CNS pharmacology Flashcards
An increase of chloride conductance is the most important result of activation of
GABAA receptors
- GABA is the most important inhibitory transmitter in the brain
- glcyine is also improtant in the spinal cord
- GABA(a) receptors causes hyperpolarization mediated by increased chloride conductance
Neurotransmitters may ________
- Increase chloride conductance to cause hyperpoarization
- Increase potassium conductance to cause inhibition
- Increase sodium conductance to cause excitation
- Inhibit calcium conductanct to reduce transmitter release
All of the listed NT change membrane excitability by decreasing K conductance except _______
Dopamine
- A decrease in K conductance is associated with neuronal excitation
Shares the same potassium channel as the 5-HT1A receptor
GABA(B) receptor
- they share the same K channel with a G protein involved in the coupling mechanism
CHemicals most likely to function as a neurotransmitter in hierarchical systems
Glutamate
- Aspartate
- small numerous inhibitory interneurons which use GABA or glycine as transmitters
- Drugs that affect hierarchical systsems often have profound effects on the overall excitability of the CNS
Actiavtion of metabotropic receptors located presynaptically causes inhibition by decreasing the inward flux of
Calcium
- This type of presynaptic inhibition occurs after activation of dopamine D2, norepinephrine a2, metabotropic glutamate, and mu opiod peptide receptors
This transmitter is mostly located in diffuse neuronal systems in the CNS, with cell boides particlary in the raphe nuclei. It appears to play amjor role in the expression of mood states, and many antidepressant drugs are thought to icnreases its functional activity
Serotonin
Criteria for neurotransmitters
- Present in higher concentration in the synaptic area than in other areas
- Released by electrical or chemical stimulation via calcium dependent mechanism
- produce the same sort of postsynaptic response
One of the first NT receptors to be identified in the CNS is loacted on the renshaw cell in the spinal cord. Activation of this receptor results in excitation via an increase in cation (Na, K) conductance independently of G protein-coupled mechanisms. Which compounds likely to activate this receptor
Nicotine
- This results in the release of glycine, which via interaction with its receptors on the motor neuron causes membrane hyperpolarization
This neurotransmitter, found in diffuse systems, can exert both excitatory and inhibitory actions. Multiple receptor subtypes and a transporterd have been identified, some of which are targets for drugs that are used in major depressive disorder and attention deficit hyperactivity disorder
Norepinephrine
- cell bodies of noradrenergic neurons located in the pons and brain stem project to all levels of the CNS
- Most of the subclasses of adrenoceptors that occur in peripheral tissues are present in the CNS
This drug is used in the management of insomnia and facilitates the inhibitory actions of GABA, but it lacks anticonvulsant or muscle relaxing properties and has minimal effect on REM sleep. Its action are antagonized by flumazenil
Eszopiclone
- Eszopiclone, zalepton, and zolpidem are related hypnotics that throught structurally different from benzodiazepines, appear to have a similar mechanism of action.
- Not used in seizures or in muscle spasticity states
true of Barbiturates
- Alkalinization of the urine accelerates the elimination of phenobarbital
- withdrawl symptoms from use of short acting babiburates (secobarbital) are more severe than phenobarbital
- The dose response curve for BZ is flatter than for barbiturates
- Induction of liver- drug metabolizing enzymes occurs with barbiturates and may lead to decreases in half life of other drugs
- Flumazenil is an antagonist at BZ receptors and are used to reverse CNS depresssant effect
A 24 year old has developed nervous disposition. He is easily startled, worries about inconsequential matters and sometimes complains of stomach cramps. At night, he grinds his teet in his sleep. Diagnosed as suffering from GAS, he is prescribed with buspirone. The patient should be informed to anticipate
That the drug is likely to take a week or more to begin working
- Buspirone is a selective anxiolytic
- minimal effects on cognition or memory
- not additive with ethanol in terms of CNS depression
- Tolerance is minimal
- no dependency liability
- not effective in acute anxiety. slow onset of action
MEchanism of action of benzodiazepines
Increase frquency of opening of chloride ion channels coupled to GABA(a) receptors
An 82 year old woman, otherwise healthy for her age has difficulty sleeping. Triazolam is prescribed for her at one half of the conventional adult dose.
The patient may experience amnesia, especially if she also consumes alcohol
- In elderly patients taking benzodiazepines
- hypotension
- prone to CNS depressant
- Additive effects on CNS depression
- antihistamines
- rebound insomnia
- alcohol enhances psychomotor depression and the amnestic effects of the BZ
Flumazenil will counteract the effect of _______
Benzodiazepines
- Binds to the chloride channel macromolecular complex and competes with the benzodiazepines, eszoporclone, zalepton, and zolpidem
- It does not reverse the effects of barbiturates and buspirone
A 40 year old woman with occasional acute attacks of intense anxiety with marked physical symptoms, including hyperventilation, tachycardia, adn sweating. If she is diagnosed as suffering from a panic disorder, the most appropriate drug to use is
Alprazolam
- Alprazolam and clonazepam are the most effective of the benzodiazepines for the treatment of panic disorders
Eszopiclone and flumazenil are__________
hypnotics
Which drug used in the maintenace treatment of patients with tonic clonic or partial seizure states increases the heaptic metabolism of manu drugs including both phenytoin and warfarin?
