevated prolactin secretion can induce infertility and amenorrhea in women and galactorrhea in men and women)
-these agents are used to treat prolactin-secreting tumors of the pituitary to counteract central dopaminergic antagonists and to suppress normal lactation
-used as adjunct agents for levodopa in the management of parkinson's disease
-these agents reducre growth hormone secretion
WHat drug is used therapuetically for diagnosis of variant angina?
-ergonovine produces a diagnostic vasoconstriction of coronary arteries that are prone to vasospasm, as in variant angina
-ergonovine is administered intravenously during angiography
What are various drug adverse effects of ergot alkaloids?
-most serious adverse effect is prolonged vasospasm which can elad to gangrene and most frequently caused by ergotamine and ergonovine
-most common side effec tis gastrointestinal disturbance (nausea/diarrhea)
-methysergide toxicity includes retroperitoneal fibroplasia and cronoary and endocardial fribrosis, as well as CNS stimulation and hallucinations
Which drug should not be given within 24 hrs of an ergot-containing or ergot-type drug b/c of vasospastic reactions?
-sumatriptan
What is the most useful drug fir reversing severe ergot-induced vasospasms?
-nitroprusside
What drug do you treat a 54 y/o male tobacco user with cancer in the larynx?
-ondansteron
Risperidone works primarily through inhibiton of receptors for?
-histamine
A patient has warfarin toxicity and has started an histimine type 2 blocker. What drug was he taking?
-cimetidine
What are voltage-gated ion channels?
-transmembrane ion channels regulated by changes in membrane potential
What are lignad-gated ion channels?
-transmembrane ion channels that re regulated by interactions between neurotransmitters and their receptors (also called ionotropic receptors)
What are metabotropic receptors?
-G protein-couple drecpetors that respond to neurotransmitrters either by a dire actuion of G proteins on ion channels or by G protein enzyme activation that leads to formation of diffusible second messengers
What are the receptors for glutamic acid? Drug actions?
-excitatory
-antagonized by ketamine, phencyclidine, and newer antiepiletics
What are the receptors for GABA? Drug actions?
-inhibitory
-sedative-hypnotics and antiepiletic drugs facilitate GABAa receptors
-baclofen activates GABAb receptors
What are the eceptors for acetylcholine? Drug actions?
-M1: excitatory
-M2:inhibitory
-N: excitatory
-M blockers antagonize both M1 and M2 receptors
-AchE inhibitors facilitate ACh
What are receptors of dopamine? drug actions?
-inhibitory
-antagonized by older antipsychotics
-activated by anti-parkinsonian drugs, amphetamines, and cocaine
How are excitatory postsynaptic potentials initiated?
-when excitatory neurotransmitters activates sodium or calcium channels
How are inhibitory postsynaptic potentials initiated?
-inhibitory neurotransmitter opens chlorine channels and the cell membrane becomes hyperpolarized
-makes it more difficult for neurons to become activated
What neurotransmitters exist in the CNS?
-5-hydroxytryptamine
-glutamate
-GABA
-dopamine
What are associated disorders with dopamine?
-parkinson's disease
-psychosis
-drug abuse
-depression
-hyperprolactinemia
What disorders are associated with acetylcholine?
-parkinson's disease
-alzheimer';s disease
-narcolepsy
What disorders are associated with serotonin?
-depression/suicide
-psychosis
-obsessive compulsive disorder
-anxiety
What disorder is associated with norepeinephrine?
-depression
-narcolepsy
What disorders are asaociated with GABA?
-anxiety
What disorders are associated with glutamate?
-seizures
Activation of metabotropuic receptors located presynaptically causes inhibiton by decreasing the influx of?
-calcium
What compound is most likely to function as a neurotranmitter in hierarchial systems?
-glutamate
What are hierarchial neuronal systems?
-pathways involved in sensory perception and motot control
-large myelinated fibers conduct action potentials over long distances and release glutamate
-major excitaotry neurotransmitters in these systems are aspartate and glutamate
-local circuit neurons have short axons and release GABA
-these systems also include numerous small inhibitory interneurons, which use GABA and glycine as transmitters
-drugs that affect hierarchial systems have major effects on the overall excitability of the CNS
What are diffuse neuronal systems?
-contain monoamine and peptide transmitters including amines (dopamine, serotonin, and norepinephrine), opiod peptides or peptides that exert actions on metabotropic receptors
-extensively branched, unmyelinated axons that conduct action potentials slowly and can innervate different regions of the CNS functions such as slep and waking, attntion, appetitee, and emotion
What is acetylcholine in the CNS?
-5% of brain neurons have receptors for ACh
-most CNS responses to ACh are mediated by G-protein-coupled muscarinic M1 receptors that lead to slow excitation when activated
-the ionic mechanism of slow excitation involves a decrease in memrane permeability to potassium
-of the nicotinic receptors present in the CNS (less common than muscarinic receptors)
, those on the Renshaw cells activated by motor axon collaterals in the spinal cord are best characterozed
-drug affecting the choliergic systems in the brain include the acetylcholine esterase inhibitors and the muscarinic blocking agents used in parkinsonism
What is dopamine in the CNS?
-exerts a sllow inhibitory action at synapses in specific neuronal systems commonly via G-protein-coupled activation of potassium channels (postsynaptic) or inactivation of calcium channels (presynaptic)
-D2 receptor is the main dopamine subtype in basal ganglia neurons and is widely distributed in the supraspinal level
-dopaminergic pathways include the nigrostriatal, mesolimbic, and tuberofundibular tracts
-drugs that block tyhe activity of dopaminergic pathways include the odler antipsychotics
-drugs that increase the brain dopaminergic activity include CNS stimulants and antiparkinsonism drugs
What is norepinephrine in CNS?
