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20 Cards in this Set
- Front
- Back
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benzodiazepine [7]
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Antianxiety (Anxiolysis)
Sedative Hypnotic Anticonvulsant Amnestic (anterograde amnesia) Muscle Relaxant Alcohol withdrawal – use the longer acting such as chlordiazepoxide make for a good premedication for surgery (midazolam, lorazepam, diazepam) |
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About same uses as Barbiturates but why use these instead?
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About same uses as Barbiturates but why use these instead?
Barbiturates have 1. Low therapeutic index (toxic) Addictive “intoxicatio” side effects |
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Early non-barbiturate agents
Methaqualone |
A nonbarbiturate sedative-hypnotic, unrelated chemically to other sedatives, methaqualone is classified as a central nervous-system depressant. Quaaludes and Sopors are pure methaqualone, while Parest, Optimil, and Somnafac are methaqualone hydrochloride. Biphetamine T and Biphetamine T 20 add amphetamine and dextroamphetamine to the methaqualone”
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midazolam
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mid-AY-zoe-lam
Quite lipid soluble – must be formulated with propylene glycol which can cause venoirritation diazepam formulated with a soybean oil Must be very careful to not mix with acid salts of other compounds such as opioids otherwise can protonate the nitrogens Since water soluble at lower than pH of 4, often formulated in acidic solution about pH 3.5 at physiological pH reverts back to lipid soluble form. |
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benzo SAR
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Must have electron withdrawing (electronegative) group at position 7
Triazolo derivatives are more potent (less metabolized). Have additional phenyl (aryl) If no triazole ring is present, must have carbonyl at position 2. Positions 6,7,9 must be unsubstituted. Substitution at N1 should be small alkyl group Additional phenyl (aryl) increases activity Substitution at 2’ with electron withdrawing group increases activity, produces greater amnesia. No substitution at 4’ position. |
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benzo's interact with
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Interacts with
GABAA Inhibitory Adenosine Receptors Inhibitory Adenosine Agonist activity increases because inhibits uptake of adenosine |
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Benzodiazepines bind to the _________ sub-unit of the _______ receptor at an allosteric site which results in increased receptor activity.
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gamma
GABA 1 |
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Benzo's are an ________ of the GABA receptor, not an _______.
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modulator
agonist |
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Potency is determined by?
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binding affinity – strength of binding
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Anatomically, benzo's inhibit neurotransmission in the?
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reticular activating system
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Benzo S/A'
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Slight respiratory depression
Synergistic with opioids Can be more pronounced with elderly patients Induction minimally decreases BP, CO and systemic vascular resistance (SVR) |
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most postent?
fastest elimination? |
lorazapam
midazolam |
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Absorption
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Not water soluble and Lipophylic
Special Formulation needed Exception is Midazolam High protein binding Midozolam ~ 94% Lorazapam/Diazepam ~ 99% Most lipophylic show more of a 3 compartment model Easily absorbed from GI – but because fairly easily metabolized, significant first pass effect Slower equilibration time with brian compared with thiopental barbiturate and propofol |
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Distribution
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Onset depends on distribution to brain which is dependent upon lipophilic character.
Distributed to peripheral tissues Extent dependent upon lipid solubility The more lipid soluble (diazepam) rapidly cross placenta |
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Metabolism
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Lipophylic so some amount of perfusion dependency.
Metabilized by cyp p450 enzymes Cyp 3A Can be slowed by drug-drug interactions Cimetidine,erythromycin, antifungals, calcium channel blockers, also fentanyl and grapefruit juice Elderly – less metabolism due to less perfusion also less protein binding so larger Vd and longer metabolism and clearance |
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no active metabolites ?
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Temazepam/Lorazepam/Oxazepam Those with only Phase II such as lorazepam usually see metabolism the same across all populations
midaz, no phase 2 Diazepam - active metabolites – can have resurgence of effect also enterohepatic recycling |
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pharmacodynamic profile doesn’t always well match drug elimination, why?
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some active metabolites undergo further metabolism even more slowly than the parent compound
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Elimination
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Classified short/long etc by t1/2
Table Summary Dependent upon kind of metabolism Does not parallel duration |
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Contraindications
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Cirrhosis of liver/renal insufficiency
Pregnancy Cirrhosis – less plasma protein so less binding and more free drug Pregnancey – readily crosses placenta |
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Antagonist
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Flumazenil
Competitive antagonist Reverses effects Quick acting (1-3 minutes) Short Duration (~ 1 hr) Physotigmine/Aminophyllin Non specific antagonist CNS stimulant that overcome depressions caused by benzodiazepines. |
