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What are the effects of noncompetitive inhibitors?
- - Do not resemble the substrate.
- - Can not be overcome by increasing substrate concentration
- - Do not bind the active site
- - Decrease Vmax
- - Do not change Km
- - Decrease efficacy
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What are the effects of competitive inhibitors?
- - Resemble the substrate
- - Can be overcome by increasing substrate concentration
- - Bind the active site
- - Do not change Vmax
- - Increase Km
- - Decrease potency
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Km reflects the _________ of the enzyme for the substrate.
affinity
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Vmax is directly proportional to the _____________.
enzyme concentration
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Volume of distribution
(definition and equation)
- - amount of drug in the body to the plasma concentration
- - Vd of protein-bound drugs can be altered by liver and kidney disease
Vd = amount of drug in the body/plasma drug concentration (units L)
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Where do drugs distribute with low Vd, medium Vd, and high Vd?
- Low Vd: distribute in blood
- Medium Vd: distribute in extracellular space or body water
- High Vd: distributes in tissues
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Clearance
- - relates the rate of elimination to the plasma concentration
- Cl = rate of elimination/plasma drug concentration
- = 0.7Vd / t1/2
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Half Life
- - time required to change the amount of drug in the body by 1/2 during elimination
- t1/2 = 0.7Vd/Cl (in hours)
- - 1 t1/2: 50% concentration
- - 2 t1/2: 75% concentration
- - 3 t1/2: 87.5% concentration
- - 4 t1/2: 94% concentration
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Loading Dose
Maintenance Dose
- Loading Dose = CpVd/F
- Maintenance Dose = CpCl/F
- Cp = target plasma concentration
- F = bioavailability
- - in patients with impaired renal or hepatic function,
- loading dose remains the same
- maintenance dose decreases
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Elimination of Drugs
- Zero Order - rate of elimination is constant, regardless of concentration
- - Cp decreases linearly with time
- - phenytoin, ethanol, aspirin
- First Order - rate of elimination is proportional to the concentration
- - Cp decreases exponentially with time
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Urine pH and Drug Elimination
- Ionized Species Get Trapped
- Weak Acids- trapped in basic environments
- - treat overdose with bicarbonate
- - pH > pKa nonprotonated form (ionic)
- Weak Bases- trapped in acidic environments
- - treat overdose with ammonium chloride
- - pH<pKa protonated form (ionic)
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Phase I and Phase II Metabolism
- Phase I- reduction, oxidation, hydrolysis
- - slightly polar, water soluble metabolites
- - cytochrome P450
- Phase II- acetylation, glucuronidation, sulfation
- - usually yields very polar, inactive metabolites (renally excreted)
- - conjugation
Geriatric patients lose Phase I first
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Efficacy vs. Potency
Efficacy - maximal effect a drug can produce (Vmax)
Potency - amount of drug needed for a given effect (Km)
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How do partial agonists effect potency and efficacy?
- - acts on the same receptor system as the full agonist but has a lower maximal efficacy, regardless of the dose
- - potency is an independent factor; therefore, a partial agonist can have lower potency, equivalent potency, or higher potency
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Therapeutic Index
- TI = Ld50/Ed50
- - want a higher TI
- - TILE pneumonic
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Acetylcholine Receptors
- Nicotinic ACh Receptors - ligand gated Na+/K+ channels
- - NN - autonomic ganglia
- - NM - neuromuscular junctions
- Muscarinic ACh Receptors - G-Protein coupled receptors
- - 5 subtypes: M1 - M5
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Alpha-1 Receptor
- - Sympathetic
- - Gq protein class (IP3 increases Ca2+, DAG increases Protein Kinase C)
- - increase vascular smooth muscle contraction
- - mydriasis (pupillary dilator muscle contraction)
- - increase sphincter contraction
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Alpha-2 Receptor
- - Sympathetic
- - Gi protein class (decreases cAMP and PKA)
- - decrease sympathetic outflow
- - decrease insulin release
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Beta-1 Receptor
- - Sympathetic
- - Gs protein class (increases cAMP and PKA)
- - increases heart rate
- - increases contractility
- - increases renin release
- - increases lipolysis
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Beta-2 Receptor
- - Sympathetic
- - Gs protein class (increases cAMP and PKA)
- - vasodilation
- - bronchodilation
- - increase heart rate
- - increase contractility
- - increase lipolysis
- - increase insulin release
- - decrease uterine tone
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M1 Receptor
- - Parasympathetic
- - Gq protein class (IP3 increases Ca2+, DAG increases Protein Kinase C)
- - CNS
- - enteric nervous system
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M2 Receptor
- - Parasympathetic
- - Gi (decrease cAMP and PKA)
- - decrease heart rate
- - decrease contractility of atria
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M3 Receptor
- - Parasympathetic
- - Gq protein class (IP3 increases Ca2+, DAG increases Protein Kinase C)
- - increase exocrine gland secretions
- - increase gut peristalsis
- - increase bladder contraction
- - bronchoconstriction
- - miosis (pupillary sphincter muscle contraction)
- - accomodation (ciliary muscle contraction)
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D1 Receptor
- - Dopamine
- - Gs protein class (increase cAMP and PKA)
- - relaxes renal vascular smooth muscle
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D2 Receptor
- - Dopamine
- - Gi protein class (decrease cAMP and PKA)
- - modulates transmitter release (especially in the brain)
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H1 Receptor
- - Histamine
- - Gq protein class (IP3 increases Ca2+, DAG increases Protein Kinase C)
- - increase nasal and bronchial mucus production
- - contraction of bronchioles
- - prutitis
- - pain
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H2 Receptor
- - Histamine
- - Gs protein class (increase cAMP and PKA)
- - increase gastric acid secretion
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V1 Receptor
- - Vasopresssin
- - Gq protein class (IP3 increases Ca2+, DAG increases Protein Kinase C)
- - increase vascular smooth muscle contraction
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V2 Receptor
- - Vasopressin
- - Gs (increase cAMP and PKA)
- - increase water permeability and reabsorption in the collecting tubules of the kindney
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