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214 Cards in this Set
- Front
- Back
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Parkinson's disease pathogenesis & Symptoms
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Progressive Neurodegenerative condition from death of dopamine containing cells of substantia nigra pars compacta with apprearance of intracellular inclusions called Lewy Bodies.
Resting tremor Slow movements Low speech Hesitation in initiating movements Psychiatric problems Progress to significant disability & handicap |
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Parkinson's diagnosis
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FDA voted to recommend DaTSCAN (Ioflupane I123 injection). Used to visualize distribution of dopamine transportors via Single photon emission computed tomography SPECT.
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PD pharmalogical therapy
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No universal first choice drug therapy
Depends on early vs late disease |
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Levodopa uses, administration, side effects
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Precursor of dopamine used for advanced patients
absorbed in upper jejunum Comepetes with dietary AA and should thus be given on empty stomach. Crosses BBB & half life of 90min Side effects due to significant peripheral metabolism such as nausea, vomiting, arrythmia |
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Carbidopa
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Given with Levodopa as Sinemet & does not cross BBB.
Primary treatment for PD Thus inhibits peripheral dopa decarboxylase to increase L-dopa half-life & decrease side effects. |
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Levodopa/Carbidopa side effects
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Short term
Nausea Orthostatic hypotension Confusion Hallucination Sleepiness Long term Motor fluctuations Dyskinesias Restlessness |
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Dopamine agonists characteristics, members, side effects, & Complications
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Act directly on postsynaptic dopamine receptors & have much longer half-life but less potent than levodopa.
Can be used early as monotherapy or in advanced disease as adjunctive therapy Bromocristine Pergolide - Withdrawn in 2007 for cardiac valve dysfunction Pramipexol Ropinirol Nonergot derivatives: Rotigotine patch Apomorphine Psychosis/hallucinations in older Edema Nausea & vomiting Fibrosis Orthostatic hypotension Drowsiness Impulsive disorders Predictable or unpredictable wearing off Poor or delayed response following each dose of L-dopa Dyskinesias Addictive behaviors Reactions with drugs to lower BP |
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Rotigotine
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Dopamine agonist patch used fo D2/D3 agonist for 24hr sustained drug delivery to bypass first order kinetics.
Used for monotherapy in early PD |
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Apomorphine
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D2/D1 dopamine agonist
Given as subq injection for quick onset of 5-15 minutes & lasts up to 2 hrs. Rescue agent for refractory off periods. Premedicate with antimimetics. |
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Selegiline uses, metabolism, side effects, potential interactions
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Mao-B inhibitor adjuvant to L-dopa used for preventitive therapy
Extensive first pass metabolism in liver into 5 metabolites. Does not inhibit peripheral metabolism of catecholamines Serotonin syndrome by interacting with serotonin reuptake inhibitors. - Confusion, agitation, restlessness. Can cause peptic ulcer disease. Potentially interact with antidepressants, narcotic pain killers, decongestants |
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Zydis
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New preparation of Selegiline absorbed transmucosally in oral cavity to bypass first-pass metabolism.
Thus higher bioavailability & lower concentration amphetamine byproducts |
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Rasagiline
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Second generation irreversible MAO-B inhibitor used once daily.
Effective as initial monotherapy AAN treatment of choice for off time |
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COMT inhibitors mechanism, members, side effects
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Entacapone
Reversible peripheral COMT inhibitor to increase L-dopa halflife by 50%. Increase on time & decrease off time. Tolcapone Higher potency but hepatotoxic Peak dose dyskinesia Psychosis Diarrhea Orthostatic hypotension Urine discoloration |
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Stalevo uses & complications
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Carbidopa, Levodopa & Entacapone
Given to patients experiencing symptom reemergince due to "wearing off". Do not take with MAOI. Also being investigated for possible association with prostate cancer & CV events. |
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Amantadine mechanism, uses, side effects
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Antiviral but can release DA stores, inhibit dopamine reuptake & antagonist of NMDAR.
Used for tremor in early PD & Fatigue symptoms Mental status changes Peripheral edema due to kidney metabolism Livedo reticularis hallucinations, nightmares |
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Anticholinergics members, uses, side effects, contraindications, potential interactions
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Trihexylphenydyl
Benzotropine Mainstay of therapy before Levodopa for young patients <60 to reduce tremor Dry mouth Urinary hesitance Confusion Contraindications: Glaucoma, Benign prostate hypertrophy Potential interactions with anti-histamines |
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Neuroprotection for Parkinson's
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Coenzyme Q10
- Electron acceptor for mitochondrial complexes that acts as potent antioxidant Creatine Vitamin C & E - Oxidant stress hypothesis |
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Treatment of early & late Parkinsons
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Early:
Levodopa - Has motor complications Dopamine agonists MAO-B inhibitors Late adjuvant therapy: Dopamine agonists MAO-B inhibitors COMT inhibitors |
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Non pharmacological treatments of Parkinsons
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Deep brain stimulation (DBS) - Uncontrolled disabling dyskinesias, no contra-indications or dementia. Potential side-effects could be weight gain, speech difficulties, depression or suicidal
Stem cells to regrow dopamine neurons Pallidotomy - usually on one side Viral delivery of GDNF Targeting affected genes in postsynaptic neurons |
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Some contrasting properties of somatic & Autonomic systems
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Both:
Use acetylcholine Somatic One neuron system No use of Norepinephrine No inhibitory Autonomic Two neuron system Does use Norepinephrine Inhibitory capability |
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Sympathetic division characteristic & Neurotransmitters
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Due to divergence & Convergence, Sympathetic system generally activated as a unit
Preganglionics release Ach, Postganglionics release Norepinephrine. Adrenal medulla release Epinephrine |
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Adrenal glands
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Adrenal medulla secrets mainly Epinephrine & some norepinephrine when stimulated by preganglionic sympathetics.
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Parasympathetic Division characteristic & Neurotransmitters
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Generally not activated as a whole b/c of little divergence or convergence.
Uses ACh as neurotransmitter to cause rest and digest effects |
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Denervation hypersensitivity
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Damage to autonomic nerve makes its target tissue more sensitive than normal to stimulating agents such as Epinephrine.
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Neurotransmitters used in the Autonomic system & their speed
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Synaptic transmissions are all via Nicotinic ACh receptors. Thus fast acting b/c of ion channel.
Parasympathetic post gang is via Muscarinic ACh Sympathetic Post gang is Norepinephrine but Epinephrine for Adrenals. Slow acting b/c they are G-protein coupled receptors. |
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Acetylchoine, Epinephrine, NE Site of release, Receptor, Termination of activity
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ACh - All preganglionics, All parasympathetic postganglionics & Sympathetic postganglionics to sweat glands; Cholinergic Nicotinic & Muscarinic; Degraded by cholinesterase
NE: All postganglionic sympathetics. 20% of secretions from adrenal medulla; a1, a2, b1 adrenergic; Reuptake, diffusion from cleft, MAO in nerve terminal & Gut, COMT in liver E: 80% of secretions from Adrenal medulla; a1,a2,b1,b2 adrenergic; COMT in liver |
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7TM receptors
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All sympathetic receptors are 7TM GPCR. homologus to light sensing eye molecule rhodopsin.