-noreadrenergic neuron cell bodies are mainly located in the brain stem and the lateral tegemental of the pons. these neurons fan out broadly to provide most regions of the CNS with diffuse noradrenergic input
-excitatory effects are produced by activation of alpha 1 and beta 1 receptors
-inhibitory effects are caused by activation of alpha 2 and beta 2 receptors
-CNS stimulents, monoamine oxidase inhibtors and tricyclic depressants are exampels of drugs that enhance the activity of noradrenergic pathways
What is serotonin in CNS?
--most serotonin pathways originate from cell bodies in the raphe or midline regions of the pons and the upper brain stem
-these pathway innervate most regions of the CNS
-multipole serotonin receptor subtypes have been identified and with the same potassium channel
-serotonin can cause excitation or inhibition of CNS neurons depending on the receptor subtype activated
-bothe xcitatory and inhibitory actions can occur on the same neutron if apporpriate receptors ar epresent
-most of thre agents used in the treatment of major depressive disorders affect serotonergic pathways
-the actions of some CNS stimulents and newer antipsychotic drugs also appear to be mediated via effects on serotonergic transmission
What isglutamic acid in the CNS?
-most neurons in the brain are excited by glutamic acid
-high concentrations of glutamic acid in synaptic vesciles arte achieved by the vesicular gklutamate transport (VGLUT)
-both iontropic and metabotropicreceptors have been characterized
-subtypes of glutamate receptors are N-methyl-D-aspartate (NMDA)
-appear to have a role in synaptic plasticity relatedto learnign adn memory
-0excessive activation of NMDA receptor after neuronal injury maybe responsible for cell death
-glutamate metbotropic receptor activation cna result in G protein-coupled activation ofphospholipase C or inhibition of adenylyl cyclase
What is GABA and glycine in the CNS?
-most neurons in the GABA is the primary neurotransmitter mediating IPSPs in neurons in the brain and is important in the spinal cord
-alpha-GABA receptor activation opens chloride ion channels
-Beta-GABA recpeotrs are coupled to G-proteins that either openj potassium channels orclose calcium channels
-fast IPSPs are blocked by alpha-GABA recpeotr anatagonists and slow IPSPs are blocked by beta-GABA receptor antagonists
-drugs thart influence alpha-GABA receptor systems include sedative/hypnotics and anticonvulsants
What are peptide transmitters in the CNS?
-best defined peptides are the opiodpeptides (beta-endorphin, met- and leuenkephalin and dynorphin)
-substance P is a mediator of slow EPSPs in neurons involved in nociceptive sensory pathways in the spinal cord and brain stem
-peptide transmitters differ from nonpeptidetransmitters in that:
-peptides are synthesized in the cell bodies and transported to the nerve ending via axonal trasnport
-no reuptake or specific enzyme mechanisms have been identified for terminating their actions
What are the different classes of antidepressants?
-MAO inhibitors
-tricyclic antidepressants
-heterocyclic antidepressants
-selective serotonin reuptake inhibitors
What si the amine hypothesis of mood?
-hypothesis that major depressive disorder result from a functionaldeficiency of norepinephrine or serotnon at synpases in the CNS
What are tricyclics as antidepressants?
-droup of strucurally-related drugs resemblind phenothiazines chemically
-block reuptake of both norepinephrine and serotonin
What are MAO inhibitors as antidepressants?
-drugs that inhibit monoamine oxidase type A, which metabolizes norepinephrine and serotonin, or monoamine oxidase B, whihc metavbolizes dopamine
What are selective serontonin reuptake inhibitors as antidepressants?
-a group of drugs that selectvily inhibit serotonin transporters of the nerve-ending membrane
Whart are heterocyclics as anti-depressants?
-drugs of varied chemical strucutures
-several have actions diferent from those tricyclic antidepressants or selective seotonin reuptake inhibitors
Whata re the prototype antidepressants of tricyclic drugs?
amitriptyline and imipramine
What are tricyclics as antidepressants?
-droup of strucurally-related drugs resemblind phenothiazines chemically
-block reuptake of both norepinephrine and serotonin
What are MAO inhibitors as antidepressants?
-drugs that inhibit monoamine oxidase type A, which metabolizes norepinephrine and serotonin, or monoamine oxidase B, whihc metavbolizes dopamine
What are selective serontonin reuptake inhibitors as antidepressants?
-a group of drugs that selectvily inhibit serotonin transporters of the nerve-ending membrane
Whart are heterocyclics as anti-depressants?
-drugs of varied chemical strucutures
-several have actions diferent from those tricyclic antidepressants or selective seotonin reuptake inhibitors
Whata re the prototype antidepressants of tricyclic drugs?
amitriptyline and imipramine
Whata re the prototype antidepressants of heterocyclic (second generation) drugs?
-amoxapine
-bupropion
-maprotiline
-trazodone
Whata re protoype antidepressantsof heterocyclics (thrid generation) drugs?
-duloxetin
-mirtazapine
-nefazodone
-venlafaxine
What are prototype antidepressants of selective serotonin reuptake inhibitors?
-fluoxetine
What are protoype antidepressants of MAO inhibitors?
-phenelzine
What is the mechanism of action of desiperamine and maprotiline as antidepressants?
-inhibiton of neuronealreuptake of norepinephrine and serotonin
-increases the synaptic
-activities of neurotransmitters
What is the mechanism of action of MAO inhibitors as antidepressants?
-inhibits monamien oxidase and increases the presynaptic stores of both norepinephrine and serotonin
-leads to increases neurotransmitter effects
What is the mechanism of action of mirtazapine as antidepressants? fluoxetin and trazadone as antidepressants?