Phenobarbital
- Clonazepam and phenobabital are both used in seizure disorders
- Chronic administration of phenobarbital increases the activity of hepatic drug metabolizing enzymes including several cytochrome P450 isozymes
A patient with live dysfunction is scheduled fora surgical procedure. Lorazepam or oxazepam can be used for preanesthetic sedation in this patient without special concern regarding excessive CNS depression because these drugs are _______
Conjugated extraheaptically
- The elimination of most NZ involves their metabolism by liver enzymes, including cytochrome P450 isoenzymes
- In a aptient with liver dysfunction, lorazepam and oxazepam are metabolized extraheaptically
benzodiazepines are barbiturates are contraindicated in ___________
breathing related sleep disorders
They compromise ventialtion
Benzodiazepines
ALprazolam, chlordiazepoxide, clorazepate, clonazepam, diazepam, flurazepam, lorazepam, midazolam
- Binds GABA(a) recptor subunits to facilitate chloride channel opening and increase frequency. membrane hyperpolarization
- Used in acute anxiety states, panic attacksm GAD, insomnia, muscle relaxation, seizure disorders
Benzodiazepine antagonist
Flumazenil
Barbiturate
Amobarbital, bitabarbital, pentobarbital, phenobarbital, secobarbital, thiopental
- Binds to GABA(a) receptor (distinct form BZ). facilitate chloride channel opening and increase duration
- Used in anesthesia (thiopental), insomnia, sedation, seizure disorders
Newer hypnotics
Eszopiclone, zalepton, zolpidem
- Bind to GABA(a) receptor sites (close to BZ site). facilitates chloride channel opening
- USed in sleep disorders especially wen sleep onset is delayed
Melatonin receptor agonist
Ramelteon
- Activates MT1 and MT2 receptors in suprachiasmatic nucleus
- Used in sleep disporders especiallywhen sleep onset is delayed
Buspirone
5-HT agonist
PArtial agonist and possibly D2 receptors
Used in GAD
A 45 year old moderately obese man has been drinking heavily for 72 hours, This level of drinking is much higher than his regular habit of drinking 1 alcoholic drink per day. his only significant medical problem is mild hypertension, which is adequately controlled by metoprolol. With this history, this man is at significant risk for
Cardiac arryhtmia
A 42 year old man with a history of alcoholism is brought to the emergency department in a condused and delirious state. he has truncal ataxia and opthalmoplegia. The most appropriate immediate course of action is to administer ______
Thiamine
- Wernicke’s encephalopathy
- delirium, gait disturbances and paralysis of the external eye muscles
The cytochrome p45 dependent mcirosomal ethanol oxidizing system (Meos pathway) of ethanol metabolism is most likely to be maximally activated under the condition of low concentrations of
NAD
A freshman student (70kg) attends a college party where he rapidly consumes a quantity of an alcoholic beverage that results in a blood level of 500 mg/dL. Assuming that this young man has not had an opportunity to develop tolerance to ethanol, his present cindition is best characterized as _________
comatose and death
Mechanism of action of fomepizole
Inhibit the emtabolic production of toxic metabolytes of methanol
The regular ingestion of moderate or heavy amounts of alcohol predisposes to heaptic damage after overdose of acetaminophen because chronic ethanol ingestion
induces hepatic-drug metabolizing enzymes
- Chronic use of ethanol induces CYP2E1, an isozyme that converts acetaminophen to a cytotoxic metabolite. This appears to be the cause of the increased susceptibility to acetaminophen-induced heapatotoxicity
a 23 year old pregnant womean with alcholism presented to the emergency department in the early stages of labor. She had consumed large amounts of alcohol throughout her pregnancy. This patients infant is at high risk of a syndrome that includes
Mental retardation and craniofacial abnormalities
The combination of ethanol and disulfiram results in nausea and hypotension as a result of the accumulation of
Acetaldehyde
- disulfiram inhibits acetaldehyde dehydrogenase, the enzyme that converts acetaldehyde to acetate
The icnrease craving experience by those who are trying to recover from chronic alcohol abuse can be ameliorated by adrug that is an
Anatagonist of opiod receptors (Naltrexone)
Naltrexone
Nonselective competitive anatgonist of opiod receptors
Reduced risk of relapse in individuals with alcohol use disorders
Acamprosate
Poortly understood NMDA receptor anatagonist and GABA(a) agonist effects
Reduced risk of relapse in individuals with alcohol use disorders
Disulfiram
Inhibibits acetaldehyde dehydrogenase. Causes acetaldehyde accumulation during ethanol ingestion
Deterrent to relapse in individuals with alcohol use disorders
Fomepizole
Inhibits alcohol dehydrogenase, Prevents conversion of methanol and ethylene glycol to toxic metabolites
Used in methanol and ethylene glycol poisoning
A 9 year old child is having learning difficulties at scholl. He has brief relapses of awareness with eyelid fluttering that occur every 5-10min. EEG studies reveal brif 3 Hz spike and wave discharges appearing synchronously in all leads. Which drug would be effecive in this child without the disadvantages of excessive sedation or tolerance development
Ethosuximide
- Absence seziure
- clonazemapam
- CNS depressant effects
- Ethosuximide
- clonazemapam
Phenytoin _______________
prolongs the inactivated state of Na channel
MOA of Benzodiazepines
facilitate GABA-mediated inhibitory actions
MOA of ethosuximide
selectively blocks calcium channels in thalamic neurons
Zonisamid eblocks ____________
voltage gated sodium channels
MOA of phenobarbital
produces multiple effects, mainly enhancement of GABA chlporide inhibitory activity
Preferred drugs for absence seizure
Ethosuximide and valproic acid
Common side effects with ethosuximide
GI die effects
Weigth ________ is common in patients on valproic acid
gain
How to reduce GI symptoms of ethosuximide?