Represent drug targets for nearly half of all drugs & comprises 4% of entire protein coding genome. But diff sites for agonist binding. |
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Adrenergic receptor subtypes & effects
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a1 - Gq/11 - Increase Ca2+; Vasoconstriction
a2 - Gi - Inhibit Adenylyl cyclase; Many similar effects to a1 but relaxes arterioles. B - Gs - Stimulate Adenylyl cyclase; B1 - Increase heart rate & strength B2 - Bronchodilation, Vasodilate |
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Difference in relative potencies of aderenegic receptors
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a: NE&E> Isoproterenol
B: Isoproterenol> NE&E B1- E=NE B2- E>NE |
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Biosynthesis of Catecholamines
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Tyrosine
Add OH to ring - DOPA Remove COOH - DOPAMINE Add OH to ring carbon - NE Add methyl to amine - Epinephrine |
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Parent compound of sympathomimetic drugs
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Phenylethylamine
Can modify terminal amino group, benzene ring, alpha or beta carbons |
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Catecholamine structure vs selectivity & digestion
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Increasing size of alkyl substituents on amino groups increases Beta receptor activity but decreases alpha receptor activity.
The 2 Hydroxy groups on positions 3&4 amplifies effect but makes it succeptible to COMT. Absence of one or both OH increases bioavailability after oral admin & prolongs duration of action Substitutions on alpha carbon will resist oxidation by MAO esp of non-catecholamines. Can also displace catecholamines from storage sites. Ephedrine & Amphetamine |
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a1 agonists members, mechanism, uses, side effects. *Special
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Phenylephrine & Methoxamine
- Relatively a1 selective & cause vasoconstriction with peripheral resistance. Used as local decongestant & used systemically for BP elevation Side effects: Local ischemia * Phenylephrine is not inactivated by COMT due to lack of OH on 4. Thus much longer duration. |
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a2 agonists members, mechanism, uses
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Clonidine & Methyldopa
Selectively activate a2 receptors causing decrease in BP through CNS. Used for hypertension & sedation of mechanical ventilated pts |
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Dopamine for autonomics
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Vasodilator at low concentrateions & decreases peripheral resistance; also increases renal blood flow via D1 dopaminergic receptors
Vasoconstrictors at high concentrations via a1 receptors |
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Adrenergic uptake inhibitor
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Cocaine & Tricyclinc antidepressants
Peripheral sympathomimetic drug works by inhibiting transmitter reuptake at NE synapses. Also inhibits dopamine reuptake in CNS causing euphoria. |
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Aderenergic releasing agent
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Tyramine & Amphetamine
Tyramine is found in high conc in some foods. Routinely metabolized by MAO in liver. If MAO is blocked, tyramine accumulation can cause release of stored catecholamines causing marked increase in BP. |
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Ephedrine
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First orally active sympathomimetic drug. Activates B receptors & hence early use as anti-asthmatic. Also a mild CNS stimulant.
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Amphetamine
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Enters CNS more readily than Ephedrine & releases catecholamines to affect mood & apetite supression.
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Beta agonists
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B1 - Dobutamine, Prenalterol
B2 - Ritodrine, Terbutaline |
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Seizure vs Epilepsy
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Short episode of symptoms caused by a burst of abnormal synchrounes elecrical activity in the brain
Epilepsy is recurrent unprovoked seizures |
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Cellular mechanisms of Seizure generation
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Too much excitation
- Ionic inward Na+, Ca++ Currents - Excitatory neurotransmitters glutamate & aspartate Too little inhibition - Inward Cl- & outward K+ currents - Inhibitory neurotransmitter GABA |
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3 mechanisms of epilepsy drugs
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Augmenting GABAnergic inhibition
Opposing Excitatory glutamatergic transmission Modification of opening & closing of ion channels |
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Neonatal seizure drugs (6)
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Fosphenytoin
Phenobarbital Benzodiazepines - Diazepam, Inorazepam Valproate Primidone |
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Febrile Seizures (2)
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Phenobarbital
Diazepam |
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First line drugs for childhood or juveline absence seizures (2)
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Ethosuxamide
Valproate |
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Drugs for Juvenile Myoclonic & Generalized tonic clonic upon awakening
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Valproate
Lemotrigine Levetriacetam Topiramate Zonisamide - Off label also for primary generalized epilepsy |
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Ethosuximide uses & mechanism of action
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Used as first line drug for childhood or juvenile absence seizures
Works by inhibiting thalamic T-type calcium current action |
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GABA drugs for epilepsy & mechanism of action
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Vigabatrin - Inhibits GABA transaminase to prevent catabolism
Baclofen - GABAb receptor agonists |
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Side effect profiles of Felbamate, Gabapentin, Lamotrigine, Levetriacetam, Oxcarbazepine, Tiagabine, Topiramate, Zonisamide, Vigabatrin
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Felbamate - Aplastic anemia & hepatic failure; anorexia, insomnia
Gabapentin - Behavioral change to hyperexcitability & aggression. Somnolence, dizziness, weight gain Lamotrigine - Rash, Stevens-Johnson syndrome or toxic epidermal necrolysis Levetriacetam - Behavior change in 10% of pts to aggression & oppositional behavior. Oxcarbazepine - Hyponetremia with doses above above 25-30 mg/kg/day Tigabine - Spike-wave status epilepticus; * Do not give for pts with primary generalized epilepsy Topiramate - Glaucoma, Impaired concentration, nephrolithiasis & anorexia Zonisamide - Heat stroke secondary to oligohydrosis. Pt must be well hydrated. Anorexia, kidney stones Vigabatrin - Visual field defect due to retinal toxicity |
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Epilepsy drugs eliminated renal & both
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Renal:
Gabapentin Levetriacetam Vigabatrin Lacosamide Both Topiramate Zonisamide Oxcarbazepine |
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Anti epilepsy drugs P450 inducers & inhibitor
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Phenobarbital
Phenytoin Primidone Carbamazepine Tobacco/ciggs Valproate - Inhibitor |
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Anti-epilepsy OCE inhibitors
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Phenobarbital
Phenytoin Primidone Carbamazepine Oxcarbazepine Felbamate Topiramate >200mg/d |
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Adrenergic receptor antagonists in clinical therapeutics
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Nonselective alpha antagonists can treat pheochromocytoma
a1 selective antagonists can treat primary hypertension & benign Prostatic Hyperplasia Beta receptor antagonists can be used to treat hypertension, ischemic heart disease, arrhythmias, arrhythmias, endocrinologic & neurologic disorders. |
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alpha receptor antagonists
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Nonselective:
Phenoxybenzamine Phentolamine a1 selective: Prazosin Terazosin a2 selective Yohimbin |
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Phenoxybenzamine mechanism, uses, side effect
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Non selective alpha antagonist that causes irreversible blockade for 14-48 hours or longer. a1>a2.
Attenuates catecholamine-induced vasoconstriction. Major use is in treatment of pheochromocytoma Major adverse effect is postural hypotension |
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Phentolamine mechanism, uses
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Potent reversible nonselective alpha antagonist. Causes a reduction in peripheral resistance through blocking receptors on vascular smooth muscle.
