Term
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Definition
o Wide spectrum of clinical conditions from cardiovascular emergencies to common cold
o Catecholamines are the major effectors of sympathetic signaling
o Sympathomimetics- Mimic the actions of drugs that affect receptors sympathetic autonomic nervous system.
o Drugs affecting this system are norepinephrine (NE) and epinephrine (Epi) and dopamine (DA)
o Sympathomimetics can act directly on adrenergic receptors (adrenoceptors) or indirectly cause release of NE or Epi
o Norepinephrine (NE) is the neurotransmitter of the sympathetic postganglionic neuron
o Adrenergic neurons and receptors are located either presynaptically on neurons post-synaptically on effector organs and are the sites of adrenergic drugs |
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Term
| Catecholamine Synthesis, Storage, Release, and Reuptake Pathways |
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Definition
Synthesis- tyrosine transported by Na+ linked carrier into adrenergic neuron and hydroxylated to dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase (TH). * This is the rate limiting step in formation of NE. DOPA is decarboxylated to form dopamine (DA) by aromatic L-amino acid decarboxylase (AKA DOPA decarboxylase)
Storage- DA is transported (anti-porter) into vesicles by vesicular monoamine transporter (VMAT1 and VMAT2). Inside DA is converted to NE by dopamine β-hydroxylase. VMAT1 expressed peripherally; VMAT2 expressed primarily in CNS. Both also transport serotonin, histamine.
• In adrenal medullary cells NE diffuses or transported back into cytoplasm and converted to Epinephrine by phenylethanolamine N-methyltransferase (PNMT)
Release-Action potential arriving at nerve junction triggers Ca2+ influx into cytoplasm causes fusion of vesicles to cell membrane and release of NE into the synapse
Receptor binding- NE can bind to post-synaptic receptors on effector organ of presynaptic receptors on nerve endings. This causes intrinsic response. Adrenergic receptors use both cAMP, and IP3, DAG second messenger systems
Termination (reuptake or metabolism)-
• Reuptake catecholamine into presynaptic neurons (NE transporter)
• Metabolism of catecholamine into inactive metabolite by membrane associated catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO-A or MAO-B) mitochondrial enzyme.
• Diffusion of catecholamine away from synaptic cleft |
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Term
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Definition
| Catecholamines released from the adrenal medulla are about 80% EPI and 20% NE. Catecholamines are released into the blood and act on receptors in target tissues at some distance thereby acting as circulating hormones |
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Term
| Norepinephrine Metabolism |
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Definition
o COMT metabolizes catecholamines post-synaptically, also located in the intestinal wall
o MAO metabolizes catecholamines intraneuronally, also located in intestinal wall and liver
o Catecholamines have brief period of action when given parentally, ineffective and inactivated when given orally
o Catecholamines are polar and do not readily cross BBB, however some drugs have clinical effects (anxiety, tremor, headaches)
o Norepinephrine is degraded to metabolites by two main enzymes. Catechol-O-methyltransferase (COMT) is a widely distributed cytosolic enzyme; COMT in the liver is particularly important in the metabolism of circulating catecholamines. Monoamine oxidase (MAO), which is localized to the outer surface of mitochondria, is found in many monoaminergic (including adrenergic) neurons. COMT, MAO, aldehyde reductase, and aldehyde dehydrogenase metabolize catecholamines to multiple intermediates (abbreviated as DOPGAL, MOPGAL, DOPEG, DOMA, and MOPEG) that are eventually excreted. Vanillylmandelic acid (VMA) is the major metabolite excreted in urine. |
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Term
| Mechanisms of Action of Cocaine and Reserpine |
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Definition
o NE released into the synaptic cleft can be taken up into the cytoplasm of the presynaptic neuron by the selective NE transporter (NET), a Na+-NE co-transporter. Cytoplasmic NE concentrates in synaptic vesicles by VMAT, an H+-monoamine anti-porter.
o Cocaine inhibits the NE transporter, allowing released NE to remain in the synaptic cleft for a longer period of time. By this mechanism, cocaine potentiates neurotransmission at adrenergic synapses.
o Reserpine inhibits the VMAT, preventing the refilling of synaptic vesicles with NE and eventually depleting the adrenergic terminal of neurotransmitter. By this mechanism, reserpine inhibits neurotransmission at adrenergic synapses |
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Term
| Acute and Chronic Effects of Indirect Sympathomimetics |
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Definition
| Figure 8-2 Mechanisms of indirect-acting and direct-acting adrenoceptor agonists. Cocaine blocks norepinephrine reuptake by the catecholamine transporter. Amphetamine inhibits the storage of norepinephrine by neuronal vesicles, leading to reverse transport of norepinephrine into the synapse by the catecholamine transporter. Direct-acting agonists bind to and activate adrenoceptors. & alpha; = α-adrenoceptor; β = beta -adrenoceptor; NE = norepinephrine. |
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Term
| Catecholamine Receptors Subtypes |
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Definition
o Adrenergic Receptors (adrenoceptors)- are selective for NE and Epi. Supraphysiologic concentrations of dopamine activate some adrenergic receptors
o Divided into 3 main classes
α1,α2, β; Each of these have 3 subtypes
• α1A, α1B, α1D- activates Gq signaling PLCIP3+DAG
• α2A, α2B, α2C- activates Gi signaling inhibitory G-protein, cAMP, K+ channels (membrane hyperpolarization), and inhibit neuronal calcium channels;Net affect is decrease neurotransmitter release
• α2 receptors are found on both presynaptic neurons and post-synaptic cells.