Take twice a day
With chronic use in seizure states, the adverse effects of this drug include coarsening of facial features, hirsutism, ang gigival hyperplasia
Phenytoin
- Common side effects:
- nystagmus, diplopia, and ataxia
- Chronic use
- abnormalities of vitamin D metabolism, coarsening of facial features, gingival overgrowth and hirsutism may also occur
Abrupt withdrawal of antiseizure drugs can result in increases in seizure frequency and severity. Withdrawal is most easily accomplished if the patient is treated with
Ethosuximide
MOA of carbamazepine
Block if sodium ion channels
MOA of topiramate
blcok glutamate receptors
MOA of vigabatrin
inhibits GABA metabolism
A young man suffers from a seizure disorder characterized by tonic rigidity of the extremities followed in 15-30 secs. of tremor progressing to massive jerking of the body. This clonic phase lasts for 1 to 2 min. leaving the patient in a stupurous state. Drug msot suitable for long term management of this patient
Phenytoin
- carbamazepine or phenytoin, or valproic acid
Cyclic ureides
Phenyoin, phenobarbital, ethosuximide
Phenytoin
Blocks voltage gated sodium channels
Used in GTC and partial seizures
Variable absortption, dose dependent elimination, protein binding ; many drug interactions
Toxicities: Ataxia, diplopia, gingival hyperplasia, hirsutism, neuropathy
Phenobarbital
Enhances GABA(a) receptor responses
used in GTCm and partial seizures
Long halflife, inducer of P450, many interactions
Toxicities: sedation, ataxia
Ethosuximide
Decreases calcium currents (T-type)
Used in absence seizures
Long half life
SE: Gi distress, dizziness, headache
Carbamazepine
Tricyclics
blocks voltage-fated sodium channels and decreases glutamate release
used in GTC and partial seizures
Well absorbed; active metabolite, many drug interactions
SE: ataxia, diplopia, headache, nausea
Benzodiazepines
Diazepam, lorazepam, clonazepam
Gabapentin
Blocks calcium channels
GTC and partial seizures
Variable bioavailability. Renal elimination
SE: ataxia, dizziness, somnolence
Pregabalin
Blocks calcium channels
used in partial seizures
Renal elimination
SE: ataxia, dizziness, somnolence
Vigabatrin
Inhibits GABA transaminase
used in aprtial seizures
Renal elimination
SE: drowsiness, dizziness, psychosis, ocular effects
Valproate
Blocks high frequency firing
Used in GTC and myoclonic seizures
Extensive protein binding and metabolism; many drug interactions
SE: nausea, alopecia, weight gain, teratogenic
Lacosamide
Blcoks sodium channels
Used in focal and generalized seizures
Minimal protein binding, no active metabolites
SE: dizziness, headache, diplopia
Lamotrigine
Blcoks Na and Ca channels, decreases neuronal glutamate release
GTC and partial, myoclonic, and absemces seizures
Not protein bound, extensive metabolism, many drug interactions
SE: dizziness, diplopia, headache, Rash
Levetiracetam
Binds synaptic protein SV2A, modifies GABA and glutamte release
used in GTC and partial seizures
Well absorbed, extensive metabolism, some drug interactions
Dizziness, nervousness, depression, seizures
Perampenel
Blocks glutamte AMPA receptors
Used in focal and GTC
Complete absorption, high protein binding, extensive metabolism
SE: dizziness, headache, somnolence, behavioral change
Retigabine
Activates K channels
Used in focal seizures
Moderate bioavailabilitym extensive metabolism
SE: DIzziness, somnolence, retinal changes
Rufinamide
Blcoks Na channels, other actions
Lennox-gastaut syndrome, focal seizures
Good absorption. No active metabolites
SE: somnolence, fever, diarrhea
Tiagabine
Blcoks GABA reuptake
Used in partial seizures
Extensive protein binding and metabolism some drug interactions
SE: dizziness, nervousness, depression, seizures
Topiramate
May blcok Sodium and calcium channels; also increases GABA effects
Used in GTC, absence, partial seizures, Migraine
Both hepatic and renal clearance
SE: sleepiness, cognitive, slowing, confusion, paresthesias
Zonisamide
Blcoks sodium channels
Used in GTC, aprtial and myoclonic seizures
Bith heaptic and renal clearance
SE: sleepiness, cognitive slowing, poor concentration, paresthesias
Agents with low blodd:gas solubility have ________onset of action
Faster
Chest muscle rigidity often follows the administration of ________
fentanyl
______ has antiemetic effect
Propofol
Halothate and other inhaled anesthetics causes ________
Bronchodilation
_________ is assocaited with muscle twithcing
Enflurane
A 23 year old man has pheochromocytoma. Which agent should be avoided?
Isoflurane
- Isofluranse sensitizes the myocardium to catecholamines as does halothane
- Arrythmias may occur
Least potent of the inhaled anesthetics
nitrous oxide
- lacks cardiovascular depression
- eliminated via the lungs
MAC
- Methoxyflurane has an extremely low MAC value
- Inversely related to potency
- gives no information about the slope of the dose-response curve
- Use of opiod analgesics or other CNS depressants lowers the MaC value
- elderly patients are more sensitive, so MAC value are lower
Fentanyl protocol
- Fentanyls effects can be reversed with naloxone after the procedure
- widely used in cardiac surgeries
- skeletal muscle rigidity than relaxation
- The additon of vasodialtors or a Beta blocker may be needed to prevent intraoperative hypertension
Malignant hyperthermia
- occur during general anesthesia with halogenated anesthetics and skeletal muscle relaxants
- succinylcholine and tubocurarine
- Release of calcium from skeletal sarcoplasmic reticulum leads to msucle spasms, hyperthermiam and autonomic instability
- Clinical myopathy associated with mutations in the gene loci for the skeletal muscle ryanodine receptor or L-type calcium receptors
Drug of choice for malignant hyperthermia
Dantrolene
If ketamine is used as the sole anesthetic in the attempted reduction of a dislocated shoulder joint, its actions will include
Analgesia
- cardiovascular stimulant
- increasing heart rate and BP
- central sympathetic stimulation from inhibition of norepinephrine reuptake sympathetic nerve endings
- Analgesia
- Amnesia
- preservation of muscle tone and minimal depression of respiration
Inhaled anesthetics
Desflurane, Enflurane,Halothane,Isoflurane,sevoflurane,Nitrous oxide
Faciliatte GABA mediated inhibition, block brain NMDA and ACHn receptors
Increase cerebral blood flow. ENFLURANE and HALOTHANE decrease cardiac output. Others cause vasodilation. All decrease respiratory functions - Lung irritation (desflurane)
Rate of onset and recovery vary by blood:gas partition coefficent. recovery mainly due to redistribution from brain to blood and thence to alveolar air and other tissues
