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295 Cards in this Set
- Front
- Back
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____nidine
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alpha 2 agonist
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______terol
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beta 2 agonist
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______osin
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alpha 1 antagonist
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_____olol
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Beta antagoinist
ol ol double beta blockage |
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_____stigmine
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AChE inhibitor (carbamate type)
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Ionotropic receptors are primarily acted upon by what 2 types of neurotransmitters?
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amino acid transmitters
ACh (nicotinic receptors) |
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G-Protein coupled receptors are primarily acted upon by what 3 types of neurotransmitters?
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monoamine transmitters
polypeptide transmitters ACh (muscarinic) |
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Name 2 excitatory NTs in the CNS
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glutamate and aspartate produce EPSPs
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Name 2 inhibitory NTs in the CNS
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GABA and Glycine produce IPSPs
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The first synapse for any efferent autonomic transmission involves what receptor type and what NT?
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Nicotinic Receptor
ACh = neurotransmitter |
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A neuromuscular junction of the somatic system involves what receptor type and what NT?
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Nicotinic
ACh |
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The final synapse of parasympathetic transmission involves what receptor type and what NT?
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Muscarinic Receptor
ACh |
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The final synapse of a sympathetic transmission to a sweat gland involves what receptor type and what NT?
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Muscarinic Receptor
ACh |
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The final synapse of a sympathetic transmission to cardiac smooth muscle, to a gland cell (other than sweat glands), or to a nerve terminal involves what receptor type and what NT?
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Alpha or Beta Adrenergic Receptor
NE = NT The neuroeffector junctions fo the SNS are usually noradrenergic. |
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The final synapse of a sympathetic transmission to a renal vascular smooth muscle involves what receptor type and what NT?
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Dopaminergic Receptor
Acted on by Dopamine |
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Which portion of the ANS is considered to be the craniosacral division?
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Parasympathetic
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Portion of the ANS called the thoracolumbar division
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Sympathetic
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The ganglia of the PSNS are located close to or far from their effector organs?
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Close to or in the effector organ
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Alpha 1 adrenergic receptors cause:
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smooth muscle contraction
via elevation of intracellular Ca++ (G protein--> phospholipase C--> IP3 & DAG) |
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Alpha 2 adrenergic receptors cause:
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in CNS: depress sympathetic tone
Presynaptic autoreceptors: decrease release of NE in PNS Mechanism: Gi--> - adenylate cyclase --> - cAMP |
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Beta-1 receptors cause:
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Heart: + CO (+chronotropic, ionotropic, dromotropic)
Kidney: + renin Mechanism: Gs--> + adenylate cyclase--> +cAMP |
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Beta-2 receptors cause:
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smooth muscle relaxation
Mechanism: Gs--> + adenylate cyclase--> + cAMP |
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Many tissues have both alpha1 and beta-2 receptors. What happens when a drug that acts on both receptors, such as Epi, is administered?
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dose dependent effect
Low dose--> more Beta-2 effect High dose--> more alpha-1 effect |
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DA receptors cause:
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receptors in renal blood vessels and in mesentery: vasodilation
in CNS: psychostimulant effects (parkinson's dz) |
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What is Mydriasis and which division of the ANS causes it?
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pupil dilation
sympathetic effect |
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What is miosis and what division of the ANS causes it?
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pupil constriction
PSNS effect |
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What are the effects of the ANS on the lens of the eye?
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SNS: focus for far vision (via relaxation of ciliary mm and flatttening of lens)--> SNS allows you so perceive a threat coming from far away
PSNS: near vision ("rest and read") via contraction of ciliary muscles to render the lens more round |
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Describe autonomic control of the glands
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SNS: secretion by sweat glands (cholinergic) & the adrenal medulla
PSNS: most glandular secretions |
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Describe the autonomic effects on metabolism.
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SNS: increase blood sugar (expend energy)
PSNS: conserve energy |
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Describe 2 general ways that mimetic agents (agonists) work.
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Agonists: stimulate receptor directly
Indirect Agonists: increase release or block removal of NT |
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Name 2 general ways that Lytic agents (antagonists) work.
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Antagonists: block receptor directly
Interfere with 1 or more presynaptic steps (synthesis, storage, release) to decrease amount of NT in synapse |
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What's the big deal about quaternary amines?
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they are permanently charged, unlike primary, secondary, or tertiary amines, and are therefore lipophobic--> cannot penetrate membranes
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How is DOPA, a catechol, able to cross the BBB?
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It's a catachol-amino acid, so it uses amino acid transporters to enter the brain before being converted to dopamine (DA).
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Synthetic Process of Catecholamine NTs
What's the rate limiting enzyme? |
tysrosine --> DOPA --> dopamine --> NE --> Epi
The 1st step is rate limiting: tyrosine hydroxylase hydroxylates the amino acid, tyrosine, to form a catechol, DOPA |
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What is adrenalin?
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a mixture of 80% Epi & 20% NE in the chromaffin cells of the adrenal medulla
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Reuptake is the major mechanism for terminating an NT's effect. But two enzymes offer an alternative means for termination by metabolizing catecholamines:
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MAO (monoamine oxidase): knocks off the amine
COMT (catechol-O-methyltransferase): acts at the catechol end |
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Blood and urinary metabolites of the catecholamines:
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Epi and NE --> VMA (vanillyl mandelic acid)
DA --> HVA (homovanillic acid) |
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Rule of thumb for beta receptor selectivity amongst the adrenergic agonists:
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bigger alkyl groups on the amine group increasingly favor beta receptors:
isoproterenol > Epi > NE |
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What is the significance of COMT metabolism of catechols?
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It shortens their half-life
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Adrenergic agonists that are catechols (ring OHs) have maximum potency but...
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decreased lipid solubility --> poor oral absorption & little CNS activity
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Name the 2 direct acting adrenergic agonists.
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DA & Epi
The OH groups on their rings make these catechols, meaning they are lipophobic and thus must act directly at receptors rather than entering cells to influence NT release. Potentiated by reuptake blockers. |
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Name 2 adrenergic agonists that act mostly as indirect agonists (releasers).
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Amphetamine & Ephedrine
These are not catechols. They don't have ring OHs. Therefore, they are lipophilic and can enter cells to increase release of or block removal of NTs. Major site of action is presynaptic (must get into terminal to work). These are therefore inhibited by reuptake blockers. |
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Phenylephrine
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alpha-1 receptor agonist
Produces Bradycardia indirectly (b/c heart has only beta-1 receptors): alpha 1 receptors--> vasoconstriction --> + BP --> baroreceptors +PSNS & -SNS tone to heart --> - HR Brand Names: Neo-synerphrine, Phenoptic, Sinex |
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Epinephrine
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Adrenergic Agonist
endogenous hormone & CNS NT efficaceous at both alpha & beta receptors => dose dependent effect can lead to biphasic response Low dose --> beta-1 (cardiac stimulation) High does--> alpha-1 (vasoconstriction) Tx of shock via vasoconstriction Included with local anesthetics to confine & prolong action Tx of allergies (beta agonist effect) Cardiostimulant Brand Names: Adrenali, EpiPen |
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Effects of a Medium Dose of Epinephrine
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Total Vascular R: unchanged
- R in skeletal mm: B2 +R in other areas: A1 +CO: Beta-1 +BP: due to +CO |
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IV injection of Epinephrine
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large + BP initially & + C.O. b/c alpha-1 stimulation causes vasoconstriction and b/c beta-1 receptors increase CO (as the drug reaches the heart first after IV injection)
as drug is distributed/ metabolized, Beta-1 stimulation predominates --> -BP and + CO |
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Methoxamine
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alpha-1 selective receptor agonist
for rapid +BP in hypotensive emergency |
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Norepinephrine
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The Noradrenergic NT
good alpha and Beta-1 agonist weak beta-2 agonist |
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Clonidine
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selective alpha-2 receptor agonist
acts on alpha-2 receptors in brain to -SNS outflow to PNS -NE release from nerve terminals via presynaptic alpha-2 autoreceptors antihypertensive |
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Brimonidine