• α2 receptors functions as auto-receptors to regulate feedback inhibition of sympathetic transmission
• β1, β2, β3- all three activate Gs (stimulatory G-proteins) cAMP and protein kinase A |
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Term
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Definition
metabolizes catecholamines post-synaptically, also located in the intestinal wall
a widely distributed cytosolic enzyme; COMT in the liver is particularly important in the metabolism of circulating catecholamines |
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Definition
metabolizes catecholamines intraneuronally, also located in intestinal wall and liver
is localized to the outer surface of mitochondria, is found in many monoaminergic (including adrenergic) neurons |
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Term
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Definition
Catecholamines have brief period of action when given parentally, ineffective and inactivated when given orally
Catecholamines are polar and do not readily cross BBB, however some drugs have clinical effects (anxiety, tremor, headaches) |
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Term
| Indirect Adrenergic Agonists |
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Definition
Releasing Agents
Uptake inhibitor
MOA Inhibitors
COMT Inhibitors |
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Term
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Definition
| activates Gq signaling PLC -> IP3+DAG |
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Term
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Definition
| activates Gi signaling inhibitory G-protein, (down) cAMP, K+ channels (membrane hyperpolarization), and inhibit neuronal calcium channels;-> Net affect is decrease neurotransmitter release |
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Definition
α2 receptors are found on both presynaptic neurons and post-synaptic cells.
α2 receptors functions as auto-receptors to regulate feedback inhibition of sympathetic transmission |
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Definition
| all three activate Gs (stimulatory G-proteins) (up) cAMP and protein kinase A |
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Term
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Definition
Expressed effector organs: Gs, increase cAMP
Heart: Primarily located on the heart, chronotropy (heart rate), inotropy (force of contractility) mediated by phosphorylation of Ca2+ channels, dromotropy (AV node conduction velocity), lusitropy (myocardial diastolic relaxation), overall increase in cardiac output, CO2 and O2 consumption.
Renal juxtaglomerular cells: renin secretion, renin converts angiotensinogen Angiotensin I angiotensin converting enzyme (ACE) Angiotensin II leads to an increase in blood pressure |
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Term
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Definition
Expressed effector organs: Gs, increase cAMP
Smooth muscle: vasodilation (relaxation)
Liver: glycogenolysis (breakdown of glycogen to glucose), gluconeogenesis (formation of glucose)
Skeletal muscle: glycogenolysis, K+ uptake
Lungs: bronchodilation
Uterus: stimulation leads to uterine relaxation
Pancreas: stimulation causes release of insulin
Abdominal viscera: motility
Somatic motor neuron terminal (voluntary muscles; tremors) |
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Term
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Definition
Expressed effector organs: Gs, increase cAMP
Adipose Tissue: lipolysis |
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Term
| α-receptors the rank order of potency is |
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Definition
| o Epinephrine ≥ Norepinephrine >> Isoproterenol |
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Term
| β-receptors the rank order of potency is |
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Definition
| o Isoproterenol > Epinephrine > Norepinephrine |
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Term
| Direct-Acting Adrenergic Agonist |
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Definition
o 5 Commonly used in therapy:
Dobutamine (synthetic)****
Isoproterenol (synthetic)***
Epinephrine **
Norepinephrine*
Dopamine
o *Affinity for β-receptors increases as the group on the amine nitrogen gets larger |
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Term
| Direct Acting Adrenoceptor Agonist Catecholamine |
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Definition
• Epinephrine*
• Norepinephrine*
• Dopamine*
• Dobutamine*
• Isoproterenol* |
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Term
| Direct Acting Adrenoceptor Agonist Noncatecholamines |
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Definition
• Albuterol*
• Clonidine*
• Phenylephrine* |
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Term
| Indirect-Acting Adrenoceptor Agonist |
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Definition
Amphetamine*
Cocaine*
Tyramine* |
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Term
| Mixed-Acting Adrenoceptor Agonist (Direct and Indirect) |
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Definition
Ephedrine
Pseudoephedrine |
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Term
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Definition
o Dopamine (DA) receptors is activated by DA but not by other adrenoceptor agonist
o However, DA is a catecholamine with mixed actions
o Prominent CNS neurotransmitter but does not cross blood brain barrier (BBB)
o Activates 1 or more subtypes of catecholamine receptors in periphery
o Continuous IV infusion (low dose< 2μg/kg/min) activates D1 receptors in renal, mesenteric, and coronary vascular beds