Thiopental/tioamylal/methohexital
Barbiturates
Facilitate GABA-mediated inhibition of GABA(a) receptors
Circulatory and respiratory depression. decrease intracranial pressure
High lipid solubility-fast onset and short duration due to redistribution
SE: extension of CNS depressant actions. additive CNS depression with many drug
Midazolam
Facilitates GABA-mediated inhibition at GABA(a) receptors
Less depressant than barbiturates
SLower onset,but longer duration than barbiturates
SE: post op respiratory depression reveresed by flumazenil
Ketamine
Blocks excitation by glutamate at NMDA receptors
Analgesia, amnesia, and catatonia but consciousness retained. Cardiovascular stimulation
Moderate duration of action - hepatic metabolism
SE: increased intracranial pressure. emergence reactions
Etomidate
Faciliatets GABA-mediated inhibition at GABA(a) receptors
Minimal effects on CV and respiratory functions
Short duration due to redistribution
No analgesia, paim on injection (may need opiod), myoclonus, nausea, and vomiting
Opiods
fentanyl, alfentanil, ramifentanil, morphine
Interact with u, k, and delta receptors
Marked analgesia, respiratory depression
Alfentanil and ramifentanil fast onset (induction)
Respiratory depression - reversed by naloxone
Phenols
Propofol, fospropofol
Vasodialtion and hypotension. negative inotropy, fospoprofol water soluble
Fast onset and fast recovery due to inactivation
Hypotension(during induction), cardiovascular depression
Characteristics properties of local anesthetics
- Increase in membrane refractory period
- Blockade of voltage dependent sodium channels
- Effects of vascular tone
- Slowing of axonal impulse condition
The pKa of lidocaine is 7.7. Infected tissue, which can be acidic, for example at pH 6.7, the percentage of the drug in the nonionized form will be
10%
- Because the drug is a weak base, it is more ionized at pH values lower than its pKa. Because the pH given is 1 log unit lower (more acid) thean the pKa, the ratio will be approximately 90:10
Speed of onset of nerve blcokage is _______ in myelinated fibers
faster
The most important effect of inadvertent IV administration of a large dose of lidocaine is
Seizure
Factors that influence the action of local anesthetics
- Blood flow through the tissue
- Dose of local anesthetic injected
- The use of vasoconstrictors
- Tissue pH
You have a vial containing 10 mL of a 2% solution of lidocaine, How much lidocaine is present in 1mL
20 mg
In overdosage ___________ (with oxygen) is helpful to correct acidosis and lower extracellular potassium
hyperventilation
A vasoconstrictor added to a solution of lidocaine for a peripheral nerve block will
Decrease the risk of seizure
Increase the duration of anesthetic
A child requires multiple minor surgical procedures involving the nasopharynx, Which drug has high surface local anesthetic activity and intrinsic vasoconstrictor actions that reduce bleeding in mucous membranes
Cocaine
Prilocaine is relatively contraindicated in patients with cardiovascular or pulmonary disease because the drug
Causes decompensation through formation of methemoglobin
Amides
Articaine, Bupivacaine, Levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine
Blockade of Na channels. slows, the prevents action potential propagation
Hepatic metabolism via CYP450 in part. Half lives: lidocaine, prilocaine <2h others 3-4hours
Analgesia via topical use or injection
Esters
Benzocaine, cocaine, procaine, tetracaine
Blockade of sodium channels, slows then prevents action potential propagation. Plus cocaine has intrinsic sympathomimetic actions
Rapid metabolism via plasma esterases. Short half-lives
Analgesia, topical only for cocaine and benzocaine
Characteristics of phase I depolarizing neuromuscular blockade due to succinylcholine
Sustaimed tension during period of tetanic stimulation
The main reason for administering atropine was to
Block cardiac muscarinic receptors
- Acetylcholinesterase inhibitors used for recersing effects of nondepolarizing muscle relaxants cause increases in ACh
- Atropine is effective, glycopyrrolate is usually preferred because it lacks CNS effects
A muscarinic receptor antagonist would probably not be needed when a cholinesterase inhibitor was given for reversal of skeletal muscle relaxant actions of a non depolarizing drug if the NM blocking agent used was
Pancuronium
- it can bloick muscarinic receptors, especially those in the heart
- Caused bradycardia and hypertension and may cause dysrhythmias
Most effective emergent managment of malignant hyperthermia
Dantrolene
- interacts with the RyR1 channel to block the release if activator calcium
The clinical use of succinylcholine, especially in patients with diabetes is associated with
Aspiration of gastric contents
- Fasciulations associated with succinylcholine may increase intragastric oressure with possible complication sof regurgitation
- patients with delayed gastric emptying such as those with esophageal dysfunction or diabetes
Which drug is most often assocuated with hypotension and is related to clonidine
Tizanidine
- causes hypotension via a2-adrenoceptor
Spasmolytic durgs
- Cyclobenzaprine decreases both oropharyngeal sectrions and gut motility
- Dantrolene has no significant effect on the release if calcium from sarcoplasmic reticulum in cardiac muscle
- Diazepam causes sedation at doses commonly used to reduce muscle spasms
- Intrathecal use of baclofen in effective in some refractory cases of muscle spasticity
- Baclofen activates GABA(b) receptors in the SC, these receptors are coupled to K channels
Which drug is most likely to cause hyperkalemia leading to cardiac arrest in patients with spinal cord injuries
Baclofen
- Skeletal muscle depolarization by succinylcholine releases potassium from the cellsm and the ensuing hyoerkalemia can be life threathening in terms of cardiac arrest]
- Most susceptioble
- extensive burns
- spinal cord injuries
- neurological dysfunction
Which drug has spasmolytic activity and could also be used in the management of seizures caused by overdose of a local anesthetic
Diazepam
- Both antiseizure and spasmolytic
- Cyclobenzaprine is used for acute local spasm and has no antiseizure activity
Myalgias are common postoperative complaint of patients who receive large doses of succinylcholine. possibly the result of muscle fasciculations caused by depolarization. WHich drug administered in the opening room can be used to prevent postoperative pain caused by succinylcholine?