-blockade of presynaptic alpha 2 autoreceptors
-prevents feedback inhibiton releaseof norepinephrine
What is the mechanism of action od
-inhibits the reuptake of serontonin
-increases synaptic acitivies of these neurotransmitters
What are tricyclic antidepressants? clinical uses?
-chemically related tophenotriazines
-includes imipramine.amitripytiline andclomipramine
-most are long-acting and often converted to acitvie metabolites
-for moderate to severe endogenous depression includign insomnia (amitriptyline) or poor appetite (trazodone)
-for panic disorders (clomitpramine)
-for neuropathic pain
-short term treatment of nocturnal enuresis in older children
What are adverse effects of tricyclic antidepressants?
-sedatuion
-postural hypotension
-dry mouth
-blurredvision
-constipation
-occasional mania and convulsions
-riskof ventricular dysrhythmias
-overdose can lead toconfusion and mania
-liableto interact with other drugs
What are selective serotonin reuptake inhibitors (SSRIs) as antidepressants? Adverse effects?
-includes fluoxetine,flucoxamine, paroxetine, sertraline, and citalopram and venlafoxine
-acute toxicity is less than that of MAOI or TCAs
-most commonly prescibed antidepressants
-side effects include nausea, insomnia and sexual dysfunction
-has dangerous serotonin reaction if given with MAOI
-venlafaxine is lisceneced to treat generalized anxiety disorder
What are monoamine oxidase inhibitors as antidepressants?
-includes phenelzine and tranylcypromine
-unsleective and produce extremely long-lasting inhibition of the enzyme
-noradrenaline-selective (reboxetine) or non-selective (venlafaxime, duloxetine) inhibitors
Whata re the differnces in thrid-generation heterocyclics as antidepressants?
-duloxetine does NE and serotonin reuptake block
-mirtazapine conducts sedation only
-nefazodone conducts sedation and muscarinic receptor block
-venlafaxine conducts norepinephrine and serotonin reuptake block
What are the differences in 2nd-generation heterocyclics as antidepressants?
-amoxapine conducts sedation,muscarinic recpetor blokc, NE and serotonin reuptake block
-bupropion ahs no effects
-maprotiline has sedative effects, and muscarinic receptor block with norepinephrine reuptake block
-trazodone coducts sedation and some serotoninj reuptake block
What is fluoxetine drug itneractions and effects as an antidepressant?
-lithium, tricyclics, and warfarin
-casues increased blood levels of the second drug
-doses may needto be decreased
What are the drug interactions with fluvoxamine as an antidepressant?
-alprazolam, theophylline, tricyclics, and warfarin
-increased blood levelsof the second drug
-doses may need to be decreased
Whata re drug interactions with monoamine oxidase inhibitors as antidepressants?
-sympathomimetics, tyramine, and SSRIs
-casues hyeprtensive crisis and serotonin syndrome
What are drug interactions with nefazodoneas a antidepressant?
-alprazolam and triazolam
-causes increased blood levels of thre second drug
-may needto be decreased
What are drug itneractions with paroxetine?
-procyclidine, theophylline, tricyclics, and warfarin
-causesincreased vlood levels of the seocnddrug
-doses may need to be decreased
Whata re drug interactions of setraline as antifdepressants?
-tricyclics and warfarin
-increased effects and doses may need to be decreased
What are drug interactuions with tricyclics as antidepressants?
- with CNS depressants, causses additive CNS depression
-with clonidine, guanethidine,and methyldopa, causes decreased antihypertensive effects
What is the serotonin syndrome?
-conditon characterized by dangerously high levels of serotonin in the body
-can occur when you take certain combinations of presciption medications that afect serotonin levels in your body
-occurs if you SSRIs or SNRI's for dperessuion along with triptan medicationsto treat migraine
-can also occur with other drugs or supplements that affect serotonin levels such as st. john's wort
-signs and symptoms range from restlessness and rapid heartbeat to muscle rigidtiy and seizures
-go away quickly with treatment
-may need to disocntinue use of medications
How do antidperessants treat major depressive disorder?
-elevate mood, increase physical acitivty and mental alertness, increase appetite and sexual drive, improve sleep patterns, and reduce preoccupation with morbid thoughtsd
-drugs are effective in 70% of patients
-SSRI'spreferred over TCA's due tolimitedtoxicity
-MAO's used rarely only if TCA's don;t work or for "atypical"depression
How is bipolaraffective disorder treated with antidepressants?
-often treated with lithium to control mania
How are antidepressants used for anxiety disorders?
-treated wtih SSRIs, although unlike benzodiazepines
-full efficacy won;t be seen for weeks
How is obsessive-compulsive disorder treatedw tih antidepressants?
-treated wtih clomipramine, fluoxetine and other SSRIs
How is social anxiety disorder treated with antidepressants?
-SSRI's only
How is enuresis (bed-wetting) treated with antidepressants?
-tricyclic antidepressants,like imi[pramine, are used to suprress enureissi in childre over 6and adults
-exact mechanism is uncertain
How is ADD/ADHD treated wtih antidepressants?
-tricyclic amines (imipramine and desipramine) are useful in patients unresponsive or intolerant to stimulents
-atomoxetine is also appreoved treatment of ADHD
How is chronic pain treated with antidepressants?
-tricyclic amines and venlafaxine are often used for chronic pain of unknown oridgin
-SSRI's areineffective
-duloxetine is approved treatment of neuropathic pain associated wtih diabetes
-drugs may work directly on pain pathways, but exact mechanism of action is unknown
What is the therapeutic effciacy of antidepresant drugs?
-all ahve simialr therapuetic effciacy
-selection based ona dvserse efects
-effciacy occurs several weeks after administration and is associated with adaptive changed overtime such as decrreased AMP accumulation and a reduction of postjunctional beta-adrenoceptors as well as an increase in responsiveness of postjunctional serotonin 1A receptors
What is the mechanism of action of tricyclic antidepressants?