o D1 receptors activates adenylyl cyclase in vascular smooth muscle cAMP and vasodilation (relaxation)
o D2 modulate neurotransmitter release, cAMP
o At higher rates (2-10μg/kg/min) of infusion dopamine is positive inotrope through β-1 adrenoceptors
o At even higher rates (>10 μg/kg/min), dopamine acts on vascular α-1 adrenoceptors to vasoconstriction
o Dopamine is used in treatment of shock particularly from low cardiac output cases and compromised renal function (oliguria- low renal output) |
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Term
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Definition
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Term
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Definition
| inadequate cardiac function |
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Term
| Neurogenic or septic shock |
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Definition
| inadequate vasomotor tone |
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Term
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Definition
| severe immediate hypersensitivity reaction, manifested by hypotension and difficulty breathing |
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Term
| Hypertrophic subaortic stenosis |
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Definition
| a form hypertrophic cardiomyopathy, a condition that impedes the ejection of blood from the ventricles and reduces cardiac output |
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Term
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Definition
| a benign condition characterized by involuntary trembling of the hand |
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Term
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Definition
| patients experience tachycardia and palpitations because thyroid hormones increase the effects of sympathetic stimulation on the heart |
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Term
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Definition
| hypotension that is most marked in the upright position; caused by venous pooling (typical of α-blockade) or inadequate blood volume (caused by blood loss or excessive diuresis) |
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Term
| Therapeutic effects of adrenoceptor antagonists are cause primarily by |
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Definition
blockade of α1 or β1 receptors, whereas adverse effects tend to be related to blockade of α2 or β2 adrenoceptors
Blockade of α1 relaxes vascular and other smooth muscle tissue, whereas blockade of β1 reduces sympathetic stimulation of the heart |
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Term
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Definition
o Local anesthetics (LA) exert their effect by mainly blocking voltage gated sodium channels, thus inhibiting the propagation of action potentials along neurons
o LAs prevent transmission of information to and from the CNS
o LA actions are not selective for pain fibers and can also block various sensory fibers such as autonomic and motor fibers and the action potential of heart and skeletal muscle |
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Term
| Nociceptors vs. Mechanoreceptors |
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Definition
o Tissue damage is considered the primary stimulus for activation of Nociceptors (i.e. hot stove, slam a door on fingers, etc)
o Mechanoreceptors respond to low threshold or tactile sensory fibers |
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Term
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Definition
Myelinated Aδ-fibers impulse faster than do nonmyelinated C-fibers
Aδ-fibers transmit what is called first pain, which is quick, sharp “pinprick-like” description and perceived as highly localized to a specific region of the body
Aδ-fiber density is high on fingertips, face, lips, low on the back
Aδ-fibers require weaker stimulus for excitation than do C-fibers |
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Term
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Definition
C-fibers are usually polymodal, which means a single fiber can be activated by noxious thermal, chemical, or mechanical stimuli
C-fibers are associated with second pain, which is slower to develop but longer lasting, dull type, throbbing, or burning, is only diffusely localizable, continues after stimulus ends |
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Term
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Definition
o Analgesics are specific inhibitors od pain pathways, whereas local anesthetics are nonspecific inhibitors of peripheral sensory (including pain), motor, and autonomic pathways.
Analgesics act at specific receptors on primary nociceptors and in the CNS
For opioid analgesics (which activate opiate receptors) potassium conductance in postsynaptic neurons, and calcium entry in presynaptic neurons… thus postsynaptic excitability and presynaptic transmitter release are reduced , and pain sensations are NOT transmitted effectively to the brain
Transmission to other sensations and motor projections is not affected |
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Term
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Definition
o Local Anesthetics inhibit conduction of action potentials in ALL afferent and efferent nerve fibers, usually in peripheral nervous system.
Pain and other sensory modalities are not transmitted effectively to brain, motor, and autonomic impulses are not transmitted effectively to muscles and end organs in the periphery |
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Term
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Definition
o Primary (1°) nociceptors have cell bodies in the dorsal root ganglion and synapse with secondary (2°) afferent neurons in the dorsal horn of the spinal cord.