Atracurium
Succinylcholine
Agonist at ACH(n) receptors causing intitial twitch then persistent depolarization
Stimualtes ANS ganglia at M receptors
Pareneteral: short action, inactivated by plasma esterases
SE: muscle pain, hyperkalemia, increased intragastric and intraocular pressure
Nondepolarizing Skeletal muscle relaxants
d-tubocurarine, Atracurium, Cisatracurium, Mivacuurium, rocuronium, vecuronium
Competitive anatagonists at skeletal muscle ACh-N receptors
ANS ganglion block(Tubocurarine). Cardiac M block(pancuronium)
Parenteral use, variable disposition; Spotaneous inactivation (Atracurium, cisatracurium); metabolism by plasma ChE (mivacurium) ; hepatic metabolism (rocuronium, vecuronium); Renal elimination (doxacurium, pancuronium, tubocurarine)
SE: Histamine release (Mivacurium, Tubocurarine); Laudanosine formation (Atracurium); muscle relaxation is potentiated by inhaled anesthetics, aminoglycosides and possibly quinidine
Centrally acting Skeletal Msucle Relaxants
Baclofen, Cyclobenzaprine, iazepam, tizanidine
Baclofen
Facilitates spinal inhibition of motor neurons
Pre-and postsynaptic GABA(b) receptor activation
Oral; intrathecal for severe spasticity
SE: sedation, muscle weakness
Cyclobenzaprine
Inhibition of spinal stretch reflex
Oral route for acute muscle spasm due to injury or inflammation
SE: M block, sedation, sonfusion, and ocular effects
Diazepam
Facilitates GABA-ergic transmission in CNS
GABA(a) receptor activation: postsynaptic
Oral and parenteral for acute and chronic spasms
SE: sedation, additive with other CNS depressants; abuse potentials
Tizanidine
Pre and postsynaptic inhibition
alpha 2 agonist in spinal cord
Oral for acute and chronic spasms
SE: muscle weakness, sedation, hypotension
Dantrolene
Direct-acting
Weakens muscle contraction by reducing myosin-actin interaction
Blocks RyR1 Calcium channels in skeletal miscle
Oral for acute and chronic spasm. IV for malignant hyperthermia
SE: muscle weakness
Ancipated action of levodopa
- Dizziness may occur, especially when standing
- Take the drug in divided doses to avoid nausea
- The drug will probably improve his symtpoms for a period of time but not indefinitely
- Uncontrollable muscle jerks may occur
Livedo reticularis is an adverse effect of ________
Amantadine
Fluctuates in its effectivieness with increasing frequency as treatment continues
Levodopa
Pramipexole is a dopamine ___________ receptor acrivator and does not require bioactivation
D3
- excreted in unchanged form
Drugs that ____________can exacerbate dyskinesia in a patient taking levodopa
activate dopamine receptors
True or false. Muscarinic receptor blcokers prevent occurence of dyskinesia
False
a 51 year old patient with parkinsonism is being maintained on levodopa-carbidopa with adjunctive use if low doses of tolcapone but continues to have off periods of akinesia. A drug used to rescue the patient that provides temporary relief
Apomorphine
- Pretreatment with the antiemetic trimethobenzamide for 3 days us essential to prevent severe nausea
_______causes mydriasis and may precipitate an acute attack if glaucoma
Levodopa
true or false. Antimuscarinic drugs may improve the tremor and rigidity
true
A previously healthy 40 year old woman begins to suffer from slowed mention, lack of coordination, and brief weithing movements of her hands that are not rhythmic. In addition, she has delusion of being persecuted. The woman has no history of psychiatric or neurologic disorders but several relatives have had similar symptoms. Although further diagnostic assessment should be made, it is very likely that the most appropriate drug for treatment will be
Haloperidol
true or false. Pramipexole is an egot derivative
False
Tolcapone may be of value in patients being treated with levodopa-carbidopa because it _______
Decreases the formation of 3-O methyldopa
Ropinirole act on the _______receptor
D2
Which of the following drugs is most suitable for management of essential tremor in a patient who has pulmonary disease
Metoprolol
Levodopa/carbidopa
PRecursor of dopamine. Carbidopa inhibits peripheral metabolism via dopa decarboxylase
Primary drug used in parkinson’s disease
Oral COMT and MAO type B inhibitors allow smaller doses and prolong actions. Duration of effects: 6-8 h
SE: GI upsets, dyskinesias, behavioral effects. On and Off phenomenon
Dopamine Agonists
Pramipexole, ropirinole, apomorphine, rotigotine,bromocriptine
- D2 agonists (Apomorphine, bromocriptine, rotigotine,ropinirole)
- D3 Agonist (pramipexole)
- Pramipexole, rotigotine and ropinirole
- sole agents in early parkinson’s disease and adjunct to L-dopa
- Apomorphine
- Rescue therapy
- Oral: pramipexole; SHort halflife, renal elimination
- Ropinirole, CYP1A2 metabolism, drug interactions possible
- rotigotine: transdermal
MAO inhibitors
Rasagiline, Selegiline, Safinamide
Inhibit MAO type B
Rasagiline, selegiline - adjunctive with L-dopa ; safinamide to reduce on-off phenomena
Oral. Half-lioves permit bid dosing
SE: Serotonin syndrome with meperidine and possibly SSRIs and TCAs
COMT Inhibitors
Entacapone, Tolcapone
Block L-dopa metabolism in periphery (bith) and CNS dopamine (tolcapone)
Prolongs L-dopa actions
Oral
Benztropine
Antimuscarinic agent
Improves tremr and rigidity not bradykinesia
Oral: once daily
Drugs of Hungtington’s disease
Tetrabenazine, Reserpine, Haloperidol
- Tetrabenzine, reserpine : Depeltes amines
- Haloperidol: D2 antagonist
Reduce symptom severity
Oral
- Side effects
- Tetrabenzine, reserpine : Depression, hypotension, sedation
- Haloperidol : Extrapyramidal dysfunction
Drugs for tourette syndrome
- Haloperidol
- D2 receptor blockers
- reducel vocal and motor tic frequency
- Oral
- SE: Extrapyramidal dysfunction
- Clonidine
- alpha 2 blocker
- oral
Pathologic basis of schizophrenia
Drug-induced psychosis can occur without activation of brain dopamine receptors
- Dopamine receptor blockers cause EPS
trifluoperazine was prescribed for a young male patient diagnosed as suffering from schizophrenia. He complains about the side effects of his medication. Which of the ff is not likely to be one of his complaints
A. Constipation
B. Decreased Libido
C. Excessive Salivation
D. Postural hypotension
C
- Phenothiazine causes sedation and are antagonist at muscarinic and alpha drenoceptors
- postural hypotension
- blurring of vision
- dry mouth
retinal pigmentation is a dose dependent toxic effect of _________
thiorizadine
_______ exacerbate tardive dyskinesia
Atropine and other muscarinic blockers
Akathisias may be relieved by ________ the dosage
Decreasing
Haloperidol is not an appropriate drug management for ______
A. Acute mania
B. Amenorrhea-glactorrhea syndrome
C. Phencyclidine intoxication
D. Schizoaffective disorders
E. Touretter sybdrome
B.