-block neuronal reuptake of norepinephrine and serotonin increasing their postsynaptic actions
-are generally highly lipid-soluble and have relativelylong half-lives
-are metabolized by ring hydroxylation and glucuronide conjugation or by demethylation
-monodemethylation of the tertiary amines imipramine and amitripytline results in the active secondary amine metabolites despiramine and nostriptyline, respectivly
-plasma levels are used primarily to monitor compliance and toxicity
What are central nervous system adverse effects of tricyclic antidepressants?
-sedation is common and probably due to antagonist activity at histamine H1 receptors. Confusion and memory dysfunction is a central anticholinergic effect but it is more common in the elderly
-mania occasionally occurs in patients with an underlying bipolar affective disorder
-tremors occur in 10% of patients and is managed with propanolol
-seizures occur occasionally becuaseof lowered seizure threshold
-they aremore common with tertiary amines
What is insomnia as an adverse effectof tricycline antidepressants?
-movement disorders are occasionally produced by amoxapine
-these effects are due to dopamine-receptor antagonist activity
-overdose of amoxapine causes seizures
What adverse effects involve the cardiovascular system wuith tricyclic amine antideperessants?
-postural hypotension, which may be severe and may be termporary, is probably due to peripheral alpha-1 adrenoceptor blockade
-may result in reflex tachycardia
-tachycardia, conduction defects, and arrythmia are common with overdose
-risk is highest with imipramine and preexisting heart block or compesated cardiac output
What adverse effects are involved in the autonomic nervous system with use of tricyclic amine antidepressants?
-reflects the muscarinic cholinoceptor antagonist activity of TCAs. effect are temporary
-use commonly produces dry mouth, blurred vision, difficulty in urination and constipation
-rarely precipitae narrow-angle glaucomaor paralytic ileusor cause urine retention. More common in the elderly
What are the rebound/discontinuation effects of tricyclic amines antidepressants?
-common effects include dizziness, nausea, hedache, and fatigue
-may persist forup to 2 months
-tapered withdrawal minimizes effects
What adverse effects are affected for tricyclic amine depressants?
-central nervous system effects
-autonomic nervous system effects
-insomnia
-cardiovascular
-rebound/discontinuation effects
-weight gain
-sexual dysfunction
-rare,but serious hematologic changes, including anemia and agranulocytosis
-infreuently cause allergic reactions and obstructive jaundice
-atomoxetine ,ay increase suicidal thoughts in childrrenm and adolescents
What is overdose and toxicity of tricyclic amine antidepressants?
-overdoase produces severe anticholinergic and antiadrenergic signs, respiratory depression, arrythmias, shock, seizures, coma, and death
-treatment is supportive and includes sodium bicarbonate for cardiac toxcity, benzodiazepines for seizures and intravenous fluids and norepinephrine for hypotension
What are adverse effects of SSRIs?
-overall, they produce less efects that tricyclic amines
-headache is temporary
-secula dysfunction up to 40% of allpatients
-gastric irritiation is transient and includes nausea and heartburn
-weight loss initally followed in somepatients by weight gain
-stimulation that is mild and often transient, may beexperianced as dysphoria, and is marked by agitation, anxiety, increased motor activity, insomnia, tremor, and excitement
-apathy (flattened affect) occurs in some patients
-rebound/discontinuation effects like those for TCAs most likly weith paroxetine
What occurs when you stop SSRI treatment?
-may result in SSRI discontiunation syndrome,with dizziness, vertigo, ataxia, nausea, vomiting, musckle pains, fatigue, tremor and headache
-psychological symoptomssuch as anxiety, crying spells, irritabiklity, feeling sad, memory problems and vivid deams may occur
-common in SSRIs witha shorter half-life such as paroxetine and venlafaxine, and occurs in up to 1/3 of patients on SSRI therapy
-fluoxetine is the least likely to cause this syndrome because of it's long half-life. This symptomis self-limiting.
What are the adverse effects of trazodone and nefazodone as heterocyclic antidepressants?
-these drugs are highly sedating, cause drowsines and dizziness
-cause insomnia and nausea
-trazodone may cause postural hypotension in the elderly and a rare priapis in men
-trazodone has no significant anticholinergic activity, has fewer autonomic and cardiovascular effects than TCAs and is than TCAs in overdose
What are the adverse effects of bupropion as heterocyclic antidepressants?
-bupropion has no significant anticholineergic activity or hypotensive activity
-causes little sexual dysfunction
-more likely than TCA's to cause seizure's
-bupropion causes stimulation. insomnia, and weight loss
-makreted as zyban
What are the adverse effects venlafaxine of hetereocyclic antidepresants?
-causes nausea dizziness, sexual disturbances, anxiety, and insomnia
What are the adverse effects of duloxetine as a heterocyclic antidepressant?
-causes gastrointestinal disturbances, sexual dissturbances, insomnia, and sedation
What are the CNS adversee effects of heterocyclic antidepressants with tricyclic amines?
-TCA's and most heterocyclics cause sedation, additive with other CNS depressants
-SSRI's, bupropion and venlafaxine may cause anxiety, insomnia, an d jitteeriness
-most of these drugs caue seizure in overdose
What are peripheral nervous system adverse effects of heterocyclic and tricyclic amine antidepressants?
--TCA's, amoxapine, maprotiline, and nefazodone cause atropine-like side effcts via muscarinic receptor antagonism
-weight gains occur with TCAs and MAOIs
-weight loss is common with SSRIs
What are general drug interactions of tricyclic amine antidepressants?