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selective alpha-2 receptor agonist
acts on alpha-2 receptors in brain to --SNS outflow to PNS --NE release from nerve terminals via presynaptic alpha-2 autoreceptors lowers IOP in open angle glaucoma |
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Tizanidine
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selective alpha-2 receptor agonist
acts on alpha-2 receptors in brain to -SNS outflow to PNS -NE release from nerve terminals via presynaptic alpha-2 autoreceptors for management of spasticity ---nidine = alpha 2 agonist Think: Resolution: "Tiz" the season to stop spazzing |
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Methyldopa
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alpha-2 receptor agonist (Prodrug)
prodrug converted to active agent (alpha-CH3-NE) in CNS and in nerve terminal alpha-CH3-NE is selective alpha-2 receptor agonist in the CNS & at presynaptic a2-autoreceptors antihypertensive agent |
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Ergot Alkaloids
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Partial Alpha Agonists
group of compounds with mixed alpha partial agonist and antagonist actions--> very nonselective produced from fungal contamination of grains |
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Dopamine
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DAergic NT
can produce renal vasodilation (DA receptors in renal vessels) Dose Dependent Effect: DA > Beta> alpha-1 (DA receptors in kidney vasculature maintain renal blood flow even at high doses) Effect on adrenergic receptors (alpha, beta) similar to Epi--> potent cardiac stimulant doesn't cross BBB controls motor activity in caudate-putamen area of brain associated with positive reinforcement in limbic area of brain Tx of shock via vasoconstriction |
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Ephedrine
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Partial Indirect Adrenergic Agonist
part of its action due to release of NE (stimulation of alpha & beta-1 receptors) mild cardiac stimulation active agent in Ephedra |
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Pseudoephedrine
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Partial Indirect Adrenergic Agonist
part of its action due to release of NE (stimulation of alpha & beta-1 receptors) mild cardiac stimulation available OTC as a decongestant simple chemical modification can produce methamphetamine Brand Names: Sudafed, Triaminic |
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Amphetamine
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Indirect Adrenergic Agonist
stimulates release of catecholamine from monamine terminal--> much of its action due to NE release Brand Name: Adderall major CNS action, elevation of central DA levels --> positive reinforcement tx ADHD, Schedule II DEA controlled agent (illicit use as psychostimulant, primarily methamphetamine, a more potent form of amphetamine) high doses--> pronounced cardiac stimulation |
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Methylphenidate
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Indirect Adrenergic Agonist
stimulates release of catecholamines (NE) from monoamine terminals important b/c of use in ADHD & illicit use as psychostimulant (primarily methamphetamine, a more potent form of amphetamine) high dose --> pronounced cardiac stimulation somewhat less active than amphetamine Brand Name: Ritalin Schedule II DEA controlled agent |
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Tyramine
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Pure Indirect Adrenergic Agonist
not a therapeutic agent natural constituent in some food (high levels in fermented foods) normally inactivated by MAO--> important interactions with MAO inhibitors MAO inhibition --> conversion to octopamine (false transmitter)--> octopamine accumulates in adrenergic synaptic vesicles--> sympatholytic effects--> -BP |
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Isoproterenol
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Pure Beta Receptor Agonist
Tx: management of bronchospasms cardiostimulant (beta 1 agonism) potent cardiac stimulant but also potent vasodilator--> produces +++HR & C.O. as result of both direct Beta-1 stimulation and indirect effect mediated by --BP (due to beta-2 mediated vasodilation) |
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Dobutamine
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Selective Beta-1 Agonist
cardiac stimulation with few other ANS side effects (no smooth muscle relaxation) Tx of shock via vasoconstriction Cardiostimulant |
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Albuterol
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Selective Beta-2 Agonist
bronchodilator with few cardiac side effects for bronchospasms, asthma, COPD ----terol = beta 2 agonist |
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Levalbuterol
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Selective Beta-2 Agonist
bronchodilator with few cardiac side effects levorotatory isomer of albuterol tx for bronchospasms, COPD |
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Semeterol
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Selective Beta-2 Agonist
bronchodilator with few cardiac side effects inhaler for bronchial asthma |
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Mydriatic agents
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dilate pupils
alpha-1 agonists (Phenylephrine) |
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Mechanism of Action of agents that produce vasoconstriction in the eye
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alpha 1 agonism
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for the treatment of narcolepsy
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CNS stimulants (methylphenidate, amphetamine)
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Agents that target smooth muscle for the treatment of allergies
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Beta agonists (ephedrine, epinephrine)
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for the treatment of migraine headaches
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Ergots
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--nidine ending
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selective alpha-2 receptor agonists
think: nidine sounds like "knitting", which is what ppl with very little SNS tone would do (alpha 2 stimulation decreases SNS tone) |
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---terol ending
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beta-2 selective adrenergic agonists
=bronchodilators with few cardiac side effects |
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---osin ending
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alpha blockers that target alpha-1 > alpha-2 (vasoconstriction > SNS depression)
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Phentolamine
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nonselective alpha receptor antagonists
competitive, reversible a1 = a2 ~short duration of action (min - hrs) lower BP in acute situation Tachycardia = side effect: b/c alpha-1 receptors blocked--> --BP --> + CO (due to SNS compensation); AND b/c alpha-2 receptors blocked --> no brake on SNS activity Tachycardia side effect makes this nonselective alpha blocker a porr drug for long-term antihpertensive tx |
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Phenoxybenzamine
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Irreversible Alpha Blocker
nonselective: alpha1 = alpha2 long acting, irreversible (suicide) antagonist tx of pheochromocytoma --BP in acute situation tachycardia side effect and thus poor drug for long-term antihypertensive tx a prodrug Think: this is the "Benz" of antihypertensives, a long acting (irreversible) alpha antagonist |
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What drugs are good for managing chronic hypertension and why?
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selective alpha-1 antagonists (Doxazosin, Prazosin, Tamsulosin, Terazosin)
These drugs are selective alpha-1 agonists. They don't block alpha 2 autoreceptors. This prevents the tachycardic side effect seen with nonselective alpha blockers, whereby there is no brake on attempted SNS compensation for decreased BP (i.e. attempted +CO) |
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Doxazosin
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Selective alpha-1 Receptor Antagonist
tx of BPH (benign prostatic hyperplasia) & hypertension much less tachycardia than nonselective alpha blockers (b/c nonselective alpha antagonists block alpha-2 receptors, increasing SNS tone to heart) --osin = alpha-1 blocker Think: "Oh, sin", antagonist to the alpha, the omega, the number 1 |
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Prazosin
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Selective Alpha-1 Adrenergic Receptor Antagonist
tx of hypertension less tachycardia than nonselective alpha blockers ---osin = alpha 1 antagonist Think "Oh, Sin" you block out the alpha, the omega, the number 1 |
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Tamsulosin
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Selective alpha-1 Receptor Antagonist
tx of BPH (benign prostatic hyperplasia) & hypertension much less tachycardia than nonselective alpha blockers ---osin = alpha-1 antagonist Think: "Tamp" down su prostate, su BP |
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Terazosin
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Selective alpha-1 Receptor Antagonist
tx of BPH (benign prostatic hyperplasia) & hypertension much less tachycardia than nonselective alpha blockers Think: "Tera o' sin" = land of sin = excess male genitalia & anything else that might elevate your blood pressure |
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What is the phenomenon of epinephrine reversal (alpha blocker context)?
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Alpha blockers convert pressor to depressor response
Epi normally stimulates alpha-1 (vasoconstriction) and Beta-1 (++C.O.) receptors A Large dose of Epi produces mainly an alpha response (resembles alpha agonist/pressor effect of Pheylephrine) == + BP But an alpha blockade changes this to a net depressor (--BP) effect because Epi can only act on its beta receptors (resemble effect of isoproterenol, a pure beta agonist) |
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Side Effects of Alpha Blockers
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postural (orthostatic) hypotension, particularly first dose effect
With non-selective alpha blockers: tachycardia --> arrhythmias, angina PSNS predominance (nasal stuffiness, urinary incontinence, poor night vision) |
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Cardioselective agents
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selective beta-1 blockers
Esmolol & Atenolol Think: "Attenuate" the heart, "Es"pecially via beta-1 blockage |
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Structural Features of Beta Blockers vs. Beta Agonists
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Beta Agonists:
Catechols Larger the alkyl group on the amine, more selective for Beta receptors Beta Blockers: Larger ring structures bind to receptors without producing effect (no intrinsic activity) |
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--lol ending
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almost always Beta Blockers
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--olol ending
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beta blocker plus a few other actions
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--lil (alil, ilil) ending
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beta blocker with some other partial action
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3 syllable beta blockers
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non-selective
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beta blockers with 4 syllable names
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cardioselective (beta-1 selective)
exceptions: Esmolol = beta-1 blocker (cardioselective) with 3 syllables in name Propanolol = nonselective beta blocker with 4 syllables (the prototypic beta blocker) |
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Which typically have a longer half life, beta blockers eliminatd by metabolic transformation in the liver of those eliminated by the kidneys largely unchanged?