Used in treatment of pheochromocytoma intraoperatively. Also used to reverse local vasoconstriction caused by infiltration of agonists during IV administration. |
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Prazosin mechanism, uses & advantage
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Highly selective a1 antagonist that causes relaxation of both arterial & venous smooth muscle
Used to manage chronic hypertension & also benign prostatic hyperplasia by relaxing prostate smooth muscle. * Less reflex tachycardia b/c a2 blockade can cause increased release of NE. |
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Terazosin mechanism, uses
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Also reversible a1 selective antagonist used to treat HTN & urinary symptoms due to benign prostatic hyperplasia.
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Clinical applications of alpha blockers
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Pheochromocytoma
Hypertension Urinary obstruction ERECTILE DYSFUNCTION Peripheral vascular disease Local vasoconstrictor excess |
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PK & general features of Beta antagonists
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Competitive inhibitors that resemble isoproterenol.
Some are partial agonists Can be orally administered Low bioavailability. Propranolol undergoes extensive first pass metabolism Major importance in treating hypertension Conventional doses do not cause hypotension in healthy individuals with normal BP |
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Possible mechanisms for antihypertensive action of Beta antagonists & CONTRAindications
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Blocking sympathetic outflow- dependent release of rennin by kidney juxtaglomerular cells
Blocking presynaptic Beta receptor stimulated release of NE By CNS mediated effects Since non are B1 specific & dependent on dose, may be contraindicated for asthmatics |
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Metabolic effects of B2 blockade & contrainducations
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Glycogenolysis in liver is partially inhibited after B2 blockade because catecholamines may be major signal in stimulating glucose release.
B-antagonists should be used with caution for type I diabetics. |
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Propranolol mechanism, PK, & characteristics
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Prototypical beta blocker
Low availability that is dose dependent upon oral administration No effects on a-receptors, muscarinic, no partial agonist activity |
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Nadolol & Pindolol
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Non selective beta antagonists
Nadolol has long duration of action Pindolol has partial beta agonist activity |
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Metoprolol & Atenolol
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B1 selective antagonist that is safer for asthmatics & type 1 diabetics.
* B1 selectivity is only partial. Thus consider benefits versus risk |
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Xamoterol mechanism, uses
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Selective beta 1 partial agonist
Agonist with sympathetic activity is low but antagonist when activity is high Used for pts with severe heart failure to benefit systolic & diastolic function |
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Beta antagonists
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Non-selective
Propranolol Naldolol - long duration Pindolol - Partial agonist B1 selective Metoprolol Atenolol Xamoterol - partial agonist |
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Clinical applications of beta blockers
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HTN
Heart disease; angina, arrythmias Hyperthyroidism Migraines Stage fright |
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ACh synthesis
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Choline is taken up into cholinergic nerves by high affinity sodium-choline cotransport
Acetyl CoA comes from mitochondria Choline acetyltransferase ChAT is synthesized in cell bodies & transported to axon terminal to catalyze synthesis of ACh |
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ACh release agents
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Activators
Latrotoxin - Black widow beta-Bungarotoxin - Snake Inhibitors Hemicholinium Vesamicol Botulinum toxin |
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a-Latrotoxin origin, mechanism
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Toxin from black widow that depolarizes nerve endings by forming tetrameric membrane pores. Leads to ACh release.
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b-Bungarotoxin origin, structure, mechanism
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Toxin isolated from snake
Large subunit is Ca++ dependent PLA2 & smaller has homology to protease inhibitors linked by disulfide bridge Acts by releasing intracellular Ca stores within nerve endings to enhance ACh release into synaptic gap. |
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Hemicholinium mechanism & characteristic
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Indirect inhibitor of cholinergic neurotransmission by blocking choline uptake.
No immediate effect on neurotransmission but can result in cholinergic nerve fibers running out of transmitter. |
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ChAT inhibitors
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Potent inhibitors exist, but no therapeutic utility because uptake of choline is rate limiting step in synthesis of ACh.
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Vesamicol
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Blocks uptake of ACh into synaptic vesicles
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Botulinum Toxin A mechanism, toxicity, Onset, Uses
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From Clostridium Botulinum & bonds to cholinergic nerve terminals & is internalized. Prevents all junctional exocytosis of ACh.
One of most poisonous substances known. Basis of potency is enzymatic; toxin is zinc proteinase that cleaves 1 or more fusion proteins. Usually occurs between 12-24 hrs or maybe days. First biological toxin licensed for treatment of human disease; Cervical torticollis, strabismus, & offlabel for migraines, chronic back pain, stroke, traumatic brain injury etc |
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mAChR isoforms, distribution
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M1,3,5 stimulate phosphoinositide metabolism
M2,4 inhibit adenylyl cyclase M1 in forebrain esp hippocampus & cerebral cortex M2 in Heart & brainstem M3 in smooth muscle, exocrine glands M4 in neostriatum M5 in substantia nigra, could regulate dopamine release |
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M1 & M3 , M2 AChR mechanisms & characteristics
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M1 & M3:
Generally mediate excitatory responses. Both activate PLC via Gq/11 protein M1 affects neuronal function M3 mediate contraction of all smooth muscles & secretion in glands by increasing cytosolic free Ca. M2: Contrast to M1 & M3 activity, M2 tends to inhibit cellular activity through Gi that inhibit adenylyl cyclase |
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mAChR systemic effects (4)
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Muscarinic agonists decrease peripheral vascular resistance & heart rate by direct slowing of SA rate & AV conduction.
Effects are opposed by reflex sympathetic discharge triggered by decrease in BP Agonist binding to M3 receptors on endothelial cells causes release of EDRF or Nitric Oxide which relaxes smooth muscle even though M3 generally causes smooth muscle contraction. M3 can stimulate smooth muscle contraction of broncial tree & stimulate broncial mucosa to secrete. Can exacerbate asthma. M3 agonists, like parasympathetic nervous system stimulation, increases secretory activity & contractility of gut |
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Cholinergic agonists & structural significance
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Acetylcholine
Methacholine Carbachol Bethanechol Methacholine & Bethanechol has extra methyl group in middle to prevent nicotinic AChR action. Carbachol & Bethanicol swapped Ester methyl group for Amino group to prevent succeptibility to cholinesterase Muscarine Pilocarpine - M3 Nicotine Lobeline |
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Anticholinesterases
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Reversible:
Echothiophate* - Glaucoma Edrophonium* - Arrythmias, Myasthenia gravis, Ileus. Long duration Neostigmine* - Myasthenia gravis, Ileus, Ambenonium* - Myasthenia Gravis & Pyridostigmine * = All are synthetic quaternary ammonium agents Physostigmine - Naturally occuring tertiary amine with greater lipid solubility used to treat Glaucoma. & Demecarium Irreversible: Organophosphates: Malathione - Insecticide Tabun, Sarin, Soman - Chemical warfare agent |
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Anticholinesterase Pharmacological effects & Uses
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Most prominent effects on CV, GI & Skeletal muscle NMJ
- Effects are similar to direct acting cholinomimetic drugs Cholinesterase inhibitors but not direct acting AChR agonists are valuable therapy for Myasthenia gravis, the autoimmune disease directed against muscle nAChRs. Short acting cholinesterase inhibitor like edrophonium can be used to treat supraventricular tachyarrhythmias |
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Effects of Cholinesterase inhibitor poisoning
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SLUDGE
Salivation, sweating Lacrimation Urination Defecation, drolling diarrhea Gastric upset Emesis |
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Pralidoxime Iodide
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Antidote to organophosphate cholinesterase inhibitors
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Therapeutic uses of Muscarinic Agonists (4)
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Reduce intraocular pressure in glaucoma
Increase esophageal sphincter tone in gastric reflux Postoperative or postpartum urinary retention Increase salivary secretion |
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Atropine origin, mechanism, uses, & effects
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Alkaloid extracted from nightshade & other plants of family Solanaceae
Blocks action of Acetylcholine at Muscarinic receptors Serves as antidote for poisoning by organophosphate Cholinesterase inhibitors. Opthalmoscopic retina exam Symptomatic relief of urinary urgency Decreased saliva, sweat Increase Heart rate, mydriasis Dilation of bronchi Decreased stomach acid secretion |
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Ipratropium
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Antimuscarinic drug used as inhalation for asthma.