-TCAs potentiate the CNS depressant effcts of alcohol and other drugs with similar activity
-TCAs potentiate the pressor activity of noreepinephrine
-TCAs have additive anticholinergic effects with antiparkinsonian drugs, antipsychotic drugs and otheer drugs with anticholinergic activity
-TCAs block alpha-adrenoceptors and thus reduce the antihypertnsive action of clonidine qand alpha-methyldopa
-interaction with MAOIs can cause excitement, hyperpyrexia, and a hypertensive episode
-serotonin syndrome also may occur with TCAs that are more selectively block serotonin reuptake
What are the general drug interractions of SSRI antidepressants?
-have a rare and potentially fatal interaction with MAOIs called serotonin syndrome that includes tremor, hyperthermia, muscle rigidity, and cardiovascular collapse
What are general drug interactions of MAOI antidepressants?
-MAOIs may result in headache, nausea, cardiac arrhythmias, and hyertensive crisis and, rarely, in subarachnoid bleeding adn stroke in the presence of indirectly acting sympathomimetics. These effects are due to the release of increaed stores of catecholamines resulting from inhibition of monoamine oxidase
-these can potenetiate the pressor ffect of high doses of directly acting ssympoathetic amines
-MAOIs may causes a serotonin syndrome in the preence of SSRIs, certain TCAs,, and opiod such as meperidine
-redult in additive sedaton and CNS depresion in the eprsence of barbiturates, alcohol,, and opioids
What is bipolar disorder?
- a mental illness characterized by mood stability that cna be serious and disabling
-manic behavior is one extreme of this disorder, and depression is the other
-deep mood swings of bipolar disorder may last for weeks or months, causing great distrubances in the lives of those affected, and those of family adn firends, too
-suicide rate is high among those with bipolar disorder
What are therapeutic uses oflithium for acute mania or bipolar afective disorder?
-lithium normalizes mood in 70% of patients. The onset of the therapeutic effect takes 2-3 weeks
-antipsychotic agents and benzodiapines can be used in the initial stages of the disease to control acute agitation
-the anticonvulsants carbamazepine and vaiproic acid have been used successfully either alone or as adjuncts to lithium therapy
-the dose is similar to that used for epilepsy
-the mechanism of actiion of these drugs are unknown
-lamotrigine may be useful in preventing depression that often follows the manic of bipolar disorders
-prophylaxis of bipolar affective disorder, for which lithium is often administered with a TCA (may precipitate mania)
What is the mechanism of action of lithium?
-the mehcanism of action for lithium is unclear , although it may be directly related to the inhibition ofphospholipid turnover (lithium inhibits inositolmonophosphatase) and, consequently, decreased activity of the second messengers diacylglycerol (DAG) anmd inositol 1,4,5-triphosphate (IP3)
-lithium also has reported effects on nerve conduction
-on the release, synthesis, and action of biogenic amines
-and on calcium metabolism
What are the pharmacologic properties of lithium?
-this drug is eliminated almost entirely by the kidney
-80 percent is reabsorbed in the proximal renal tubule
-lithium has a low therapeutic index
-plasma levels must be monitore continuously
What are the adverse effects of lithium?
-adverse effects are common at therapeutic doses of .5- 1.4 mmol/L or slightly higher
-these effects include nausea, vomiting, diarrhea, fine tremor, polydipsia,edema, and weight gain
-lithium administration produces polyuria, which occurs as the kidney ciollectibng tubule becomes unresponsive to antidiuretic hormone (reversible)
-more rarely, decreased renal function occurs with long-term treatment, similar to nephrogenic diabetes insipidus
-adverse effects of lithium also include benign, reversible thyroid enlargement caused by reducing tyrosine iodination and the synthesis of thyroxine
-lithium more rarely causes hypothyroidism
-lithium is generally contraindicated during the first trimester of opreganacy because of possible risk of fetal congenital abnormalites
-renal clearance of lithium increases during pregnancy
-breast feeding is not recommended because lithium is secreted in breast milk with possible neonate dysfunction
What are the drug interactions with lithium?
-sodium depletion isincreased by low-salt diets, thiazide diuretics, durosemide, ethacrynic acid, or severe vomiting or diarrhea
-this depeltion results in increased renal reabsortpion oflithium and an increased chance of toxicity
-renal clearance of lithium is decreased and the chance of toxicity is enhanced by some nonsteroidal anti-inflammatory drugs (such as indomethacin and phenylbutazone)
What is the toxicity of lithium?
-at a toxicity level above 2mmol/L, confusion (first sign of toxicity), drowsiness, vomiting, ataxia, dizziness, and severe tremors develop
-at a toxicity level above 2.5 mmol/L, clonic movements of the limbs, seizures, circulatory collapse, and coma occur
-treatment includes discontinuing lithium administration, hemodialysis, and the use of anticonvulsants
How are antipsychotic drugs classified?
-either conventional or atypical
-subclassfied by oral milligram potency
-high potency drugs (fluphenazine and haloperidol) are more likely to produce extrapyramidal reactions
-low potency drugs (triflupromazine and thioridazine) are less likely to produce acute extrapyramidal reactions and more likely to produce sedation and postural hypotension
-atypical agents (risperidone and olonzapine) have generally replaced the conventional drugs for intial treatment of first-episode patients. clozapine is reserved for treatment-resistant patients
-other conventional heterocyclic antipsychotic drugs such as loxapine and molindone, with intermediate potency, have no clear advantage over other conventional drugs
What is the dopamine hypothesis of schizophrenia? what is the drug of choice for it?
-caused by abnormally high activity in brain systems that use dopamine as their primary neurotransmitter
-usually treated with chlorpromazine, a drug that binds to dopamine receptors withotu stimulating them, renderign them unavailable for activation by Dopamine
What is the mechanism of action of conventional antipsychotic drugs? Atypical drugs?