Lithium dosage may need to be ________ in patients taking thiazides
Decreased
- slow onset
_________urinary sodium inhibits renal tubular reabsorption of Lithium
High
A 30 year old male patient on drug therapy for a psychiatric problem. He complains that he feels “flat” and that he gets confused at times. He has been gaining weight andnhas lost his sex drive, As he moves his hands, you notice a slight tremor. He tells you that since he has been on medication he is always thirsty and frequently has to urinate. The drug he is most likely taking is ?
Lithium
A young woman recentley diagnosed as schizophrenic develop severe muscle cramos with torticollis, a short time after drug therapy is initiated with haloperidol. The best course of action would be
Inject benztropine
Drug with established to be both effective and safe to use in pregnant patient suffering from bipolar disorder
Olanzepine
A drug that has a high affinity for 5-HT2 receptors in the brain, does not cause EPS or hematoxicity, but is reported to increase the risk of significant QT prolongation?
Ziprasidone
PHENOTHIAZINES
(chlorpromazine, Fluphenzine,Thioridazine)
Block of D2 receptors >>> 5-HT2 receptors
Blocks alpha, M, and H1 receptors. Sedation, Decreas seizure threshold
Used in Schizophrenia, Bipolar disorder (Manic phase), antiemesis, preop sedation
Oral and parenteral forms, hepatic metabolism, long half life
SE: Extensions of alpha and M receptr blocking. EPS, tardive dyskinesias, hyperprolactinemia
THIOXANTENE
(Thiothixene)
Similar to phenothiazones
Used in schizophrenia
less risk of tardive dyskinesia
BUTYROPHENONE
(haloperidol)
Block of D2 receptors >>> 5 HT2 receptors
Some alpha block. less M block and sedation than phenothiazines
Used in Schizophrenia, bipolar disorders (manic phase), Huntington’s choreat, Tourette
Oral and parenteral forms. Heaptic metabolism
SE: EPS (Major)
SECOND GENERATION
(Aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone)
Block of 5-HT2 receptors >> D2 receptors
Some alpha block (Clozapine,risperidone, ziprasidone) and M block (clozapine, olanzapine), variable H1 Block
Ued in Schizophrenia (positive and negative symptoms), bipolar disorder (Olanzapine, risperisone), MDD (aripiprazole), agitaion in Alzheimer’s andParkinson’s\
SE: Agranulocytosis (clozapine), diabetes and weight gain (clozapine ,olanzapine), hyperolactinemia (risperidone), QT prolongation (Ziprasidone)
Lithium
Uncertain, suppresses IP3 and DAG signalling
No specific actions on ANS receptors or specific CNS receptors. No sedation
Used in Bipolar affective disorder. prevents mood swings (prophylaxis)
Renal elimiantion, halflife (20h), narrow therapeutic window, clearance decreased by thiazide and NSAIDs
SE: tremor, edema, hypothyroidism, renal dysfunction, pregnancy category D
Alternative drugs for bipolar affective disorder
(Carbamazepine, lamotrigine, Valproic acid)
Unclear actions in bipolar disorder
Ataxia and diplopia (carbamazepine), Nausea, dizziness, and headache (lamotrigine), GI distress, weigh gain, alopecia (valproic acid)
Valproic acid competes with lithium as firsth choice in BPD, acute phase. Others also used in acute phase and for prophylaxis in depressive phase
Carbamazepine forms active emtabolite (phase 1); lamotrigine and valproic acid form conjugates (phase II)
SE: Hematotoxicity and induction if drug metabolism (carbamazepine). Rash (lamotrigine), Hepatic dysfunction, weight gain, and inhibition of drug metabolism (Valproic acid)
A 36 year old woman with symproms of MDD. She is not currently taking any prescription. She was given sertraline. In your informtation to the patient, you will tell that
- Sertaline may take 2 weeks or more to become effective
- Preferable to take the drug in the morning
- Muscle cramps and twitches can occur
- She should notify you if she anticpates using other prescription medications
Chronic treatment with __________ leads to downregulation of adrenoceptors in the CNS
TCA
Selegiline is a selective inhibitor of ___________
MAO-B
Nefazodome is a highly selective antagonist at the _________receptor
5-HT2
A 34 year old man who was prescribed citalopram for depression has decided he wants to stop taking the drug, WHen questioned, he sait that it was affecting his sexual performance. You ascertain that he is also trying to overcome his dependency on tocacco products. If you decide to reinstiture drug therapym the best choice would be
Buprion
- SSRIs and venlafacine causes sexual dysfunction
- TCA may also decrease libido
_____ are effective in depresssions with attendant anxiety, phobi features and hypochondriasis
MAO inhibitors
True about Imipramine overdose
- Administer bicarbonate and potassium chloride (to correct acidosis and hypokalemia)
- Adminsiter lidocaine (to control cardiac arrythmias
- Maintain heart rhythm by electrical apcing