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Nicotinic AChR subtypes & Structure
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Muscle (Embryonic, Adult)
Neuronal - Ganglionic & CNS Pentameric structure |
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Purified from Electric fish
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Electric rays are enriched in nicotinic acetylcholine receptors which made it possible to purify & characterize these receptors from these tissues
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Myasthenia Gravis mechanism, symptoms, & treatments
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Autoimmune disease with 80% of anti-AChR antibodies directed against MIR on AChR a-subunits.
Symptoms are weakness & fatigue Treat with: Cholinesterase inhibitors Neostigmine, Ambenonium, Pyridostigmine Add atropine or other muscarinic blockers to control muscarinic side effects if necessary. May use corticosteroids or perform thymectomy if thymoma is associated |
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d-tubocurarine mechanism & delivery
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Curare - Quaternary ammonium competitive nAChR blocker. Thus must be delivered parenterally
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Succinylcholine mechanism, advantages, disadvantages
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Depolarizing nicotine blocker
Faster onset & shorter duration than non-depolarizing blockers Potential for malignant hyperthermia Muscle pain Hyperkalemia |
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RyRs structure, purpose, mechanism, mutations
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Ryanodine receptors
Oligomeric transmembrane calcium channels in SR membranes responsible for Ca release for muscle contraction. Direct physical coupling to dyhydropyridine receptors(DHPRs) in adjacent T-tubule membranes Mutations associated with malignant hyperthermia |
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Ganglionic Nicotine receptor actions
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Ganglionic Nicotine receptors stimulate both sympathetic & parasympathetic actions
CV effects are mainly sympathomimetic GI are mainly parasympathetic |
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Therapeutic uses of Ganglionic blocking agents
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Mecamylamine & Trimethaphan causes vasodilation to reduce BP & also inhibits sympathetic reflexes
Thus can be used for initial control in HTN crisis & Production of controlled Hypotension during surgery |
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Muscle nAChR drugs
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Activators: ACh, Carbachol
Blockers: Competitive d-Tubocurarine Pancuronium Rocuronium Atracurium Mivacurium Depolarizing: Succinylcholine |
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Autonomic nAChR drugs
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Activators: ACh, Nicotine
Blocker: Competitive d-tubocurarine Hexamethonium Trimethaphan Mecamylamine Depolarizing: Nicotine |
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Sedativs vs Hypnotics
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Sedatives: Calming, decrease neurologic effects, moderate excitement. Treats symptoms of anxiety. aka anxiolytics
Hypnotics: Produce drowsiness to facilitate onset & maintenence of sleep. Treats insomnia |
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5 classes of anxiolytic & hypnotic drugs
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Benzodiazepines - Treats both anxiety & insomnia
5HT1A receptor agonists - Recently introduced & treats anxiety, alcoholism, & sexual function with low sedation. Other 5HT receptors can treat migraine & schizophrenia Barbiturates - Occasionally prescribed as both anxiolytic & sedative Beta-adrenoceptor antagonists - Reduces anxiety Z-drugs |
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PK of hypnotic-sedative drugs & special
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Main action is to inhibit neurological activity in CNS by enhancing GABA.
Gabanergic potentiation is more limited in benzodiazepines, which have widest clinical use |
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GABAa receptor characteristic & binding sites
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5 subunits that result in increased Cl- ion conductance & requires binding of 2 molecules of GABA.
GABA molecules bind at alpha1 & beta2 interfaces while Benzodiazepines bind at alpha1 & gamma2 interface. (Nonselective agonist) Barbiturates, alcohol & neuroactive steroids bind to channel on or near alpha or beta subunits. Are less specific |
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Benzodiazepines, structure, uses, mechanism of action & Special
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First introduced as anxiolytics, sedatives, muscle relaxants, hypnotics & antiepileptics
All have a benzene & diazepine ring structure Increase activity of GABA to decrease neuronal excitability & supress Reticular Activating System to cause sedation or hypnosis depending on dose & GABA receptor subunit specificity. - Also decreases sleep onset latency but increases time from onset to first burst of REM. Changes sleep architecture |
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Benzodiazepines side effects (4)
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Periphery: Coronary vasodilation & Neuromuscular blockade at very high doses
Respiration - Higher doses or when taken with opioids or alcohol can cause respiratory acidosis & apnea during anesthesia. Pts with sleep apnea should not take alcohol or benzodiazepines due to decreased muscular tone CV - Severe intoxication can decrease blood pressure & increase heart rate. Diazepam increases coronary flow probably by increasing interstitial adenosine GI - Improvement in anxiety related GI disorders |
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Alprazolam Uses, half life, metabolism, & special
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Longer acting benzodiazepine used to treat both short & long term panic disorders.
t1/2 = 12hrs Metabolized by hepatic enzymes 70% protein bound & highly abused |
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Chlordiazepoxide uses, half life & special
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Longer acting benzodiazepine used to treat anxiety & acute alcohol withdrawal. IV used to treat anxiety & acute alcohol withdrawal
t1/2 5-30 hrs Contraindication: Myasthenia Gravis |
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Clorazepate uses & half life
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Longer acting benzodiazepine used in management of anxiety disorders or symptomatic relief of acute alcohol withdrawal. Also used as adjunct to antiepileptic drugs.
t1/2 2days |
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Diazepam uses, Half life, Administration, metabolism
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Longer acting benzodiazepine used for anxiety with depression or schizophrenia, & status epilepticus
Given orally but can also be given by IV in acute situations Long acting 1-3 days Hepatic metabolism produces active metabolite |
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Lorazepam use, half life, Administration & metabolism
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Intermediate acting benzodiazepine
Half life 10-20 hrs with 2-4hr peak action. Rapidly absorbed, can given through IM in addition to PO & IV. *** Does not produce active metabolites |
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4 efficacy criteria for hypnotic treatment
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Sleep latency: Depends heavily on absorption rate
Sleep maintenence: Depends on Vd & half life Sleep architecture: Should ideally maintain physiological structure of sleep & depends on drug's mechanism of action Quality of life - Includes influence on physical, psychologica, & social aspects of pt |
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Flurazepam uses, & PK
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Shorter acting benzodiazepine used to reduce sleep induction time & increase duration of sleep. Decreased number of awakenings.