-antagonist activity at postjunctional dopamine D2-receptors, where dopamine normally inhibits adenylyl cyclase activity
-antagonist activity at both serotonin and dopamine D2 or D4 receptors
-aripiprazole is a partial agonist at dopamine D2 and like ziprasidone, also stimulates with serotonin receptors
-actions are in the mesolimbic and mesocortical areas of the CNS
What are the therapeutic uses of antipsychotic drugs on schizophrenia?
-produce an immediate quieting action
effects include decreased symptoms of thought disorders, paranoid features, delusions, hostility, hallucinations, and decreased withdrawal, apathy, and blunted affect
-curb acute psychotic attacks and delay subsequent relapses
What are other therapeutic uses of antipsychotic drugs other than scizophrenia?
-acute mania in bipolar disorder
-atypical psychotic disorders
-depression with psychotic manifestations
-tourette;s syndrome to supress severe tics and vocalization
-severe nausea or vomiting associated witha variety of diseases, radiation treatment, and cancer chemotherapy, as well aspostoperative nausea, and vomiting
What are pharmacologic properties of antipsychotic drugs?
-most of these drugs show little correlation between plasma levels and therapeutic action
-highly lipophilic and have long half-lives (10-20 hrs)
-metabolized by liver microsomal oxidation and conjugation
-thiroidazine is metabolized to mesoridazine (active metabolite)
-esterification of fluphenazine and haloperidol results in long-lasting depot forms that can be used to manage compliance issues
-plasma esterases convert the parent compound to the active drug when the ester diffuses into the blood-stream
Why do anti-psychotic drugs have adverse effects?
-due to antagonistic actions at dopamine D2 and histamine H1 receptors (and possibly serotonin receptors) in the CNS and to their antagonist actions at muscarinic cholinoceptors and alpha-adrenoceptors in the periphery.
What are adverse effects of anti-psychotic drugs on the CNS?
-extrapyramidal syndomes
-tardive dyskinesia
-neuroleptic malignant syndrome
-sedation
-confusional state with memory impairment
-seizures
What are the adverse effects of anti-psychotic dryugs on other than the central nervous system?
autonomic nervous system:
-alpah-adrenoceptor blockade
-muscarinic cholinoceptor blockade
-endocrine and metabolic distrubances
-withdrowal-like syndrome
-cardiac arrhythmias
-blood dyscrasias
-cholestatic jaundice
-photosensitivity
How are extrapyramidal syndromes in the central nervous system from adverse effects of anti-psychotic drugs?
-related to dopamine-receptor blockade in basal ganglia that leads to an imbalance in dopamine and acetylcholine actions in the nigrostriatal pathway
-major cause of noncompliance
-most likely to occur with high-potency conventional drugs that have a high afinity for post-junctional dopamine D2 receptors in the basal ganglia
-also unlikly to occur with atypical drugs such as clozapine and olanzapine
-sometimes spontaneously remit
What are extrapyrimidal syndromes from anti-psychotic drugs?
-acute dystonia
-akathisia
-parkinsonian-like syndrome
What is acute dystonia as an extrapyrimidal syndromes from anti-psychotic drugs?
-characterized by spastic retrocollis or torticollis
-respiration may be compromised
-may be elicited durign first week of therapy
-can be controlled with more-centrally action antimuscarinic drugs such as benztropine and biperiden with antihistamine diphenhydramine and by reducing antipsychotic drug dose
-this may lead to increase in psychotic symptoms
What is akathisia as an extrapyrimidal syndrome from anti-psychotic drugs?
-akathisia is the irresistaible compulsion to be in motion
-this condition cna develop as early as the first 2 weeks of treatment or as late as 60 days into therapy
-like acute dystonia, can be controlled by drugs with antimuscarinic activity and by beta-receptor antagonist propranolol
How is parkinson like effects a syndrome of extrapyrimidal adverse effects of anti-psychotic drugs in the CNS?
-characterized by tremors, bradykinesia rigidity, and othe signs of parkinsonism
-can be controlled with anti-muscarinic drugs or by reducing anti-psychotic drug dose
What is tardive dyskinesia as an adverse effects of anti-psychotic drugs in the CNS?
-much morelikely with conventional antipsychotic agents than atypical agents
-does not occur with clozapine
-primarily chacterized by disfiguring orofacioligual movements (tics), but it coccasionally includes dystonic movements of the trunk
-these effect may be the result of a developing supersensitivity of the postjunctionaldopamine receptors in the CNS, perhaps in the basal ganglia
-generally occurs after months to years of drug exposure
-it may be exacerbated or precipitated by the discontinuation of therapy
-often irreversible
-has an estimated incidenc eof 10-20%
-more likely to occur with the elderly or in institutionalized patients who receive long-term, high-dose therapy
-only treatment is discontinuation of treatment
How is neuroleptic malignant syndrome an adverse effect of antipsychotic drugs in the CNS?
-is most likely in patients sensitive to the extrapyramidal effects of the conventional high-potency antipsychotic agents
-characterized by autonomic instability, muscle rigidity, diaphoresis, profound hyperthermia, and myoglobinemia
-condition occurs often explosively in 1% of patients
-associated with 20% mortality rate
-treated by discontinuing drug therapy and intiating supportive measures, including the use of bromocriptine to overcome the dopamine receptor blockade and the use of muscle relaxants such as dantrolene and diazepam to reduce muscle rigidity
What is sedation as an adverse effect of anti-psychotic drugs of the central nervous system?
-more likely with low-potency drugs with atypical agents
-are due to a central histamine H1-receptor blockade
-these effects may be mile to severe, elderly are particularlyat risk
-may be temporary
How is confusional state with memory impairment an adverse effect of anti-psychotic drugs on CNS?