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those eliminated by kidney
Liver metabolism works quickly |
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Treatment of Pronounced Vasoconstriction as in Raynaud's Dz or Pheochromocytoma (tumor of adrenal medulla)
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nonselective alpha blockers
Phenoxybenzamine Phentolamine |
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Propranolol
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prototypic Beta blocker
nonselective: beta1= beta2 attn: doesn't follow syllabic rule for beta blockers--this 4 syllable beta blocker is nonselective large ring structure (not a catechol) attached to amine allows drug to bind and block beta receptors with no intrinsic activity liver elmination (~short half life) & marked first pass effect -> poor bioavailability (caution: decreased liver function can cause high blood levels and toxicity) Tx: primarily cardiovascular--> attenuate SNS Beta receptor activation to heart --> decreased HR, BP C.O. -HT, angina, cardiac palpitations, arrhythmias tx during and after acute MI to --BP with aneurysms Brand Name: Inderal |
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Timolol
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nonselective Beta Blocker
beta1 = beta2 Tx: glaucoma, elevated IOP Tx: HT, prophylaxis post-MI, management of migraines (remember that Beta Blockers cause initial rise then a fall in BP) |
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Atenolol
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Cardioselective (Beta-1) Blocker
Tx: HT, angina --olol ending = Beta Blocker 4 syllables = beta-1 selective |
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Esmolol
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Cardioselective (Beta-1) Blocker
short acting (liver elimination) short half life = amenable to IV admin. in ICU (adverse rxn? infusion stopped & drug gone quickly) management of tachycardia Brand Name: BreviBloc |
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Labetalol
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Mixed Adrenergic Antagonist
blocks Beta (1 & 2) > Alpha receptors mixed action produces less increas in vascular R upon initial administration due to some alpha-1 blockade; also this beta blocker has some beta agonist activity antihypertensive Think: work in a "lab" to figure out a very exact way to decrease BP (like 'carving out' an antihypertensive treatment via carvedilol)) |
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Carvedilol
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Mixed Adrenergic Antagonist
blocks Beta (1 & 2) > Alpha receptors mixed action produces less increase in vascular R upon initial administration due to some alpha-1 blockade antihypertensive Think: allows you to "carve" out a tx for HT b/c stimulating both alpha & beta receptors causes a less severe initial rise in BP |
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Why give a beta blocker to a patient with HT?
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Blocking vasodilatory beta-2 receptors causes HT initially, but there is a gradual decrease in BP after several days b/c:
1) beta-1 blockage causes --C.O. 2) some blockade of renin release form kidney 3) perhaps effects due to blockage of beta receptors in CNS (sedation, depression) Furthermore, some beta blockers are also partial beta agonists (i.e. Labetalol). And, some beta blockers also block alpha receptors' vasoconstrictive effect (Carvedilol & Labetalol) |
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2 Effects of Beta Blocker on Eyes
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Block SNS tone to ciliary muscle --> contraction --> near vision (far vision difficult when can't relax ciliary mm)
lower intraocular Pressure by decreasing production of aqueous humor |
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Beta Blockers effects on Respiratory tract
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Bronchoconstriction
beta blockers CONTRAindicated in asthmatics Blockade of beta-2 receptors --> bronchoconstriction Beta-1 selective (cardioselective) blockers preferred in order to avoid bronchoconstriction (atenolol, esmolol) |
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Metabolic Effects of Beta Blockers
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Blockage of beta-2 inhibits lipolysis & glycogenolysis;
--HDL b/c Beta-2 receptors normally serve to increase blood sugar (cause glycogenolysis and gluconeogenesis) |
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Risk with Beta Blockers in Type II Diabetics
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Beta blockers lower blood sugar
b/c SNS normally raises blood sugar by acting on beta-2 receptors hypoglycemia may be a problem in diabetic patients |
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Beta Blocker Toxicity
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can result in CHF, AV block
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Abrupt withdrawal of beta blockers can cause:
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continuous admin. of beta blockers (as would be required for management of chronic cardiovascular problems) results in upregulation of beta receptors (attempt by body to overcome effect of blocked receptors)
withdraw medication and there are too many beta receptors--> beta stimulation is overwhelming --> MI, angina, arrhythmias |
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Effect of Beta Blockers on Renin secretion
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Beta-1 receptors in kidney --> +renin
so blockage will decrease plasma renin |
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4 categories of drugs that act on presynaptic nerve terminal:
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1) drugs that interfere with storage &/or release of NT
2) the DOPA drugs 3) drugs that block NT reuptake 4) drugs that inhibit metabolism (inhibitors of MAO & COMT) |
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Indirect Agonists
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indirect stimulation by affecting NT release
prototype = amphetamine not catechols (no OH on ring) so lipid soluble, long duration, and no COMT metabolism Major site of action: presynaptic inhibited by reuptake blockers (must gain entry to nerve terminal in order to exert effect; if they can't get in, they can't do their work) tachyphylaxis dvps (= desensitization due to upregulation of receptors) receptor selectivity no greater than NT itself |
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General Features of the Inhibitors of NT storage &/or Release
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key is that they must get inside the nerve terminal in order to do their work
actions prevented by reuptake blockers (some antidepressants, cocaine) long duration of action (protected within nerve terminal) supersensitivity develops to direct agonists (due to upregulation of receptors on post-synaptic nerve) renders releasers (amphetamine, ephedrine, methylphenidate) less effect (less NT in vesicles, so less released) |
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Reserpine
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Sympatholytic
Presynaptic Inhibitor of Transport of monoamine NTs into synaptic vesicles ( less NT in vesicles so less NT released) Depletes monoamine NTs (Epi, NE, DA, 5-HT) from both PNS and CNS terminals crosses BBB --> CNS depression (some suicides have resulted so rarely used anymore to treat HT) |
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Guanethidine
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Presynaptic Inhibitor of NE storage and release = Sympatholytic
accumulates inside synaptic vesicle ==> vesicle eventually contains guanethidine as a false transmitter --> causes a slow release and depletion of NE no CNS activity tx severe HT Think: That's "Guano!" That false SNS transmitter |
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Bretylium
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Sympatholytic => blocks NE release from nerve ending
Presynaptic Inhibitor of NE Release--> blockade of depolarization-induced NE release = membrane stabilizing (local anesthetic) effect Think: puts "brake" on NE release doesn't cross BBB anti-arrhythmic |
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Side Effects of Reserpine, Guanethidine, and Bretylium
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These are sympatholytics (presynaptic inhibitors of NT storage &/or release)
cause PSNS predominance (diarrhea, GI cramps, nasal stuffiness, ulcers) postural hypotension sexual dysfunction in men Reserpine: CNS actions --> depression |
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Levodopa
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Immediate Precursos to Dopamine (DA)
crosses BBB to +DA levels in CNS (presynaptic effect) Tx for Parkinson's a catecholamino acid which can gain entry to CNS can co-administer with Carbidopa & COMT inhibitors for increased availability to brain Carbidopa prevents DOPA --> DA conversion COMT Inhibitors prevent break-down of drug Brand Name: L-DOPA, Dopar |
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Carbidopa
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Inhibitor of DOPA Decarboxylase (L-Aromatic Amino Acid Decarboxylase)
protects Levodopa from metabolism in PNS cannot cross BBB (quaternary amine) serves to increase availability of L-DOPA to brain (similarly, COMT inhibitors can be added to increase availability of DOPA to brain b/c COMT acts on catechol end of catecholamines) Brand Name: Sinemet (with Levodopa) |
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Methyldopa
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prodrug that enters catecholamine biosynthetic pathway to become a-CH3-NE, which stimulates alpha 2 (inhibitory) receptors in CNS
considered presynaptic agent b/c enters nerve for bioconversion causes --BP primary effect is in CNS similar to Clonidine, except that Clonidine directly stimulates alpha-2 receptors Note: Methyldopa, Clonidine, & other CNS acting alpha-2 agonists usu. have less side effects than other adrenergic agents |
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What do reuptake blockers do and what is a side effect of this?
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block presynaptic transporter (reuptake pump) of many monamine NTs (NE, Epi, DA, 5-HT) thereby increasing their concentration in the synapse
Different drugs affect different transporters they can also block the entry of drugs which must enter nerve terminal to work (amphetamine, reserpine, methyldopa, bretylium, MAOIs, Carbidopa, etc.) |
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2 Major Groups of Reuptake Blockers
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ANtidepressants (tricyclic and heterocyclic)
Cocaine |
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SSRIs
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Group of Antidepressants that block 5-HT reuptake pumps
includes Zoloft, Prozac, Paxil Selective Serotonin Reuptake Inhibitors can also block uptake of drugs that must get into nerve terminal to work (amphetamine, methydopa, MAOIs, Carbidopa, reserpine, bretylium, etc.) |
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Cocaine
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blocks monomaine reuptake pumps to increase NT levels in synapse
also local anesthetic effect pronounced increase in DA evels in brain --> euphoria and drug abuse no accepted clinical use Schedule II DEA controlled agent |
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MAO-A
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isozyme of MAO present in PNS nerve terminals, GI, & liver
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MAO-B
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MAO isozyme present in CNS
primarily responsible for metabolism of DA MAOIs usu. selective for this subtype |
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Selegiline
(aka Deprenyl) |
MAO Inhibitor
potentiates monoamine actions (Levodopa, DA, NE, etc.) since they survive destruction in gut, liver, etc. potentiates action of indirect agonists (amphetamine) since more of the displaced NE reaches the synaptic cleft antihypertensive effect of MAO inhibitors (paradoxical): due to form'n of octopamine, a false transmitter as adjunct to treat Parkinson's |
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Paradoxical Effect of MAOIs on BP
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MAOIs actually have antihypertensive effect
ihibition of MAO in gut and liver allows ingested tyramine (natural in diet) to survive--> more tyramine reaches nerve terminals where it is still not oxidized by MAO --> tyramine taken into vesicles and converted by dopamine-b- hydroxylase to octopamine--> octopamine = false NT, which is stored and released but has little intrinsic activity on postsynaptic receptors octopamine has sympatholytic effects that actually decrrease BP |
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MAOIs side effects
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1) If a large amt of tyramine is ingested, it can overwhelm dopamine-beta-hydroxylase, failing to produce octopamine and instead causing large release of NE via the indirect agonist effects of tyramine ==> dangerous increase in BP, HR, and C.O.