Effective up to 4 wks with apparent halflife of 2.3 hrs while plasma halflife is 40-250hrs. Peak action occurs 30min to an hr. Due to long half-life, peak hypnotic effect reached after 2-3 nights of use. |
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Temazepam use, PK, recommendation
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Intermediate acting benzodiazepine used to reduce frequent awakening
Recommended for short term use of 7-10 days Peak effect 1.5 -2 hrs after oral dose. Half life of 11 +/- 6 hrs. |
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Triazolam use, PK, side effects
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Short acting benzodiazepine for pts with recurring insomnia
3hr half-life with 1-2hr peak action. Tolerance develops in days & withdrawal produces rebound insomnia & anterograde amnesia. Use intermittently for less than 2-4 wks. May also cause severe allergic reaction |
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Flunitrazepam uses, half life & special
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Benzodiazepine that produces diazepam life-effects
18-26hr half-life Date rape drug Not legal in US & smuggled in by traffickers. |
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Midazolam use & half life
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Benzodiazepine only available as injectable form for adjunct to anesthesia.
1.8 to 6.4 hrs |
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Clonazepam use & half life
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Long acting benzodiazepine used to treat seizure disorders
18-50hr half life |
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Benzodiazepine PK (3) * Special
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Highly lipid soluble so easily absorbed orally**-Except Clorazepate- & crosses BBB. Longer activity in pts with more fat - obese & elderly
Hepatic oxidation gives long t1/2 & creates active metabolites Hepatic glucuronidation gives short t1/2 & no active metabolites Do not induce microsomal enzymes, although they are metabolized by this system. |
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Benzodiazepine mechanism characteristics (3)
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Do not have intrinsic activity but are allosteric modulators of GABA
Not all GABAa receptors bind benzos a1,2,3,5 B1,2 & g1,2 receptors are most abundant & have high affinity for benzodiazepines a4,6, delta & episilon are least abundant & do not bind benzodiazepines. Benzos with higher affinity for a1 & a5 tend to do more sedation, ataxia, & amnesia a2 & a3 tend to do more anti-anxiety |
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Zolpidem use, mechanism, PK, administration, side effect
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Ambien
Non-benzodiazepine sedative & hypnotic drug used to treat insomnia. * However, Not effective anticonvulsant or muscle relaxant. Binds to GABAa alpha subunit Half life 2hrs, peak action 1.6 hrs Absorbed from GI Les risk of dependence compared to benzodiazepines Can cause memory problems like sleep walking activities |
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Zaleplon use, PK, mechanism, side effects
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Newer class of hypnotics with rapid onset & short duration of action used for people with difficulty falling asleep.
0.5-1hr half life & peak action Acts as benzodiazepine Can cause headache, nausea, abdominal pain, & interacts with cimetidine |
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Flumazenil Mechanism, Uses Administration, Half life, Side effects
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Antagonist of Benzodiazepines for recovery from anesthesia. Sedation recurs
Delivered via IV in series of small injections & eliminated by hepatic metabolism to inactive products 0.7-1.3 hr half life Associated with Seizures |
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Barbiturates use, & mechanism
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Not currently used for anxiety or insomnia due to low therapeutic range & potent heptatic enzyme inducers. Could result in fatal respiratory depression & interactions.
Binds at separate site as benzodiazepines requiring only alpha & beta subunits. Low concentrations potentiate GABA, but higher concentrations can activate receptor. Also blocks AMPA/KA glutamate receptors to supress firing. |
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Barbiturates Pharmacology, admin, PK, & special
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CNS - Mild sedation to general anesthesia, some anticonvulsant activity
PNS - Reduce nicotinic excitation/decrease BP. Enhance effects of tubocurarine & decamethonium Respiration - Depress respiratory drive. Coughing sneezing, laryngospasm CV - Benign effects when given orally. IV can decrease renal plasma flow & CSF pressure. Also depress resting K+ conductance of heart to depress ionotropic effects. GI - Decreased GI muscle tone Liver - Interact with several P450 & interfere competitively with metabolism of drugs & steroids. Chronic admin increases rate of drug metabolism. Oral doses absorbed rapidly & completely. IV for status epilepticus or for induction & maintenence of anesthesia. Onset 30-60min after oral admin Metabolism occurs in liver via drug microsomal metabolizing system but also induces production of microsomal enzymes. * Cross placenta & more concentration in less vascular tissues such as muscle & fat. |
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Barbiturate therapeutic uses & side effects
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Not very specific compared to other hypnotic/sedatives. Short acting can be used in combo with other anesthetics in OB. Also used for narcoanalysis & narcotherapy. Treatment of convulsions for children <1yo.
Supresses REM sleep & rebound after discontinuation resulting in nightmares, anxiety & restlessness - Ataxia, incoordination, nystagmus, slurred speech, altered consciousness, respiratory depression, coma, apnea, & hypotension secondary to negative cardiac inotropic effects. * Also Pulmonary edema, hypothermia, delayed gastric emptying, skin leisions |
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Busprione mechanism, use, PK, metabolites & side effects
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Partial agonist of 5-HT1A serotonin agonist.
Can relieve anxiety without sedation, muscle relaxant, or anticonvulsant actions. Slow onset, thus not effective for panic disorders. 2-4hr half life Primary metabolite - 1-2pyrimidyl-piperazine blocks a2 adrenoceptors No withdrawal & no abuse but can cause tachycardia, palpitations, GI distress. Watch for pts with MAO inhibitors. |
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Paraldehyde use, characteristic & metabolism
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Other sedative/hypnotic drug used as anticonvulsant under emergency
Strong odor & bad smell irritates mouth & throat & causes tissue damage in stomach. Can decompose to acetic acid in open containers. |
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Meprobamate use, mechanism, side effects
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Other sedative/hypnotic drug that lies between barbiturates & benzodiazepines to treat anxiety but really sedative.
Acts on GABAa but has wide spread effects. CNS & Respiratory depression with Common hypotension |
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Chloral Hydrate uses, *special, metabolism, side effects
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Other sedative/hypnotic drug used as general CNS depressant & *has odor of pears
Rapidly converted to active metabolite in liver trichloroethanol & can be abused. Cerebellar incoordination, severe gastritis, GI bleed, multiple skin effects like blisters, hives, Erythema multiforme. |
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Glutethimide use, side effect, abuse
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Other sedative/hypnotic drug with anticholinergic effects.
May cause delayed gastric emptying, hyperthermia or heat stroke. Abused in combo with codeine b/c it induces hepatic enzymes to convert codeine to morphine |
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Ethinamate uses, mechanism
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Other sedative/hypnotic drug used as short term treatment of insomnia.
Unknown mechanism & not used frequently Loss of effectiveness after 1 wk |
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Diphenhydramine uses & mechanism
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Other sedative/hypnotic drug commonly used as antihistamine (Benadryl)
Causes sedation due to anti-cholinergic effects. |
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Valerian uses & mechanism
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Other sedative/hypnotic drug that inhibits GABA breakdown
Effectiveness is inconclusive |
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Melatonin uses & mechanism
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Other sedative/hypnotic drug that regulates sleep-wake cycle & jet lag. High doses gives direct & low doses indirect effects on GABA receptors.
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Ethchlorvynol use & side effects
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Other sedative/hypnotic drug used as CNS depressant with Rapid onset & short duration
Pungent odor or breath & gastric contents Prolonged coma ARDS predominates during IV use |
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Methaqualone use, administration, side effects
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Other sedative/hypnotic drug introduced as barbiturate substitute but quickly became common drug of abuse.