- Use IV diazeoam to control seziures
- Hemodialysis is not helpful
Which drug is an antagonist at 5-HT2 receptors and widely used for the management of insomnia in depressed patients
Trazodone
Ideal drug to be given to elderly patients with depressive symptoms
Citalopram
SSRIs are much less effective than TCA in the management of
Chronic neuroathic pain
Drug that is most likely tobe of value in OCD
Clomipramine
To be effective in breast cancer, tamoxifen must be converted to an active fotm by CYP2D6. Cases of inadequate treatment when tamoxifen was administered with
Fluoxetine
TCAs
(amitriptyline, clomipramine. Imipramine)
Blcok NE and 5-HT transportes
Used in MDD, OCD, chronic pains
CYP substrates; interactions with inducers and inhibitors. Long half lifr
SSRIs
(Citalopram, fluoxetine, paraxetine, sertaline)
Blcok 5-HT transporters
Used in MDD, anxiety disorders, OCD, MDD, PTSD, bulimia
CYP2F6 and 3A4 inhibitors (fluoxetinem paroxetine). 1A2 (fluvoxamine). Half life 15h
SR: severe dehydration
5-HT2 antagonists
(Nefazodone, trazodone)
Blocks 5-Ht2 receptors
MDD, hypnosis (trazodone)
Usually required bid dosing. CYP3A4 inhibitor
SE; sedation. modest alpha and H1 blockade (trazodine)
Heterocyclics
(Amoxapine, buprioprion, maptrotilline, mirtaxapine)
Mirtazapine blocks MOA-A and B. Selegiline more active vs MAO-B
Used in MDD, smoking cesasation (bupropriom), sedation (mirtazapone)
Extensiven heaptic metabolism. CYD2D6 inhibition *bupropion)
SE: lowers seizire threshold (Amaxapine, Bupropion). Seadtion and wait gain (mirtazapine)
MAO inhibitors
(Isocaboxazod, phenelzine, selegiline)
Inhibi MAO -A and B ; selegiline more active vs MAO-B
Used in MDD and unresponsive to other drugs
Hypetension with tyranine, ANd sympathomimectis. Serotonin syndrome if combine with ssris. If combined with ssris. very long hafl lives
SE:hypotension, insomnia
Patient is a cancer patient currently on oxycodone plus acetaminophen taken orally. Despite increasing doses of the analgesic combiantion, the pain is getting worseThe most appropriate oral medication for his increasing pain is
Hydromorphone
- Pain associated with metastatic carcinoma ultimately necessitates the use of an opiod analgesic that is equivalent in strength to morphine
- hydromorphone
- oxymorphone
- levorphanol
Tolerance will not develop to a significant extent with respect to _____________
Pupillary constriction
You are on your way to take an examination and you suddenly get an attack of diarrhea. If you stop a nearby drugstore for an over the counter opiod with antidiarrhea action, you will be asking for
Loperamide
An emergency department patient with severe pain thought to be of GI origin received 80 mg of meperidine. She subsequently developed a severe reaction characterized by tachycardia, hypertension, hyperpyrexia and seizures. Questioning revealed that the patient had been taking a drug for psychiatric condition. Which drug is most likely to be responsible for this untoward interaction with meperidine?
Phenelzine
Concomitant administration of meperidine and monoamine oxidase inhibitors such as isocarboxazid or phenelzine has resulted in life threatening hyperpyrexic reaction that may culmiante in seizures or coma
Concomitant use of selective serotonin reuptake ihibitors and meperidine has resulted in the serotonin syndrome
Genetic polymorphisms inc ertain hepatic enzymes involved in drug metabolism are established to be responsible for variations in analgesic response to ___________
Codeine
- Codeine, hydrocodone, and oxycodone are metabolized by CYP2D6 and variations in analgesic response to the drugs have been attributed to genetic polymorphisms in this isozyme
A yound man is brought to the emergency department in an anxious and agitated state. He informs the attending physician that he usues “street drugs” and that he gave himself an IV “fix” approximately 12h ago. After an initial period of contenment and relaxation, he has now has chills and muscle aches and has also been vomiting. His symptoms include hyperventilation and hyperthermia. The attending physician notes that his pupil size is larger than normal
The sign and symptoms are those of opiod abstinence
Methadone should be given
Beneficial action of diazepam are restricted to the relief of anxiety and agitation
Which statement about nalbuphine is most accurate??
Response to naloxone in overdose may be unreliable
Which drug does not activate opiod receptors, has been proposed as maintenance drug in treatment programs for opiod addicts. and with a single oral dose, will block the effects of injected heroin for up to 48 hours
Naltrexone
Which drug is a full agonist at opiod receptors with analgesic activity equivalent to morphine, a longer duration of action, and fewer withdrawal signs on abrupt discontinuance than morphine?