2) concurrent use of MAOIs and indirect agonists can lead to larger amts of NTs released (more released & less broken down) --> HT |
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Entacapone
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a COMT inhibitor
given with Levodopa (a catechol) to decrease its metabolism in the PNS, allowing more availability to brain (similar to Carbidopa, which inhibits DOPA Decarboxylase) Side effect: exaggerates effect of administered catecholamines such as DA, Epi, etc. Think: "Enta' Capone" the stealthest mafiosa, ready to take on COMT with all his compadres (ie. Levodopa) |
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choline acetytransferase
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enzyme that uses acetyl-coA to acetylate choline (taken up from outside nerve terminal by choline uptake pump) to ACh
ACh then pumped nto vesicles where it is stored with proteins and ATP |
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Release of ACh
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depolarization causes Ca++ influx through voltage gated Ca++ channels --> docking proteins--> vesicle fusion with active zones--> quantal release
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General Characteristics of Muscarinic Receptors
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ACh receptor
transduction type slow response (up or down) modulation of response chronic stimulation leads to conitnue effect (like an organ) |
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General Characteristics of Nicotinic Receptors
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Ionophore type
fast response (depolarization only) inititiation of response chronic stimulation --> depolarization blockade (like piano) |
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M1 receptor
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stomach, ganglia, CNS
IP3, DAG 2nd messengers |
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M2 receptros
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Heart
2nd mesenger: decreased cAMP |
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M3 receptors
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glands, eye
IP3, DAG |
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Nm = muscle subtype of nicotinic receptor
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located in neuromuscular junctions
selective antagonist: Tubocurarine |
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Nn = neuronal type nicotinic receptor
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located in ganglia, adrenal medulla, CNS
Selective Antagonist: Mecamylamine |
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Removal of ACh
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acetylcholinesterase (AChE) metabolizes ACh to acetic acid and choline (for reuptake)
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cholinesterase subtypes
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AChe
located in all cholinergic synapses, plus some other site (RBC membrane); does NOT hydrolyze succinylcholine BChe = butyrylcholiesterase (sometimes called Pseudo-ChE, Plasma-ChE, or serum-ChE)--> nonneuronal, hydrolyzes succinylcholine |
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What enzyme hydrolyzes succinylcholine?
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BChe
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2 types of cholinergic agonist
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Choline esters
Alkaloids |
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Bethanechol
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Cholinergic Agonist (choline ester type)
muscarinic selective (due to beta methyl group) ==> PSNS junctions not hydrolyzed by ChE synthetic derivative of ACh 4ary amine--> lipophobic = poor CNS activity, poor oral absorption |
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Muscarine
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Muscarnic alkaloid (cholinergic agonist of alkaloid type)
isolated from mushrooms first parasympathomimetic discovered |
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Pilocarpine
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Muscarine agonist (alkaloid type)
selective for muscarinic subsypte of ACh receptor = parasympathomimetics tertiary amine so crosses membranes well Useful Drug: Tx for glaucoma (open and closed angle) Tx for xerostomia Effects: miosis, accomadation for near vision (contraction of ciliary m), decrease IOP |
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Arecoline
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Cholinergic Alkaloid (=cholinergic agonist of alkaloid type)
muscarinic = nicotinic from betel nut (chewed for pschoactivity) tertiary amine --> CNS activity Think: "are" "choline": a cholinergic agonist as ubiquitous as the "air" we breath (meaning it acts at all the cholinergic junctions) |
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Cardiovascular Effects of Cholinergic Agonists (Muscarinic Agonists)
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PSNS effects
Vasodilation: although blood vessels not innervated by PSNS nn, they do contain muscarinic receptors that respond to stimulation with the release of NO Heart: Bradycardia via muscarinic receptors (little effect on contractility b/c little PSNS innervation to ventricles) |
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Cholinergic Agonists contraindicated for patients with:
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asthma (cause +bronchoconstricition, bronchosecretion)
Ulcers (cause glandular secretion and smooth muschle contraction in GI) |
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Effects of prolonged AChesterase Inhibitors (and consequent build-up of ACh) on the 2 types of cholinergic receptors:
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Muscarinic: excess PSNS stimulation
Nicotinic: initial stimulation followed by depolarization blockade (ionophore receptor is like a piano) |
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What properties render an AChE inhibitor selective for muscarinic vs. nicotinic receptors?
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None! AChE inhibitors are not selective --> they increase ACh levels at all cholinergic synapses
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4 groups of AChE inhibitors
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1) short acting competitive inhibitors
2) noncompetitive inhibitors 3)carbamates 4) organophosphates |
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ChE Enzyme's 2 major sites of attachment
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esteratic site (where ACh binds as substrate)
Anionic Site |
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Mechanism of Short-acting competitive AChE inhibitors
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rapid reversible interaction with ChE (min.)
competition at active site (esteratic site) not a substrate for enzyme |
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Mechanism of Noncompetitive Inhibitors of ChE
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block channel entry to active site (hours)
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Mechanism of Carbamate Inhibition of AChE
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Suicide Inhibitors of ChE--> these are substrates for the enzyme
interact at ionic & esteratic sites cause slow hydrolysis of a carbamylated enzyme over a period of hourse (wheras ACh causes rapid hydrolysis of acetylated enzyme over period of micorsecs) result in slowly reversible covalent bond attachment |
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Mechanism of Organophosphate Inhibition of ChE
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cause extremely slow (days-weeks) hydrolysis of Phosphorylated enzyme
act at esteratic site Aging: organophosphates would be slowly reversible ChE substrates except that they form a 2nd (this time covalent) bond at the esteratic site, creating an Irreversible Complex |
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Edrophonium
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short-acting competitive ChE Inhibitor
used when brief action required Used for diagnosis and dose adjustment in Myasthenia Gravis Think: "Er," is this "dro" the eu"phoni"c dose for this MG pt? |
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Donepezil
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Noncompetitive ChE Inhibitor
longer acting (hours) Lipophilic--> effective inhibition of AChE in CNS used for symptomatic Tx of Alzheimer's Dz noncompetitive (blocks channel entrance to active site) but reversible Think: stick 'em on a "pedastool" & leave 'em there for hours, locked in tetany like a statue all alone, like a person with Alzheimer's |
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Physostigmine
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Carbamate type ChE Inhibitor
suicide inhibitor acts via competition for esteratic site, and acts at anionic site acts over period of hours tertiary amine alkaloid ==> CNS activity clincally useful b/c lipid soluble, safe Tx: glaucoma (used for over a century) THink: and almost as hard to say (for someone with a lisp) as astygmatism, another eye problem |
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--stigmine ending
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therapeutic Carbamate type ChE inhibitors
Think: "stick it" to those ChEs |
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Neostigmine
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Carbamate type ChE Inhibitor
synthetic 4ary amine = no CNS activity, poor oral absorption some direct nicotinic receptor stimulation Tx: increased muscle tone in myasthenia gravis Reversal of nondepolarizing NMJ blockers, which cause paralysis (e.g. Tubocurarine, pancuronium, atracurium) |
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Pyridostigmine
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Carbamate type ChE Inhibitor
synthetic 4ary amine = no CNS activity, poor oral absorption some direct nicotinic receptor stimulation Tx: increased muscle tone in myasthenia gravis Reversal of nondepolarizing NMJ blockers' induction of paralysis (e.g. Tubocurarine, pancuronium, atracurium, etc.) |
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Carbaryl
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Insecticide with Carbamate type Inhibition of ChE
selective toxicity to insects |
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Malathion
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Organophosphate type ChE Inhibitor (works for days-weeks)
prodrug --> converted in vivo to an organophosphate insecticide: aerial crop spraying, mosquito control ~safe due to inactivation by mammals and birds Think: "mal"evolent substance! insecticide! "th"ough not too, too bad for ppl |
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Parathion
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Organophosphate type ChE Inhibitor (works for days-weeks)