Taken orally & absorbed rapidly More pronounced motor problems - aka wallbanger Severe muscular hypertonicity & seizures |
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Psychotropic drug absorption
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Antipsychotics tend to have rapid but incomplete absorption while antidepressants are generally completely absorbed
Oral concentrate & rapid dissolving formulations act more quickly Large first pass effect, thus lower dose if antipsychotics are given IM |
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Psychotropic metabolism through p450 system
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1A2, 2C subfamily, 2D6, 3A3 & 3A4
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HIstamine H1 blockade
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Sedation, Decreased BP, Weight gain
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Muscarinic acetylcholine blockade
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Increased HR
Constipation Urinary retention Dry mouth Decreased memory Blurred vision Worsening of narrow angle glaucoma |
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a Adrenergic Blockade
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Sedation
Sexual dysfunction Decreased BP Increased Heart rate |
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Antidepressant general classes & mechanism
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SSRI
SNRI MAOI Tricyclic antidepressants Atypical antidepressants - 2nd & 3rd generation heterocyclic antidepressants Blocks NE and 5-HT reuptake sites. Also by blocking monoamineoxidase |
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Onset of action for antidepressants & adaptive changes
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All antidepressants generally require atleast 2-3 weeks for therapeutic effects to appear
Parallels adaptive changes of Decreased Neurotransmitter receptor numbers in 5HT & A2 & B adrenergic Neurotransmitter receptor affinity Decreased intracellular processes of cAMP in response to b-agonists. Neuronal firing rates |
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General effects of reuptake blockade for antidepressants
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NE - Antidepressant, Increased attention in ADHD - Tremors, tachycardia, Insomia, sexual side effects
5HT - Antidepressant, antianxiety, antiobsessional - GI distress, nausea, headache, nervousness, akathisia, sexual side effects, can increase or decrease anxiety depending on dose DA - Antiparkinsonian, & antidepressant - psychomotor activation, aggravation of psychosis |
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SSRI antidepressants
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Fluoxetine
Citalopram Escitalopram Sertraline Paroxetine Fluvoxamine |
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Adverse effects of SSRI antidepressants
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GI problems
Insomnia/Anxiety/Restlessness Sexual dysfunction Bruxism Withdrawal syndrome noted with precipitous discontinuation |
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SSRI antidepressant specific features
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Halflife same order as drug.
Paroxetine has more prominent sedation & anticholinergic effects Activation/Insomnia more prominent with Fluoxetine & Fluvoxamine Fluoxetine, Fluvoxamine, Paroxetine have high CYP450 metabolism |
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SNRI antidepressants & their specific features
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Venlafaxine
Short halflife Low plasma protein binding Minimal activity at CYP450 enzymes potential risk of increased BP at >300mg/day Desvenlafaxine - Metabolite of Venlafaxine Duloxetine Moderate half life 12hrs with some CYP metabolism |
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Atypical antidepressants
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Amoxapine
Bupropion Trazodone Mirtazapine Nefazodone |
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Bupropion type, mechanism, uses, side effects
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Atypical antidepressant also used for smoking cessation
Dopamine releasing properties, thus can activate or exacerbate psychosis. Also appears to act via NE Problems with seizures & short half-life. Esp in bulimic patients. Thus contraindicated in eating disorders. Low rates of sexual side effects |
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Trazodone type, uses, duration, mechanism, side effects
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Atypical antidepressant used primarily for insomnia
Short acting on 5HT1b & 5HT 2A/2C receptors. Risk of priapism in males |
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Mirtazepine Type, mechanism, side effects & administration
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Atypical antidepressant
a2 & 5HT receptor blockade Can result in sedation & weight gain Available in rapidly dissolving form |
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Amoxapine type, uses, side effects
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Atypical antidepressant
Rarely used Active metabolite has dopamine D2 blocking effects that are associated with Extrapyramidal symptoms, or tardive dyskinesia |
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Nefazodone type, side effects
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Atypical antidepressant
Has FDA black box warning for liver failure |
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Tricyclic Antidepressants & general features
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Clomipramine
Amitriptyline:Nortriptyline Imipramine:Desipramine Generally used as 3rd or 4th line agents after SSRI or atypical antidepressant More prominent side effects & toxicity Still used for individuals who do not respond to SSRI or atypical antidepressants |
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Tricyclic Antidepressants PK, Side effects, toxicity
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Anticholinergic properties may slow absorption in GI
Highly lipophilic & highly protein bound Half life of about 24hrs Metabolism vua hydroxylation & conjugation with glucuronic acid involving CYP2D6 Must consider active metabolites when monitoring serum levels or tertiary amine TCAs EKG - Twave flatening or inversion, prolonged conduction time, arrhythymias Seizures Sexual dysfunction, but less frequent than SSRI. Weight gain Interactions with MAOI can be life threatening Serious overdose can result in cardiac arrythmias, anticholinergic toxicity, seizures, & coma |
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MAOI members, general characteristics & forms
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Phenelzine
Isocarboxazid Tranylcypromine Originally used as antihypertensive drugs but now rarely used because of dietary reactions & other potential toxicities. Still occasionally used in some treatment resistant patients especially with atypical depressive episodes. Important to know b/c of life threatening reactions MAO-A NE, 5HT, Tyramine Blockade stimulates antidepressant action MAO-B DA, phenylethylamine At low doses is specifically blocked by seligiline & other MAO-B inhibitors which are used in Parkinson's disease |
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PK of MAOI
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Rapid absorption with moderate first pass effect & liver metabolism. No use of P450 system.
*Effective halflife depends on MAO resynthesis since MAOI antidepressants are almost all irreversibly bound to enzyme |
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Toxicity syndromes associated with MAOI
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Serotonin syndrome
Noradrenergic crisis aka hypertensive crisis |
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Serotonin syndrome
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Given in combination with MAOIs
TCAs SSRI Tryptophan Meperidine Dextromethorphan Diphenoxylate St. John's Wort Fever Abnormal muscle movements Rarely, generalized seizures May have hypotension, anxiety, agitation, shivering, enhanced startle response, confusion, shock;death |
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Noradrenergic Crises
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Can occur with MAOI given with
L-dopa OTC sympathomimetics Ephedrine, Pseudoephedrine, Phenylephrine, Phenylpropanolamine, Primatene, High doses of Caffeine. Hypertension Occipital headaches Stiff or sore neck Flushing, sweating, cold & clammy skin Arrhythmias Nausea, vomiting nosebleeds, visual disturbances, chest pain, strokes, coma, death |
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Tyramine containing foods
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Avoid with MAOI
All matured or aged cheeses Broad bean pods such as fava beans which contain dopamine Meat extract, concentrated yeast extracts Dried salted fish Sauerkraut Aged sausage Red wine, beer & sherry |
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St. John's Wort characteristics, mechanism of action, Adverse effects, drug interactions
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Herbal antidepressant
Unclear efficacy & high placebo response rates Presumably acting via hypericin and/or hyperforin Low amounts of MAOI activity but inhibits 5HT, NE and DA non-competitively. Also has some gabanergic activity Dry mouth, dizziness, GI complaints. Serotonin syndrome. Mania. Phototoxicity. Can cause serotonin syndrome if taken with MAOI Acts on CYP450 to induce CYP3A4 to decrease levels of protease inhibitors and cyclosporin Induces intestinal drug transporter P glycoprotein to decrease levels of digoxin |
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Psychosis
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Mania
Depression Schizophrenia Delusional disorder Delirium |
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Major categories of antipsychotics
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Typical
- Major tranquilizers, neuroleptics or 1st generation antipsychotics - Relatively predictable side effect profile Atypical antipsychotics - Also known as 2nd generation antipsychotics - Have diverse side effect & binding profiles |
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Therapeutic uses of antipsychotic agents
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Schizophrenia & schizoaffective disorder
- Predominant action on hallucinations, delusions & thought disorder - Possible actions of atypical agents on cognition & negative symptoms Bipolar disorder - Acute mania - Mood stabilization Tourette's disorder Suicidal behaviors - especially clozapine in schizophrenia Aggressive behaviors & agetation - only use low doses in dementia. May increase stroke risk & mortality. Adjunctive use in anesthesiology - Droperidol NOT indicated for anxiety of insomnia |
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Antipsychotic members
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Typical
Fluphenazine Perphenazine Chlorpromazine Haloperidol Atypical antipsychotics Clozapine Olanzapine Risperidone Paliperidone Quetiapine Ziprasidone Aripirazole Iloperidone Lurasidone Asenapine |
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Dopamine hypothesis & other receptor sites
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Hypothesis that antipsychotic drugs worked by blocking dopamine D2 receptors.