-efect is likely with anti-psychotic agents with pronounced antimuscarinic activity
How are seizures an adverse effect of anti-psychotic drugs in the CNS?
-seizures are common with chlorpromazine and clozapine
-this effect is due to a lowering of the seizure threshold
-antipsychotic drugs may precipitate or unmask epilepsy
How is alpha-adrenoceptor blockade an adverse effect of anti-psychotic drugs in the ANS?
-more likely to occur with conventional low-potency and atypical agents
-causes orthostatic hypotension, and possibly syncope as a result of peripheral vasodilation
-central depression of the vasomotor center may also contribute
-this effect may be severe and may resulty in reflex tachcardia
-elderly patients and those with heart disease are more at risk
-effect may be temporary
How are muscarinic cholinoceptor blockade an adverse effect of anti-psychotic drugs in the ANS?
-more common with conventional low-potency agents and atypical agents sucgh as clozapine
-resulting in dry mouth and blurred vision
-blockade may also produe constipation, tachycardia, and difficulty in urination leadign to urine retention
-rarely causes paralytic ileus and severe bladder infections
-elderly patients are more at risk
-effects may be temporary
How are endocrine and metabolic distrubances an adverse effect of anti-psychotic drugs?
-likely with most conventional agents and atypical agent risperidone
-due to dopamine D2 receptor antagonist activity in the pituitary
-resulting in hyperprolactinemia
-in women these disturbances include induced galactorrhea, loss of libido, and delayed ovulation and menstruation or amenorrhea
-in men, distrubances include gynecomastia and impotence
-weight gain may be due in part to histamine- H1 receptor antagonist activity
how is withdrawal-like syndrome an adverse effect of anti-psychotic drugs?
-characterized by nausea, vomiting, insomnia, and headache in 30 % of patients, especially with low-potency agents
-symptoms last up to 2 weeks
-minimized with a tapered reduction of drug dosage
How are cardiac arrythmias an adverse effect of anti-psychotic drugs?
-result froma quinidine-like effect in which ther is local anesthetic activity wtih an increased likelihood of heart block
-more likely with thioridazine and ziprasidone, whcih can prolong the Q-T interval and elad to conduction block adn sudden death
How are blood dyscrasias an adverse effect of anti-psychotic drugs?
-rare except in the case of clozapine, which may induce agranulocytosis in up to 3% of patients and therefore used only when other drug groups prove ineffective
How is cholestatic jaundice an adverse effect of antipsychotic drugs?
-caused primarily by chlorpromazine
How is photosensitivity an adverse effecy of anti-psychotic drugs?
-effect is specific to chlorpromazine
-includes dermatitis, rash, sunburn, and pigmentation, and it may be irreversible
-chlorpormazine and high-dose thioridazine also produce retinitis pigmentosa
What is overdose in anti-psychotic drugs?
-rarely fatal,. except when caused by thiroidazine or mesoridazine ( and posibly ziprasidone)
-may result in drowsiness, agitation, coma, ventricular arrhythmias, heart block, or sudden death
What are possible drug interactions with anti-psychotic drugs?
-have potentiated sedative effects in the rpesence of CNS deopressants (sucha s hypotics, opiods, aned antihistamines)
-produce additive anticholinergic effects with tricyclic antidepressants, antiparkinsonian drugs, and other drugs with anticholinergic activity
What is sedation?
-characterized by decreased anxiety, motor activity, and cognitive acuity
What is hypnosis?
-characterized by drowiness and an increased tendency to sleep
What are general properties of benzodiazepines as sedatives-hypsnotics?
-have a great margin of safety over previously available sedatvices-hypnotic agents
-have qualitively similar therapeutic actions
-however, because of quantitative differences in theri relative lipid solubility, biotransformation, and elimination half-life,some benzodiazepines are marketed for specific therapeutic purposes
What is the mechanism of action of benzodiazepines as sedative-hypnotics?
-facilitate gamma-aminobutyric acid (GAB)-mediated inhibiton of neuronal activity in the CNS
-they bind to a benzodiazepine receptor (2 subtypes available) that is part of, but distinct from the pentameric GABA-rceptor-chloride channel complex that consists of at elast four subuits and their multipleisoforms
-allosterically increase GABA affinity and the frequency of GABA-stimulated chloride channel opening, chloride conductance, and neuronal hypepolarization
-they also inhibit depolarization by excitatory neurotransmitters
-no action in the absence of GABA
-certain B-carboline and other ligands called "inverse agonists", some of which may be endogenous, bind with high affinity to the benzodiazepine receptor and can cause anxiety and induce seizures
What are the pharmacologic properties of benzodiazepines as sedative-hypnotics?
-generally administered orally to treat anxiety adn sleep disorders, some cna be given parenterally
-onset of benzodiazepine action is relatedto a relative degree tolipid solubility
-benzos that are highly lipid soluble have a rapid onset of action that benzos that are less lipid soluble
-redistribution from the brain to peripheral tissues is considered an important factor in terminating the actions of single, or intermittent nonaccumulating doses of the most highly lipid-soluble benzos
-hepatic metabolism accoutns for the clearnace of all benzos
-active metabolites, particularly desmethyldiazepam, result from acid hydrolysis in the stomach or phase I hepatic microsomal oxidation and extend the half-life of some benzos to as long as 60 hours or more
-biotransformation to ianctive metabolites is the msot imprtant factor for termianted actions fo less-lipid soluble benzos
-excreted by kidney
-clearnace is decreased in the elderly and in patients with liver disease
What are the theraputic uses of benzodiazepines as sedative-hypnotics?