prodrug --> converted in vivo to an organophosphate insecticide: aerial crop spraying, mosquito control ~safe due to inactivation by mammals and birds |
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Diazinon
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Organophosphate type ChE Inhibitor
agricultural insecticide Think: "Dios" "Zion" You gonna Die & go to Zion The organophosphate ChE inhibitors (Malathion, Parathion, Diazinon, and the nerve gases) are all insecticides. They'll kill you. Except that Malathion & Parathion are prodrugs, not converted to the deadly substance by mammalian & bird systems. |
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VX
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Organophosphate type ChE Inhibitors used in chemical warfare
extremely toxic, very lipid soluble and volatile liquids used as nerve gases high dermal and pulmonary absorption irreversible ChE inhibitors that bind only esteratic site large stockpiles in US, Russia used in warfare: Iran, Iraq used in terrorism: Japan |
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Sarin
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Organophosphate type ChE Inhibitors used in chemical warfare
extremely toxic, very lipid soluble and volatile liquids used as nerve gases high dermal and pulmonary absorption irreversible ChE inhibitors that bind only esteratic site large stockpiles in US, Russia used in warfare: Iran, Iraq used in terrorism: Japan |
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ChE Inhibitors' Effects
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ANS systems: same as direct acting agonists
PSNS effects plus sweating (b/c sweat glands are under SNS control via muscarinic ACh receptors) CNS: confusion, convulsions, coma plus CNS respiratory depression NMJ: 1) initial muscle twitching, involuntatry mvt 2) high dose --> flaccid paralysis (build-up of ACh in synapse causes Depolarization Blockade of Nicotinic Receptors) Cardiovascular: 1)little effect on BP b/c blod vessels have little PSNS innervation so there is no ACh to perpetuate and produce vasodilation) 2) initial exposure causes Tachycardia (due to decreased BP <-- ganglionic blockade, CNS depression of respiration & hypoxemia, Epi release from adrenal medulla) 3) prolonged exposure, high doses: Bradycardia due to direct effect on heart (stimulation of PSNS muscarinic receptors in heart) |
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ChE Inhibitors' Side Effects and Contraindications
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Parasympathomimetic Effects
DUMBELS Diarrhea, Diaphoresis, Urination, Miosis (pupil constriction), Bradycardia, Bronchospasm, Bronchorrhea, Emesis, Lacrimation, Salivation Contraindicated in patients with asthma, ulcers |
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Toxicity from ChE Inhibitors
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Respiratory Paralysis & Asphyxia
1) paralysis of diaphragm, intercostal mm; this is compounded by: 2) respiratory congestion and bronchoconstriction 3) CNS respiratory depression |
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Atropine
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Muscarinic Receptor Antagonist
the major belladonna alkaloid Tx: 1) for ChE poisoning--> revreses all muscarinic effects incluing CNS 2) OTC diarrhea, cold tablets administered frequently (3-5 min) until sx of muscarinic blockade appear (dry mouth, dilated pupils, etc.) |
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2-PAM or Pralidoxime
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Cholinesterase Reactivator
restores the free ChE has higher affinity for organophosphates than ChE (before aging occurs) so it essentially rips the organophosphate off the ChE protein Tx for ChE inhibitor poisoning with organophosphates only (b/c anionic site is occupied with other inhibitors) |
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Bethanechol & Neostigmine used to treat
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paralytic ilius, abdominal distension without obstruction
urinary retention, bladder atony without obstruction Bethanechol = cholinergic agonist Neostigmine = ChE inhibitor |
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drugs for rapid reversal of nondepolarizing NMJ blockade
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Physostrigmine & Neostigmine
both are ChE inhibitors. they increase the amt of actual ACh in the synapse, so it can compete with whatever is blocking the receptor (tubocurarine, pancuronium, atrcurium, etc.) |
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Drugs for Tx of Atropine toxicity
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Physostigmine and Neostigmine (ChE inhibitors offset the effects of Atropine, a muscarinic antagonist)
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Drugs for Tx of Glaucoma
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Pilocarpine (Muscarinic/ Cholinergic agonist)
Carbachol Physostigmine (ChE inhibitor) Echothiphate (ChE inhibitor) etc. |
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Primary open-angle glaucoma
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develops slowly as eye's drainage canals gradually become ineffective
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Closed Angle Glaucoma
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pupil enlarges too much or too quickly--> outer edges of iris block eye's drainage canals --> sudden and severe rise in eye pressure
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Aqueous humor production
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takes pace at ciliary process
exits through trabecular meshwork amount of IOP is balance between inflow and outflow & tx for glaucoma targets either of these |
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Cholinomimetic Tx of Glaucoma
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Pilocarpine (Muscarinic Agonist) & Physostigmine (ChE inhibitor)
Increase Outflow produce miosis to increase angle b/e cornea and iris--> increase outflow contract ciliary mm to realign trabecular meshwork & facilitate aqueous humor outflow |
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Beta Blocker Tx of Glaucoma
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Timolol
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Adrenergic Agonist Tx of Glaucoma
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Epinephrine & Brimonidine
not for narrow-angle glaucoma (rapid pupil/iris enlargment) |
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Myasthenia Gravis:
what is it? tx? |
auto-IgG attack of pt's own nicotinic receptors results in decreased number of functional cholinergic receptors at motor end plates and muscle weakness
Tx: 1) immunosuppressants 2) ChE Inhibitors (to increase amount of ACh in synapse and stimulate remaining receptors) Neostigmine = charged ChE Inhibitor (won't enter CNS; plus it has some direct receptor stimulation action) PSNS side effects (control with 4ary atropine derivatives) |
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Inhibition of AChE in a normal person vs. person with Myasthenia Gravis
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Normal person: buildup of ACh leads to depolarization blockade and decreased strength
Myasthenia Gravis patient: incraed muscle strength This is the basis of the Edrophonium Test for diagnosis and dose adjustment in Myasthenia Gravis. Dosage adjustment: if pt has been over-treated, will respond to Edrophonium like a normal person, i.e. with decreased strength. If pt has been under-treated, Edophonium will increase strength. |
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Belladonna Alkaloids (3)
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Atropine, Hyoscyamine, Scopolamine
Muscarinic Blockers 3ary amines (have CNS effects) |
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Atropine
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Muscarinic Receptor Blocker (belladonna prototype)
3ary amine (CNS effects) Organ effects: heart (tachycardia) > GI (inhibits motility) > Glands (inhibits secretion) > CNS (drowsiness) Tx: 1) blockade of muscarinic side effects due to ChE therapy (i.e. myasthenia gravis, organophosphate poisoning) 2) OTC cold, diarrhea tablets |
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Hyoscyamine
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Belladonna Muscrainic Blocker
relief of GI spasms, IBS, spastic colon management of rhinitis, hyperhidrosis |
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Scopolamine
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Muscarinic Blocker (belladonna type)
3ary amine with CNS effects Organ Effects: CNS (drowsiness) > Glands (inhibits secretion) > GI (inhibits motility) > heart (tachycardia) Important side effects: drowsiness, amnesia Tx: OTC sleeping pills, motion sickness |
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Benztropine
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Muscarnic Blocker
synthetic cmpd 3ary amine Tx of Parkinson's |
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Ipratropium
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Muscarinic Blocker
3ary amine inhaler for tx of bronchoconstriction in COPD, chronic bronchitis, emphysema, asthma often co-administered with beta-2 receptor agonists |
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Quaternary derivatives of belladonna alkaloids
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also muscarinic recptors
limited to PNS |
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Effects of Muscarinic Antagonists/ anti-Cholinergics
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Cardiovascular:
1) Heart: Tachycardia due to blocked vagal tone 2) Vessels: little direct effect b/c no PSNS innervation (except flushing in case of hyperthermia due to anhidrosis) Eye: 1) mydriasis, photophobia 2) block ciliary mm to lens --> paralysis of accomodation (cycoplegia) Glands: 1) Block secretions 2) block sweating --> can cause hyperthermia --> can cause cutaneous vasodilation (flushing) Other PNS: 1) --GI motlity (constipation) 2) bronchodilation CNS: drwosiness and amnesia (esp. scopolamine) |
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Increased Doses of Muscarinic Antagonists increasingly effect these organ systems in this order:
Low dose to High Dose |
Salivation, Sweating > Eye, Heart > GI, Bladder, Bronchiols, (CNS) > Gastric Secretions
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Side Effects of Muscarinic Antagonists:
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~safe in adults, but children 100x more sensitive (esp. to hyperthermic effect of anhidrosis)
contraindicated in px predisposed to narrow angle glaucoma Belladonna toxicity = ingestion of plants from which these alkaloids are derived Gastric Ulcers may be exacerbated (GI secretions not effectively blocked by antimuscarinic agents despite partial control of GI secretions by muscarinic receptors--maybe b/c high doses required before gastric secretions effected?) |
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Farmer comes in with vomiting, muscle tremors, hyperventilation. Progresses to flaccid (?) paralysis and convulsions. What's going on?