This was based on evidence that clinical potency correlated with D2 blockade. However, newer discoveries suggest other possible sites of dopaminergic antipsychotic drug action such as D1, D3 or D4 5HT receptors can also be involved. Olanzapine on 5HT3 & Clozapine on 5HT6 & 5HT7 NMDA blockade of glutamate receptors can also alter dopamine levels |
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5HT binding properties of atypical antipsychotics
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Highly variable across atypical agents
May contribute to therapeutic effects or some side effects such as weight gain May decrease some side effects such as EPS |
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Extrapyramidal side effects EPS due to D2 blockade, treatment
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Dystonic reactions: Torticollis, Opithotonus, Oculogyric crisis
Parkinsonism: Shuffling gait, tremor, masked facies Because of interactions between dopamine & ACh neurons in nigrostriatal pathway, anticholinergics can treat EPS. - Diphenhydramine which also has antihistamine effects, Benzotropine, Trihexyphenidryl |
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D2 receptor blockade side effects that do not respond to treatment
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Increase side effects with increased potency.
Akathisia - restlessness in legs Neuroleptic Malignant syndrome NMS - Can be fatal muscle rigidity, fever, increase in WBC. DO NOT use anticholinergics Tardive dyskinesia - Late onset side effect of antipsychotics involving mouth & tongue movements. Does not resolve after stopping drug. Due to hypersensitivity of D2. Additional blocker can supress movement in short term but bad in long term. Stopping precipitously can result in similar dyskinesia that will fade. Hyperprolactinemia - because dopamine is prolactin inhibitory factor, so blocking D2 receptors increases prolactin. Gynecomastia, galactorrhea, sexual dysfunction, amenorrhea & menstrual irregularities. |
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Dopaminergic pathways
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Mesiolimbic & mesocortical - Antipsychotic
Nigrostriatal - EPS Tuberoinfundibular - Prolactin Chemoreceptor trigger zone of medulla - Antiemetic effects Medullary preventricular - Possible effects on eating behavior. |
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Antipsychotic effects not due to D2 receptor blocking, & with Clozapine?
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More potent has less side effects
Hyperglycemia, ketoacidosis, hyperosmolar coma, or death. Weight gain QTc prolongation & sudden death particularly with mesoridazine, thioridazine, droperidol, haloperidol & perhaps ziprasidone. Sudden death may occur in absence of QTc prolongation Increased risk of stroke with increased mortality in individuals with dementia primarily with atypical agents but also typical agents Derm - hypersensitivity, photosensitivity Poikilothermia Ophthalmological effects Seizures Clozapine Neutropenia Myocarditis Tachycardia Sialorrhea |
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Antipsychotic CYP2D6 inhibitors
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Perphenazine, thioridazine, Fluphenazine
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Risperidone & Paliperidone type & side effects
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Atypical antipsychotic with greater risk of EPS, esp in high doses. Less sedation than some & once per day dosing
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Olanzapine type & side effects
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Atypical antipsychotic with significant weight gain & sedating
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Clozapine Type & side effects
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Atypical antipsychotic with sedating, common weight gain, seizure, myocarditis, agranulocytisis. Beneficial in treating resistant pts & those with high risk of suicide
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Quetiapine type & side effects
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Atypical antipsychotic
Moderately sedating with increase risk of cateracts. BID & low EPS |
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Ziprasidone type & side effects
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Atypical antipsychotic
More activating & increased risk of Inc QTc interval. Low EPS. BID |
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Apripiprazole type & side effects
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Atypical antipsychotic that acts as D2 partial agonist.
Long half-life. Active metabolite with minimal antichol effect. Low EPS |
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Goals of bipolar disorder therapy
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Treat acute symptoms during episode of mania or depression
Prevent additional episodes with prophy mood stabilizers & minimize risk of switching from depression to mania during treatment with antidepressants |
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Bipolar treatment
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Severe:
Lithium + antipsychotic Valproic acid + antipsychotic Less severe Lithium or Valproic acid alone Antipsychotic alone. Usually atypical like Olanzapine Agitation may need benzodiazepines Other anticonvulsants occasionally needed: Divalproex/valproic acid. Lamotrigine. Carbamazepine |
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Lithium mechanism of action
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Na+ Substitution - Interactions with cation transport processes by substituting with Na+.