-effectjve and safe for short-term treatment of anxiety disorders such as generalized sxiety disorder, situational axiety disorders, panic disorders, and social anxiety disorder
-used for insomnia
-used for seizures to elevate threshold, lorazepam (and diazepam) are given by IV, and clonazepam and clorazepate are used as adjuncts for absence, myoclonic, and atonic seizures
-used for preanesthetic and short medical/surgical procedues
-muscle relaxation
-acute mania of bipolar disorder
-can casue physcial dependence from short-acting benzodiazepines, use long-acting
What is midazolam as a benzodiazepine?
-short acting
-used as a preanesthetic
What is triazolam as a benzodaizepine?
short acting
-for insomnia and preanesthetic
What is alprazolam as a benzodiazepine?
-intermediate acting
-for anxiety
-antidepressant for panic disorders
What is clonazepam as a benzodiazepine?
-itnermediate acting
-for seizures
What is estazolam as a benzodiazapine?
-intermediate acting
-for insomnia
Wgat is lorazepam asa benzodiazepine?>
-intermediate acting
-for anxiety, insomnia, and preanesthetic
What is oxazepam as a benzodiazepine?
-intermediate acting
-for anxiety
What is temazepam as a benzodiazepine?
-intermediate acting
-for insomnia
What is chlordiazepoxide as a benzodiazepine?
-long-lasting
-for anxiety
-preanesthetic
What is clorazepate as a benzodiazepine?
-long-lasting
-for anxiety
What is diazepam as a benzodiazepine?
-long-lasting
-for anxeity
-preanesthetic
-seizures
What is flurazepam as a benzodiazepine?
-long-lasting
-insomnia
What is prazepm as a benzodiazepine?
-long lasting
0for anxiety
What is quazepam as a benzodiazepine?
-long-lasting
-for insomnia
What are flumazenil as a sedative-hypnotic? Adverse effects?
-competitive antagonist at benzodiazepine receptors
-used to prevent or reverse the CNS effects from benzodiazepine overdose or to speed recovery from the effects of benzodiazepines used in anesthetic and diagnostic procedures
-it may precipitate withdrawal
-its short duration of action often necessitates multiple dosing
What is zolpidem, zaleplon, and eszopiclone as sedative-hypnotic drugs? adverse effects?
-zolpidem (and zaleplon, which has a shorter duration of action) is widely used for short-term treatment of insomnia, it also has anxiolytic activity as well
-acts on a specific subtype of the benzodiazepine receptor BZ1 to reduce chloride conductance, has a similar mechanism of action but is structually unrelated to the benzos
-these drugs have only weak muscle-relaxing or anticonvulsant activity, with reduced potential for tolerance, drug abuse, and physical dependence
-their actions are blocked or reversed by flumazenil
-adverse effects of zolpidem and zaleplon include modest daytime sedation, headache, GI upset, and amnesia
-eszopiclone is unreported to alsoproduce dry mouth, headache, some sedation, and an unpleasant taste
What is buspirone as a sedative-hypnotic? adverse effects?
-nonbenzodiazepine that selectively relieves anxiety without the sedation, hypnosis, general CNS depression, or drug abuse liability of the benzos. Has no other benzo-like activities
-used primarily to treat generalized anxiety disorder, particularly in the elderly, who are more susceptible to the CNS depressant action of the benzos
-buspirone is a partial agonist at serotonin receptors
-a wekk or more of administration may be required to achieve the therapeutic effects of buspirone
-adverse effects include nervousness, restlessness, dysphoria, tachycardia, or GI distress more often than benzos
-causes pupillary constriction
What are barbituates as sedative-hypnotics?
-includes amobarbital, pentobarbital, secobarbital, and phenobarbital
-weak organic acid
-redistrivbtuion from highly vascular to less vascular tissues is responsible for the short duration of highly lipid-soluble barbituates
-metabolism and excretion are more important determinants for less lipid-soluble babrituates
-25% of a dose of phenobarbitali is excreted unchanged
-alkalinization of the urine enhances excretion and shortens its duration of action
What is the mechanism of action of barbituates as sedative-hypnotics?
-interact witha binding site on the GABA-receptor-chloride channel complex that is separate from the benzo receptor
-at low doses, barbituates allosterically porlong the GABA-induced opening of chloride channels and enhance GABA-inhibitory neurotransmission
-at higher doses, these drugs have GABA-mimetic activity (open chloride channels independently of GABA)
-with long-term use, these drugs, particularly phenobarbital, may induce the synthesis of hepatic microsomal enzymes and increase their own metabolism or the metabolism of numerous other drugs
-increase porphyrin synthesis by the induction of hepatic sigma-aminolevulinic acid synthase, and they can precipitate acute intermittent porphyria
-use as sedative-hypnotic agents is almost obsolete, supplanted by benzos and toehr nonbenzos
What are the therapeutic uses of barbituates as sedative-hypnotics?
-mostly obsolete
-phenobarbital is used to some extent
-still widely used as an anticonvulsant
-thiopental is used as an IV general anesthetic
-limited by their strong sedation effects, rapid tolerance, drug interactions, abuse potential, and lethality in overdose
-used to treat physical dependece associated with long-term use of sedative-hypnotic drugs
What are adverse effects of barbituates?
-produce dose-related respiratory depression with cerebral hypoxia, possibly leading to coma or death
-this effect results from abuse or suicide attempt
-treatment includes ventilation, gastric lavage, hemodialysis, osmotic diuretics and alkalinization of urine
-depress the medullary vasomotor center , with circulatory collapse
-use of barbituates is contraindicated in patients with pulmonary insuffiency
-hepatic and renal disease may prolong barbiturate action
What is the prototype of benzodiazepines as sedative-hypnotic?
-diazepam
What is the prototype of benzodiazepine antagonist as sedative-hypnotic?
-flumazenil
What is the prototype of barbituates as sedative-hypnotics?
-phenobarbital