Methadone
- Fentanyl, hyrodmorphone, and methadone are full agonists with analgesic efficacy similar that of morphine
Strong agonists
(fentanyl, Hydromorphone, meperidine, morphine, methadone, oxymorphone)
Strong mu agonists. variable delata and kappa agonists
Used in severe pain, anesthesia (adjunctive). Dependence maintenance (methadone)
Hepatic metabolism. Duration: 1-3 h (methadone 4-6h)
SE: respiratory depression, constopation, addiction liability
Parial agonists
(Codeine, hydrocodone)
mu agonists, VAriable delta and kappa agonists
Used in mild to moderate pain; cough (codeine). Analgesic combinatios with NSAIDs and acetaminophen
Genetic variations in metabolism
SE: Respiratory depression, constipation, addiction liability (weaker effects)
Buprenorphine
Mixed agonist-antagonist
Partial mu agonist and kappa antagonist
Used in moderate to severe pain. Dependence maintenance, reduces craing for alcohol
Long duration
Nalbuphine
Mixed agonist-antagonist
Kappa agonist and mu antagonist
Used in mdoerate to severe pain
Parenteral only
Opiod antagonist
(Naloxone, Naltexone,nalmefene)
Antagonists at all opiod receptors
Used in opiod overdose. Dependence maintenance (naltexone )
Duration: naloxone 2h. Naltrexone and nalmefene >10h
SE: rapid antagonism of all opiod actions)
Antitussives
(codeine, dextromethorphan)
Mechanism uncertain. Weak mu agonist, Inhibits NE and 5-HT transporters
Used in acute debilitating cough
Duration: 0.5-1h
SE: reduces cough reflex. Toxic in overdose
Tramadol
Weak mu agonist. Blocks serotonin reuptake.
Used in mdoerate pain. ASjunctive to opiods in chronic pain states.
Duration: 4-6h
SE: toxic in overdose (seizures)
Antagonists of peripheral opiod action
(methylnaltrexone, alvimopan, naloxegol)
Peripheral antagonistm of mu receptors
Used in treatment of opiod induced constipation, postoperative ileus
Do not enter the CNS. DUration: variable
SE: similar to peropjera; toxicities of morphine
True about Alprazolam
- Abrupt discontinuance of alprazolam after 4 weeks of treatment may eleicit withdrawal signs
- Additive CNS depression occurs with Ethanol
- Most benzodiazepines are Schedule IV-controlled drugs
- Tolerance can occur with chronic use of any benzodiazepine
Schedules of controlled drugs
- I - no medical ise; high addicition potential
- Flunitrazepam, heroin, LSD, mescaline, PCP, MDA, MDMA, STP
- II - Medical use; high addiction potential
- Amphetamines, cocaine, methylphenidate, short acting barbiturates, strong opiods
- III - Medical use; moderate abuse potential
- anabolic steroid, barbiturates, dronabinol, ketamine, mdoerate opiod agonists
- IV - Medical use; low abuse potential
- benzodiazepines, chloral hydrate, mild stimulants, most hypnotics (zaleplon, zolpidem), weak opiods
Which drug, a partial agonist at nicotinic acetylcholine receptors is used in smoking cessation programs but may cause seizures in overdose?
Verenicline
- Acamprosate
- antagonist of NMDA glutamate receptors
- used together with counseling in alcohol treatment programs
- antagonist of NMDA glutamate receptors
Abuse of opiod analgesic
- Symptoms usually begin within 6-8 h and the acute course may last 6-8 days
- Lacrimation, rhinorrhea, yawning, and sweating are early signs
- Secondary phase of heroin withdrawal
- bradycardia, hypotension, hypothermia, and mydriasis may last 26-30 weeks
- Clonidine may be useful in reducing symtoms caused by sympathetic overactivity
- Methadone alleviates most of the symptos of heroin withdrawal
- Naloxone may precipiate a severe withdrawal state in abusers of opiod analgesics with symptoms starting in less than 15-30 min
Intravenous cocaine overdose causes _______
Tachycardia, agitation, hyperthermia, MI, seizures
Dilated pupils and tachycardia are characteristic effects of ______________
scopolamine
_____ Acts as a positive reinforcer of self adminsitration in animals
PCP
The inhalation of ______ is likely to cause headache, hypotension, and flushing
isobutyl nitrite
_____ and _____ are the most widely abused opiods by medical personnel
Fentanyl and meperidine
Sign or symptom most likely to occur with marijuana>
Conjunctival reddening
A college student us brought to the emergency department by friends. The student had taken a drug and then went Crazy. The Patient is agitated and delirious, Several persons are required to hold him down. His skin is warm and sweaty. and his pupils are dilated. Bowel sounds are normal. SIgns and symptoms include tachycardia, marked hypertension, hyperthermia, increased muscle tone, and both horizontal and vertical nysgtagmus
Phencyclidine
- Management:
- ventilarory support and control of seizures (with a benzodiazepine, hypertension and hyperthermia
- Antipsychotic drugs (haloperidol) may also be useful for psychosis
- Acidificication of urine
Opiod antagonists
(Naloxone, Naltrexone)
Reverse or block effects of opiods
Naloxone - opiod overdose; Short half life (1-2h)
Naltrexone - Treatment of alcoholism (like morphine -4h)
Methadone
Synthetic opiod
Slow acting agonist at mu opiod receptors
Acute effects like morphine
Used in substitution therapy for opiod addicts
Variable but longer halflife. ToxicityL like morphine reagarding acute and chronic effects including withdrawal
Buprenorphine
Partial mu receptor agonist
Attentuates acute effects of morphine and other strong opiods
Substitution therapy for opiod addicts
Long half-life (>40h). Formulated with nalorphine to avoid illicit IV use
Varenicline
N-receptor partial agonist.
Agonist at ACH(n) receptor subtype
Blocks rewarding effects of nicotine
SMoking cessation
SE: Nausea and vomiting, psychiatric changesm seizeures in high dose
Oxazepam, lorazepam
Benzodiazepines
Modulators of GABA(a) receptors.
Enhance GABA functions in CNS
Attenuate withdrawal symptoms including seizures from alcohol and other sedative-hyptonics
Half-life 4-15 h; lorazepam kinetics not affected by liver dysfunction
Acomprosate
Antagonist at glutamate NMDA receptors
May blcok synaptic plasticity
Treatement of alcoholism (in combination with counseling)
SE: allergies, arrythmias,variable BP effects, headache and impotence. Hallucination in elderly
Rimonabant
Inverse agonist at CB1 receptors
Decrease GABA and glutamate release in CNS
Treatment of obesity. Off label use for smoking cessation
Major depression. Increased suicide risk