Intracellular effects by inhibiting Phosphoinositol pathway inhibitting intracellular calcium release. Effects on glycogen synthase kinase 3 Modifies Adenyl cyclase mediated response - thyroid abnormalities, nephrogenic diabetes insipidus to inhibit ADH & competes for sodium reuptake |
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Lithium PK
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Differes from other psychotropics
Completely absorbed from GI Initial distribution to ECF followed by gradual tissue accumulation thereafter No evidence of plasma protein binding Avg half-life of 20-24 hrs. with 95% elimination in urine but 80% are reabsorbed by proximal renal tubules. Significant drug interactions & require dose adjustment for age & renal function |
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Lithium therapeutic range & toxicity
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Draw level 10-12 hrs after last dose
Acute treatment 1-1.2 mEq/L Chronic 0.7-1.0 mEq/L Can become toxic during dehydration, sodium depletion, excesive dose, medications: diuretics, ACE inhibitors, NSAIDS, calcium channel blockers - Can also occur with rapid fluctuations in levels & serious toxicity mandates dialysis 1.2-2.0 Nausea, vomiting, diarrhea, tremor 2.0-3.0 Confusion, gross tremor, seizures, hyperreflexia, focal neuro 3 - cardiac arrhythmias, coma, death |
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Chronic Lithium adverse effects
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Kidney
Nephrogenic diabetes insipidus - polydipsia, polyuria Chronic interstitial nephritis Glomerulonephropathy Thyroid - Common reversible & not contraindication to continue tx Cardiac - sinus node depression, T wave flattening Leukocytosis, allergic, cognitive, edema, weight gain, Derm - Rash, Acne, Alopecia |
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Lithium use during pregnancy
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Relative not bot absolute contraindication
Teratogenicity esp in 1st trimester CV malformations Goiter Hypotonia CNS depression |
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Valproic acid uses, dosing, side effects
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Used to treat bipolar
Used in acute mania & reasonable prophy benefit High TI. 45mg/ml - 125mg/ml Can cause neural tube defects during pregnancy |
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Lamotrigine use, side effects
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Used to treat bipolar
Can prevent mood episodes in pts with prominent bipolar depressive episodes. Risk of serious & potentially fatal rash requires titration Significant interaction with valproic acid |
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Di-Ethyl ether use, characteristics, & improvements
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Inhaled anesthetic
Hydrocarbon & is not very potent but very fat soluble. Very slow induction Newer inhalational agents were halogenated which increases potency & decreases flammability |
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Stages of Anesthesia
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I - Onset of anesthetic admin to loss of consciousness
II - Loss of consciousness to onset of surgical anesthesia III - To loss of respiration IV - To Coma/Death - Anesthetic overdose |
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Classification of types of Anesthesia
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Local - Field block, IV block, Infiltration
Regional - Spinal(Subarachnoid block), Epidural, Axillary, wrist, ankle etc |
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Componenets of general Anesthesia
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Amnesia
Analgesia Anesthesia Muscle relaxation Hemodynamic stability |
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Amnesia members & characteristics
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Diazepam
Midazolam Generally anterograde amnisia with little analgesia Referred to as sedatives or Tranquilizers |
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Analgesics in Anesthesia
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Primarily Narcotics
Morphine Fentanyl Sufentanil Remifentanil IV NSAID - Ketorolac |
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Anesthesia agents
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Induction agents
Pentothal Etomidate Ketamine Propofol Narcotics, Benzodiazepines Maintenence of Anesthesia Inhalation Anesthetics Narcotics, Benzodiazepines |
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Muscle relaxation agents
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NMJ blocking agents
Depolarizing - Succinylcholine Non-Depolarizing - Curare type Mivacurium - Short acting Atracurium/Vecuronium - Medium Pancuronium - Long Pipercurium/Doxacurium - Very long |
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Mechanism of Action of Inhalation anesthetics
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Essentially unknown
Probably no specific anesthesia receptor Many structurally different compounds produce anesthetic state Presumptually a membrane effect due to relationship between potency & lipid solubility. Generalized membrane effect can explain non-selective nature of general anesthesia. |
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Inhalation anesthetics members
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Nitrous Oxide
Diethyl Ether Cyclopropane "The ranes" - Halothane;only one brominated, Enflurane, Isoflurane, Desflurane, Sevoflurane |
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Inhalation anesthetic potency
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Measured as Anesthetic concentration in Alveolar gas
M.A.C - Minimum Anesthetic concentration in Alveolar gas that will produce immobility in 50% of patients in response to surgical stimulation Lower MAC = Higher anesthetic potency |
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Balanced anesthesia
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Lower concentrations for fewer side effects of any given drug.
Macs are additive |
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Inhalation anesthetic uptake, elimination, some physiological effects & Metabolism characteristics
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Increase uptake via concentration effect & Second gas effect by adding Nitrous.
Major elimination through lungs & only metabolized to a variable but small extent Moderate decrease on BP & Large decrease on respiration Metabolism does not affect time course of Anesthesia Toxicity is related to degree of metabolism |
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Methoxyflurane toxicity
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Diabetes Insipidus from metabolism to Fluoride
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Enflurane toxicity
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Metabolism to flouride can result in possible nephrotoxicity esp in Obese patients
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Halothane toxicity
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Hepatotoxicity: Halothane Hepatitis
Exact mechanism unknown with possible reactive intermediary metabolites of reductive metabolism Autoimmune hepatic necrosis Allergic reaction or Arterial hypoxemia |
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Sevoflurane toxicity
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Production of free flouride to cause renal toxicity & diabetes insipidus
Due to formation of Compound A through degredation with Carbon Dioxide Absorber Barylime & Sodalime. |
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Potential adverse effects of Inhalation Anesthetic agents to pt & Staff
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Respiratory & Cardiac Depression
Sensitization of heart to Catecholamines - Halothane & Methoxyflurane Malignant hyperthermia Aspiration of gastric contents Staff: Headaches, drowsiness, possible increase in spontaneous abortion, Methionine Synthetase inhibition by NO; affects DNA synt |
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Malignant Hyperthermia causes, mechanism, Physiology & Treatment
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Unique to Anesthesia
Can be triggered by Succinylcholine & Halothane but may be any inhalation agent Seen in families - Hereditary Calcium release from Sarcoplasmic Reticulum is ALtered. In some patients with MH, Ryanodine Ryr1 receptor is abnormal. Hypermetabolic State Increased Sympathetic activity Muscle Damage Hyperthemia Stop inhalation agents by switching to total IV anesthesia Cooling blankets Sodium Dantrolene, Sodium Bicarbonate |
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Termination action of non-depolarizing agents, Succinylcholine, Rocuronium
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Neostigmine or edrophonium with glycopyrrolate or atropine
Succinylcholine terminated by pseudocholinesterase NOT FDA - New approach to termination of drug Rocuronium by direct agent binding of Sugammadex |
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Local Anesthetics Nomenclature, Mechanism of action, allergic response, toxicity
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If there is an i before Caine, it is an Amide, otherwise its an ester
Blocks Sodium channels in Axon membranes to preven entry of sodium into axons Allergy is low with Esters and very low with amides. May be allergic to Epinephrine or Perservative Methylparaben CNS - Seizures, drowsiness to unconsciousness, death from respiratory depression CV - Vasodilation, Cardiac depression, Dec excitability of Myocardium & conduction, Bradycardia, A-V block, hypotension, Cardiac arrest |
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Pharmacology of Local
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Local anesthetics block open Na+ channels
Speed of onset related to pKa Duration of action related to protein binding Potency related to lipid solubility |
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Potency & duration of action of local
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Short/Low
Procaine Chloroprocaine Intermediate Lidocaine Mepivacaine Prilocaine Cocaine Long Bupivacaine Tetracaine Etidocaine |
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Effects of pH and structure activity relationships of Local anesthetics
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Locals as unprotonated Amines are only slightly soluble but sold as water soluble salts
Less effective in Acidic environments like infected areas Has hydrophilic & hydrophobic domains separated by Amide or Ester Linkage. Increased hydrophobicity increases potency & toxicity |
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Tetrodotoxin & Saxitotoxin
|
Tetrodotoxin from japanese fugu or puffer fish & from some newts & costa rican frogs
Saxitoxin may be present in shellfish that ingest certain organisms Both blocks Na channel resulting in hypotension, respiratory muscle paralysis & death |
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EMLA composition, characteristics, uses
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Mixture of 2.5% Lido with 2.5% Prilocaine
COmbination has melting point that is less than either compount alone. Thus oily prep that can penetrate intact skin Produces anesthesia to 5mm depth & needs 1-2 hrs for effect *Intact skin only |