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Green Tobacco Sickness
Farmer likely exposed to wet tobacco during harvest. Sx due to stimulation of Nicotinic Receptors in PNS, PSNS, Somatic Nervous System, and CNS. nausea, vomiting repiratory paralysis ganglionic and neuromuscular blockade coma convulsions death |
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3 pathways of transmission at Autonomic Ganglia responsible for creating TRIPHASIC action in postganglionic nerves
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1) Primary EPSP (millisec) Nicotinic/Cholinergic -- ganglionic drugs act on this pathway
2) IPSP (sec) Muscarinic (M2)/Cholinergic via DA interneuron 3) late EPSPs (min) Muscarinic (M1) Cholinergic |
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Nicotine
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Ganglionic > NMJ Agonist
= Depolarizing Blocker at high doses stimulates both major types of nicotinic receptors (nueronal > muscle) Dose dependent effects: Low dose --> stimulation activates SNS & PSNS nn + Epi from adrenal medulla CNS stimulation High Dose--> depolarization blockage (ganglionic & NMJ) --> respiratory paralysis, vomiting, coma 3ary amine = penetrates membranes (incl. placenta) stimulates release of DA in CNS (positive reinforcement) Rx for smoking cessation |
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Physiological Effects of Nicotine
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Stimulates neuronal > muscular Nicotinic Receptors in ANS, CNS, somatic system
CNS: psychostimulant Somatic: no significant effects at low doses, depolarizing blcokade of ganglia and NMJ at high doses ANS: since most organ systems have dual (SNS & PSNS) innervation, little effect of nicotine on particular organ systems EXCEPT: 1) heart: tachycardia 2) vessels: vasoconstriction and + BP (due to SNS stimulation from ganglia & + Epi release from adrenal medulla) 3) GI nausea |
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Mecamylamine
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Nondepolarizing Ganglionic Blocker (Antagonist at Nicotinic Receptors)
Ganglionic >> NMJ though, like nicotine, can cause NMJ blockade at high doses induces Hypotension causes vasodilation due to --SNS stimulation to vessels from ganglia lowers BP w/o major effecs on other ANS systems (b/c stimulation of SNS & PSNS nicotinic receptors cancels each other out in most organ systems) no longer used to manage HT due to CNS side effects; now only used to induce hypotension during hypertensive emergencies or during surgery CNS side effects of this 3ary amine: sedation & orthostatic hypotension |
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What do NMJ nicotinic agonists do to a normal person?
|
Initial stimulation of NMJ produces involuntary contractions (NO INCREASED MUSCLE STRENGTH, as with ChE inhibitors)
followed by Depolarization Blockade |
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What would a ChE inhibitor due to a Depolarizing NMJ Agonist?
to a Nondepolaizing NMJ Antagonist? |
ChE Inhibitors would:
potentiate the blockade produced by an Agonist reverse the blockade produced b an Antagonist (b/c would increase the levels of competing NT) |
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Succinylcholine
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Depolarizing NMJ Blocker
depolarizing agent (inital stimulation followed by depolarizing blockade) short acting hydrolyzed by BChE this plasma degradative enzyme gives the drug its very short half life NOT hydrolyzed by AChE |
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Tubocurarine
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NMJ Blocker
South American arrow poison prototype nondepolarizing NMJ blocker (competes with NT for somatic nicotinic receptors) causes release of histamine from mast cells --> hypotension Brand Name: Curare |
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Atracurium
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NMJ Blocker
non-depolarizing NMJ blocker (competes with NT for somatic nicotinic receptors) ~ short acting Hoffman Elimination: makes it useful for px with hepatic, renal failure b/c undergoes non-enzymatic degradation Think: "atta" boy, Hoffman |
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Pancuronium
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NMJ Blocker
Non-depolarizing NMJ Blocker (competes with NT for somatic nicotinic receptors) long acting (think "pan" = everywhere or dispersed in time) due to pure renal excretion (no metabolic alteration) adjunct to general anesthesia, facilitation of tracheal intubation, mechanical respiration |
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---urium & ___onium endings
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Nondepolarizing NMJ ANtagonists
block the Nicotinic NMJ receptors |
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What do all NMJ Blockers (Depolarizing Agonists & Nondepolarizing Antagonists) have in common?
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All are Charged
so no CNS activity, ineffectiv p.o.--> usu. administered by I.V. infusion Onset wihtin several minutes |
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Train of Four Stimulation
|
Allows assessment of the type and level of NMJ blockade via delivery of 4 stimui at 1/2 second intervals.
No Blockade? 4 equivalently high responses Depolarizing Blockade? 4 equivalent but reduced responses Nondepolarizing (antagonist) Blockade? Responses fade in relation to the degree of blockage Note: Succinylcholine produces 2 phases of blockade. Phase I produces a constant but diminished response to TOF. But Phase II resembles nondepolarizing blockades, and the responses will fade. |
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Effects of NMJ Blockers on Cardiovascualar and CNS
|
Vessels: Hypotension (histamine release with some agents, venous pooling, slight ganglionic blockade of SNS)
Heart: Tachycardia (reflex from hypotension, some ganglionic blockade) CNS: no effects b/c they're all 4ary amines |
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Contraindications and Risks of Succinylcholine Use
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1) patients with Myasthenia Gravis are very sensitive to any NMJ Blocker
2) patients with abnormal BChE--> use Dibucaine (local anesthetic whihc inhibits normal enzyme more than abnormal one) to determine if BChE is normal or not 3) risk of malignangt hyperthermia (tx = Dantrolene) 4) hyperkalemia |
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Botulinum Toxin
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Cholinergic Neurotoxin
prevents ACh release from Somatic nerve terminals Presynaptically prevents stimulation of Nicotinic Receptors at NMJ Produces Flaccid Paralysis Brand Name: BoTox toxin from Costridium Botulinus extremely potent |
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Procaine
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Local Anasthetic
binds to open Na+ channels on inner surface of axonal membrane to prevent AP prototypic local anesthetic--> given potency of 1 (not very potent at all) Ester type local anesthetic ---> short duration of action (b/c rapidly hydrolyzed by ester cholinesterase in plasma) |
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3 structural features of local anesthetics
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Amine end (hydrophilic)
Aromatic Group (lipophilic) Intermediate Chain binds the two and determines the class of anesthetic: ester vs. amide |
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What is the most important determinant of onset of action of a local anesthetic?
|
its pKa
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|
Why add a catecholamine to a local anesthetic?
|
Catecholamines, such as epinephrine, serve to offset the vasodilatory side effects of local anesthetics. This keeps the anesthetic local, making it more effective and reducing toxicity (by reducing systemic concentration.)
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|
What is the major toxic risk of local anesthetics?
|
Cardiovascular toxicity.
All local anesthetics, with exception of cocaine, are vasodilators. All have direct myocardial depressant actions. Anesthetics carried to heart will block APs there as well. Note: Bupivacaine and Etidocaine are very cardiotoxic b/c they are highly lipid soluble and b/c they can bind specifically to cardiac conduction systems. |
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Prilocaine
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Local Anesthetic
Amide type liver metabolism = longer duration of action Associated with Methemoglobinemia: oxidized iron in Hb has reduced O2 carrying capacity--> especially risky in kids |
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Which class of local anesthetics is associated with more allergies?
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Ester agents
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|
Are resting nerves more or less sensitive to local anesthetics than frequently stimulated/used nerves?