Primary afferents use the neurotransmitter glutamate. |
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Term
| secondary (2°) afferent neurons |
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Definition
| The 2° afferents travel in the lateral areas of the spinal cord and eventually reach the thalamus, where they synapse with tertiary (3°) afferent neurons |
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Term
| tertiary (3°) afferent neurons |
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Definition
| The processing of pain is complex, and 3° afferents have many destinations including the somatosensory cortex (localization of pain) and the limbic system (emotional aspects of pain). |
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Term
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Definition
| o Procaine (A) and lidocaine (B) are prototypical ester-linked and amide-linked local anesthetics, respectively. Local anesthetics have an aromatic group on one end and an amine on the other end of the molecule; these two groups are connected by an ester (-RCOOR′) or amide (-RHNCOR′) linkage. In solution at high pH, the equilibrium between the basic (neutral) and acidic (charged) forms of a local anesthetic favors the basic form. At low pH, the equilibrium favors the acidic form. At intermediate (physiologic) pH, nearly equal concentrations of the basic and acidic forms are present. Generally, ester-linked local anesthetics are easily hydrolyzed to a carboxylic acid (RCOOH) and an alcohol (HOR′) in the presence of water and esterases. In comparison, amides are far more stable in solution. Consequently, amide-linked local anesthetics generally have a longer duration of action than do ester-linked anesthetics. |
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Term
| Chemistry of Local Anesthetics Aromatic group |
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Definition
| influences hydrophobicity of the drug. Adding alkyl substitutes on the aromatic ring or amine nitrogen hydrophobicity of the drug |
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Term
| Chemistry of Local Anesthetics Amine group |
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Definition
| influences charge on the drug |
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Term
| Chemistry of Local Anesthetics Ester or amide linkage |
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Definition
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Term
| Chemistry of Local Anesthetics |
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Definition
o LAs are weak bases
o LAs are hydrophobic
target site, which is the cytoplasmic side of the voltage gated sodium channel
o As hydrophobicity so does the membrane permeability of the drug
o A local anesthetic MUST partition into, diffuse across, and dissociate from the membrane into the cytoplasm; compounds that exhibit this character have moderate hydrophobicity. These drugs are most effective clinically |
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Term
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Definition
Topical LAs provides short-term pain relief to mucous membrane and skin
Epidermal barrier presents some obstacle
A mixture of tetracaine, epinephrine, and cocaine (TAC) is sometimes used for suturing small cuts
Pruritus (itching) by poison ivy, insect bites, eczema, cutaneous manifestation of systemic diseases such as chicken pox |
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Term
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Definition
Is used to numb an area of the skin or mucosal surface via injection
The LA is injected intra-dermally or subcutaneously often at several sites around the area
Produces faster numbness than topical
Used in dental procedures |
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Term
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Definition
This technique uses a small electric current to force molecules of anesthetics into tissue
A needle free device (trade name Zingo) delivers powered lidocaine by rapid gas pressure
Primarily for dentistry, approved for children |
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Term
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Definition
Minor Nerve block is typically use for distal extremities (i.e. radial nerve, digits)
Major nerve block would block larger regions (i.e. brachial plexus, entire limb)
Other peripheral blocks include: intercostal (anterior abdominal wall), cervical plexus block (neck surgery), sciatic and femoral block (lower limb) |
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Term
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Definition
| LA delivered near the spinal cord; epidural anesthesia, intra-thecal (spinal) |
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Term
| Intravenous Regional Anesthesia |
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Definition
| Also called Bier’s block; LA is injected into a vein in the extremity and a tourniquet prevents systemic toxicity by limiting blood flow to and from the extremity |
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Term
| Therapeutic Applications of Lidocaine |
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Definition
Peripheral nerve block, epidural, spinal, topical anesthesia,
Class I anti-arrhythmic
Pruritus (itching) by (poison ivy, |
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Term
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Definition
Short acting ester-linked; low hydrophobicity
1st synthetic LA
A metabolite of procaine para-aminobenzoic acid (PABA) is a known allergen; can exacerbate bacterial infections.
Therapeutic Applications of Procaine
Infiltration anesthesia for dental procedures
Diagnostic nerve block |
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Term
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Definition
Ester-linked and naturally occurring LA. First anesthetic to be discovered
Medium duration of action
Primary use is is for ophthalmic anesthesia and part of TAC (tetracaine, adrenaline, cocaine)
Marked vasoconstriction action due to inhibition of catecholamine uptake in PNS and CNS
Cardio toxicity and the potential abuse limits its therapeutic use |
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Term
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Definition
The “caine” ending on each drug indicates local anesthetic
Most commonly used; amide-linked drug moderate hydrophobicity
Initially causes vasoconstriction but later times produces vasodilation
Biphasic actions may be due to separate actions on the sympathetic nerves that innervate arterioles and vascular smooth muscle
Bronchodilation is also affect biphasically; initial bronchoconstriction, then subsequent bronchodilation
LAs act as anti-arrhythimics due to the ability to prevent ventriculuar tachycardia and ventricular fibrillation
LA s cause have negative inotropic activity on the heart
Lidocaine’s DOA is approximately 1-2 hrs. The amide linkage prevents degradation by plasma esterases. |
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