|
less sensitive
The more frequently a nerve is used, the lower the dose of anesthetic needed--> b/c more Na+ channels are in the open configuration needed for drug action. |
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Cocaine
|
Local Anasthetic
binds to open Na+ channels on inner surface of axonal membrane to prevent AP Ester type local anesthetic ---> short duration of action (b/c rapidly hydrolyzed by ester cholinesterase in plasma) only local anesthetic that does not produce vasodilation |
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Tetracaine
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Local Anasthetic
binds to open Na+ channels on inner surface of axonal membrane to prevent AP Ester type local anesthetic ---> short duration of action (b/c rapidly hydrolyzed by ester cholinesterase in plasma) |
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Chloroprocaine
|
Local Anasthetic
binds to open Na+ channels on inner surface of axonal membrane to prevent AP Ester type local anesthetic ---> short duration of action (b/c rapidly hydrolyzed by ester cholinesterase in plasma) |
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Benzocaine
|
Local Anasthetic
binds to open Na+ channels on inner surface of axonal membrane to prevent AP Ester type local anesthetic ---> short duration of action (b/c rapidly hydrolyzed by ester cholinesterase in plasma) |
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Lidocaine
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Amide Type Local Anesthetic
Metabolized in Liver--> longer duration of action that ester anesthetics binds to open Na+ channels on inner surface of axonal membrane to prevent AP |
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Mepivacaine
|
Amide Type Local Anesthetic
Metabolized in Liver--> longer duration of action that ester anesthetics binds to open Na+ channels on inner surface of axonal membrane to prevent AP |
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Bupivacaine
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Amide Type Local Anesthetic
Metabolized in Liver--> longer duration of action that ester anesthetics High lipid solubility ==> very potent, very toxic high cardiotoxicity due to specific binding to cardiac conduction system binds to open Na+ channels on inner surface of axonal membrane to prevent AP |
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Etidocaine
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Amide Type Local Anesthetic
Metabolized in Liver--> longer duration of action that ester anesthetics High lipid solubility ==> very potent, very toxic high cardiotoxicity due to specific binding to cardiac conduction system binds to open Na+ channels on inner surface of axonal membrane to prevent AP |
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Dibucaine
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Amide Type Local Anesthetic
Metabolized in Liver--> longer duration of action that ester anesthetics binds to open Na+ channels on inner surface of axonal membrane to prevent AP |
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Ropivacaine
|
Amide Type Local Anesthetic
Metabolized in Liver--> longer duration of action that ester anesthetics binds to open Na+ channels on inner surface of axonal membrane to prevent AP |
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Effects of Histamine
|
allergies, inflammation, anaphylaxis
(H1 receptors in smooth muscle, endothelium, posst-synaptically in brain) gastric secretions (H2 receptors) CNS: role in sleep-wake cycles, regulation of feeding & obesity, cognition, memory |
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|
What causes Histamine release?
|
allergy/anaphylaxis via antigen-antibody rxn (Immediate HS rxn)
==> allergen-IgE cross-linking on mast cells any chemical that causes frank tissue dmg some organic bases (d-tubocurarine, morphine and other opiates, some antihistamines) |
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H1 receptors
|
Histamine receptors in smooth muscle, endothelium, brain (postsynaptic)
most important Histamine receptor Bronchoconstriction arteriolar dilation (via NO) & -BP + venule permeability mimic ACh effects Gq--> Phospholipase C--> +IP3, DAG --> + Ca++ & protein kinase (esp. Myosin Light Chain Protein Kinase) --> smooth m Contraction in bronchi, intestine, large vv |
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H2 receptors
|
Histamine receptors in gastric mucosa, cardiac muscle, mast cells, brain (postsynaptic)
effects mimic stimulation of Beta adrenergic receptors in heart (+CO) +Gastric Secretions +C.O. Gs--> +cAMP |
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Effects of Histamine on Vasculature
|
Vasodilation (H1 > H2)
H1 effect indirect via Endothelial Derived Relaxation Factor (NO) --> similar to ACh stimulation of muscarinic receptors in PSNS NB: large veins actually constrict b/c no NO synthase H2 effect similar to Beta-2 agonists in SNS Vasodilation causes: 1) Reflexive increase in HR (baroreceptors) 2) Increased venule permeability (H1 cause endothelial cells to actually shrink) 3) Decreased BP Triple Response of Lewis = Wheal & Flare |
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Effect of Histamine on Heart
|
Increased C.O.
Decreased BP causes reflexive increase in CO H2 receptors directly stimulated to cause +ionotropic and +chronotropic effects |
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General Effects of Histamine on Smooth Muscle
|
contraction of bronchi via H1 receptors: Bronchoconstriction
Vasodilation with +Permeability (H1 > H2) & -BP |
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Triple Response of Lewis
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Wheel & Flare response on skin
1) localized red spot (H1 dilation of vessels) 2) red flush or Flare (H1 stimulation of sensory n endings--> reflex dilation of vessels over wider area) 3) Wheel actually surrounds original small spot (H1 receptors --> + venular permeability) |
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Effects of Histamine on Exocrine Glands
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Gastric Secretagogue
H2 on parietal cells--> + HCl, Pepsin, Intrinsic Factor output H1 --> + bronchial, lacrimal, nasal secretions |
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Nervous System Effects of Histamine
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PNS: stimulates peripheral sensory nerve endings
1) urticaria, hives (itch) when injected subdermally 2) axon reflex = flare response 3) pain produced on deep injection CNS: possible NT or neuromodulator; may be involved in wakefulness, arousal |
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Clinical Use of Histamine
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used in past as gastric secretion test
replaced due to side effects (nausea, dizziness, abdominal pain, urge to defecate) |
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Mechanism of Action of Anti-histamines
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Inverse Agonists of H receptors
previously thought to be a competitive antagonist (bind indiscrimately to active & inactive receptors) now thought to be an Inverse Agonist: binds to active form of receptor & converts it to inactive form selective for either H1 or H2 receptors |
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Diphenhydramine
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1st generation Antihistamine
3 functions besides antihistamine effects: 1) anti-cholinergic (Atropine-like) 2) sedative 3) anti-motion sickness Brand Name: Benadryl Note: Dimenhydrinate = salt form of this drug, which is a free base (same properties, but used more for motion sickness) |
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Dimenhydrinate
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1st generation Antihistamine
3 other functions: 1) anti-cholinergic (Atropine-like) 2) sedative 3) anti-motion sickness = major Clinical Use Brand Name: Dramamine Note: salt form of the free base Diphenhydramine (identical pharmacology) |
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Promethazine
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1sst generation Antihistamine
Effects: marked sedation anti-emetic Brand Name: Phenergan Pharmacology identical to Diphenhydramine & Dimenhydrinate Think: this guy's a "pro" at taking your nausea back down to the 'mezzanine' |
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Chlorpheniramine
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1st generation Antihistamine
Less Sedative Effects than other 1st generation antihistamines common component of OTC cold medication only mild anti-cholinergic effects |
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Fexofenadine
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Antihistamine
No sedative effects 2nd generation antihistamine so has mast cell stabilizing & anti-inflammatory effects Brand Name: Allegra often sold with decongestant as Allegra-D Initially sold in prodrug form, Terfenadine, which caused arrythmias. Discovered that Terfenadine is actually metabolized by CYP450 to therapeutic form that is not toxic. So pharm cos began manufacturing the metabolite. |
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Cetirizine
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Antihistamine
2nd generation antihistamine so has mast cell stabilizing & anti-inflammatory effects metabolite of Hydroxyzine via CYP450 Brand Name: Zyrtec |
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Levocetirizine
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Antihistamine
enantiomer of Cetirizine (Zyrtec) 2nd generation antihistamine so has mast cell stabilizing & anti-inflammatory effects; longer duration of action (24 hrs) Brand Name: Xyzal |
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Loratadine
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Antihistamine
Brand Name: Claritin 2nd generation antihistamine so has mast cell stabilizing & anti-inflammatory effects Laratadine metabolized to Desloratadine (Clarinex) by CYP450 OTC drug metabolized to Prescription drug! |
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Desloratadine
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Antihistamine
2nd generation antihistamine so has mast cell stabilizing & anti-inflammatory effects Brand Name: Clarinex Irony: this prescription drug is a metabolite (via CYP450) of Loratadine, an OTC drug. |
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What are some added benefits of 2nd generation antihistamines?
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1) anti-allergic/ anti-inflammatory properties
2) longer duration (half life) --> only need to dose once a day 3) They don't have anti-cholinergic properties (don't inhibit PSNS) |
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What symptom are 1st generation antihistamines effective against that 2n generation are not, and why?
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Rhinorrhea
1st generation antihistamines have anticholinergic properties. Nasal secretions are increased by PSNS stimulation by ACh at muscarinic receptors. |
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3 manifestations of allergies that oral antihistamines can be used to control
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allergic rhinitis
conjunctivitis uriticaria (itch & rash) |
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Olopatadine
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Topical Antihistamine
drops for allergic conjunctivitis nasal spray for allergic rhinitis |
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What is Filgrastim and what is it used for?
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Granulocyte Colony Stimulating Factor analog used to treat anemias & as a biological response modifier in certain cancers.
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What do nasal steroids do better than antihistamines?
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They have nasal decongestant ability.
Decongestants (alpha agonists) often added to antihistamines--> stimulation of alpha1 receptors causes smooth m constriction, decreasing rhinitis. Caution: continued use of topical nasal sprays containing alpha agonists as decongestants can result in Rebound Congestion. |
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What is the most effective type of drug to use for tx of allergic rhinitis?
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Intranasal steroids
(more effective than nasal antihistamine sprays) |
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How do you treat anaphylactic shock?
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physiological antagonists like Epinephrine are the 1st line of defense
Antihistamines (H1 & H2 together) may offer some supplementary benefits. |
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How do you treat motion sickness?
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Dimenhydrinate & Promethazine = Antihistamines
Best given prophylactically Scopalamine = anticholinergic |
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How do you treat a cold?
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Anti-cholinergics (antagonize Muscarinic receptors of PSNS that cause glandular secretions)
Anti-histamines, especially 1st generation anti-histamines that have anti-cholinergic properties. Blockage of Muscarinic receptors in glands will decrease rhinorrhea but also decrease salivary secretions, causing dry mouth. |
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Antihistamines as Sedatives
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1st generation anti-histamines
Diphenhydramine (Benadryl) Promethazine (Phenergan) Also useful as local anesthetics in people allergic to ester AND amide agents. |
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Why do 2nd generation antihistamines not cause sedation?
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They don't cross the BBB
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CNS side effects of Antihistamines
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1st generation Antihistamines:
sedation, drowsiness, impaired psychomotor performance, impaired learning. Recall that these sx are also a consequence of allergic dz. Kids can sometimes show excitation. CNS side effects not an issue with 2nd generation antihistamines b/c they don't cross BBB. Fexofenadine = 2nd generation with minimal sedative properties Cetirizine = 2nd generation with greatest sedative properties |
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Antihistamine Side Effects
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due to anti-cholinergic effects of 1st generation anti-histamines = blockage of Muscarinic receptors of PSNS = anti-PSNS activity
CNS: drowsiness Respiratory: dry nose, mouth, throat Ophtalmic: blurred vision, possible exacerbation of narrow angle glaucoma GU: exacerbate BPH Cardiovascular: Terfenadine (Seldane) caused arrythmias (now its active metabolite, Fexofenadine, is given) Teratogenic side effects |
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Glutamate
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main excitatory NT in CNS
glutamine--> glutamate 2 receptor categories: Ionotropic: AMPA Kainate NMDA -- long term potentiation (antagonists include ketamine, dizocilpine, 2-amino-5-phosphonovalerate) Metabotropic=G protein linked: Grp I: post-synaptic/excitatory G--> PLC --> IP3/DAG --> +Ca++ Grps II & III: presynaptic, inhibitory (when glutamate levels get too high)--> decreased cAMP |
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Postsynaptic Density
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thickening of postsynaptic membrane (at excitatory synapses) with glutamate receptors & proteins
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Main inhibitory NTs
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GABA & Glycine
typically released from local interneurons (glycine only from interneurons in brain stem & spinal cord) |
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Glycine receptors
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selectively permeable to Cl-
blocked by Strychnine |
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GABA receptors
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throughout CNS
GABAa fast component of IPSPs ionotropic (Cl- permeable) can be selectively inhibited picrotoxin bicuculline GABAb slow part of IPSPs Metabotropic (inhibit Ca++ channels, activate K+ channels, or inhibit adenyl cyclase to decrease cAMP) long lasting & slow Blocked by 2-OH-Saclofen |
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2 categories of Antispasmodics/Muscle Relaxants
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1) drugs that work in CNS
2) drugs that work in muscle cell itself (Dantrolene inhibits Ca++ efflux from sarcoplasmic reticulum) can be taken orally & are safer than paralytics (that work either by blocking nicotinic receptors at NMJs or by presynaptically inhibiting ACh release, such as with botulinum) |
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Side Effects of Muscle Relaxants/ Antispasmodics
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drowsiness/sedation
muscle weakness ANS: no effect NMJ: no effect on ACh binding at nicotinic receptors |
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3 clinical uses of Muscle Relaxants/ Antispasmodics
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1) tx for muscle tenstion & pain
2) spasmolytic in cerebral palsy, MS, stroke, muscular dystrophy 3) tx for malignant hyperthermia (Dantrolene) |
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Glutamate
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main excitatory NT in CNS
glutamine--> glutamate 2 receptor categories: Ionotropic: AMPA Kainate NMDA -- long term potentiation (antagonists include ketamine, dizocilpine, 2-amino-5-phosphonovalerate) Metabotropic=G protein linked: Grp I: post-synaptic/excitatory G--> PLC --> IP3/DAG --> +Ca++ Grps II & III: presynaptic, inhibitory (when glutamate levels get too high)--> decreased cAMP |
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Postsynaptic Density
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thickening of postsynaptic membrane (at excitatory synapses) with glutamate receptors & proteins
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Main inhibitory NTs
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GABA & Glycine
typically released from local interneurons (glycine only from interneurons in brain stem & spinal cord) |
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Glycine receptors
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selectively permeable to Cl-
blocked by Strychnine |
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GABA receptors
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throughout CNS
GABAa fast component of IPSPs ionotropic (Cl- permeable) can be selectively inhibited picrotoxin bicuculline GABAb slow part of IPSPs Metabotropic (inhibit Ca++ channels, activate K+ channels, or inhibit adenyl cyclase to decrease cAMP) long lasting & slow Blocked by 2-OH-Saclofen |
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2 categories of Antispasmodics/Muscle Relaxants
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1) drugs that work in CNS
2) drugs that work in muscle cell itself (Dantrolene inhibits Ca++ efflux from sarcoplasmic reticulum) can be taken orally & are safer than paralytics (that work either by blocking nicotinic receptors at NMJs or by presynaptically inhibiting ACh release, such as with botulinum) |
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Side Effects of Muscle Relaxants/ Antispasmodics
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drowsiness/sedation
muscle weakness ANS: no effect NMJ: no effect on ACh binding at nicotinic receptors |
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3 clinical uses of Muscle Relaxants/ Antispasmodics
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1) tx for muscle tenstion & pain
2) spasmolytic in cerebral palsy, MS, stroke, muscular dystrophy 3) tx for malignant hyperthermia (Dantrolene) |
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Dantrolene
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Muscle relaxant/ Antispasmodic
works inside muscle cell itself by inhibiting Ca++ efflux from sarcoplasmic reticulum Tx for Malignant Hyperthermia |
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Diazepam
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GABA mimetic
Muscle relaxant/ Antispasmodic anti-anxiety acts at GABAa synapses produces sedation at levels required to reduce muscle tone Brand Name: Valium THink: "dios"-- Valium is like a god, like a false idol to ppl it's like it goes "shabam!" |
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Baclofen
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GABA mimetic Muscle Relaxant/ AntiSpasmodic
GABAb receptor agonist just as effective as Diazepam but with fewer side effects (less sedation, less decreased muscle strength) can cause drowsiness & seizures in epileptic px |
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Carisoprodol
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Muscle Relaxant/ AntiSpasmodic
possibly GABA mimetic centrally acting |
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Tizanidine
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Central Alpha-2 Agonist
Muscle Relaxant/ Antispasmodic |
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Cyclobenzaprine
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Muscle Relxant/ AntiSpasmodic
Centrally acting but unknown mechanism structurally related to tricyclic antidepressants & produces anti-muscarinic side effects Ineffective for Cerebral Palsy or spinal cord injuries Side effects: sedation, confusion, hallucinations |
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Metaxolone
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Muscle Relaxant/ AntiSpasmodic
centrally acting by unknown mechanism Think "metatextual" --> meta for central, textual for a nice relaxing read in the bathtub |
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Methocarbamol
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Muscle Relaxant/ Anti-spasmodic
centrally acting by unknown mechanism |
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Echinacea
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Herbal Med
Used to prevent Cold Sx anti-inflammatory, anti-viral, anti-fungal, anti-oxidant |
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Coenzyme Q10
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dietary supplement
Tx for Parkinson's (reduced levels in Parkinson's px) Prevention of statin induced myopathy Interactions: structural similarity to VIT. K so interacts with WARFARIN to decrease warfarin levels |
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Glucosamine
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Dietary Supplement
Cartilage nutrient Risk of BLEEDING in px on WARFARIN |
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Melatonin
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Dietary Supplement used to regulate sleep-wake cycles
should not be used by men or women trying to conceive, breast feeding women metabolized by CYP1A2--> may interact with drugs that induce or inhibit this enzyme |
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Garlic
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Herbal Med
Anti-Platelet Caution if using with anti-clotting meds Anti-microbial reduces availability of Saquinavir, an antiviral anti-neoplastic |
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Ginko
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Herbal Med
Vasodilation and + blood flow Interaction with ANTI-CLOTTING MEDS: increased RISK OF BLEEDING |
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Ginseng
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Herbal Med
cold prevention anti-platelet post-prandial glucose reduction Interactions: psychotropic drugs estrogenic or hypoglycemic drugs NO WARFARIN |
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Milk Thistle
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Herbal Med
Tx for LIVER Dz Chemotherapeutic anti-inflammatory antidote to mushroom toxicity no interactions Think: give 'milk' to nurse your dying liver |
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St. John's Wort
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Herbal Med
Antidepressant inhibits reuptake of serotonin, NE, DA Caution with MAO-I --> high levels of drug/NT Induction of CYPs & p-glycoprotein--> reduces levels of some drugs (OCPs, Warfarin, etc.) |
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Saw Palmetto
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Herbal Med for Tx of BPH
Think: "Saw" down that "P"rostate |
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meds that inhibit CYPS
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It CAAGES the liver.
Cimetidine Amiodarone Azoles Grapefruit juice Erythromycin Sulfonamides (trimethoprim Sulfamexazole) |
