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661 Cards in this Set
- Front
- Back
What is pharmacokinetics?
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Deals with what the body does to the drug: absorption, distribution, sites of action, tissue storage, metabolism and excretion.
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What factors are involved in drug permeation/absorption?
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Solubility, concentration gradient, surface area, vascularity, ionization.
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In what form can drugs cross cell membranes?
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Non-ionized form (lipid soluble).
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In what form are drugs excreted?
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Ionized form (water soluble) are better renally excreted
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What factors affect renal clearance of drugs?
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The drug must be in free form, ionized or nonionized. Only nonionized drug can be actively secreted or reabsorbed.
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What effect does acidification of urine have on drugs?
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Increases ionized fraction of weak bases and increases their renal elimination. NH4Cl, vitamin C, cranberry juice.
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What effect does alkalinization of urine have on drugs?
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Increases ionized fraction of weak acids and increases their renal elimination. NaHCO3, acetazolamide.
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Urine alkalinization agents
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NaHCO3, acetazolamide
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Urine acidification agents
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NH4Cl, vitamin C, cranberry juice
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What is Cmax?
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Maximal drug level obtained with the dose
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What is Tmax?
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Time at which Cmax occurs
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What is the lag time?
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Time from administration to appearance in blood
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What is onset of activity?
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Time from administration to blood level reaching minimal effective concentraion
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What is duration of action?
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Time that the plasma concentration remains above minimial effective concentration
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What is time to peak?
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Time from administration to Cmax.
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What is bioavailability?
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Is the fraction of a dose that reaches the systemic circulation after 1st pass metabolism
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What is the first-pass effect?
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Is the decrease in bioavailability of an oral drug after passing through intestines or from the portal blood through the liver. Portal blood will always have a higher concentration of the drug before passing for the first time through the liver.
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What is bioequivalence and what factors are involved?
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Bioequivalence is the similarity between two formulations of the same drug. To be bioequivalent they must have the same bioavailability and the same rate of absorption.
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How are rate of absorption, Tmax and Cmax related?
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The faster the rate of absorption the smaller Tmax and larger Cmax. Tmax and Cmax are rate dependant.
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What is distribution?
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Is the process by which a drug reaches the target tissues from systemic circulation.
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What factors affect distribution of a drug?
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Protein-binding capacity and competition between drugs for protein-binding sites, barriers such as placenta or brain.
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What is volume of distribution?
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Correlates dose given with the plasma level at time X. Vd=Dose/C0. C0=[plasma] at zero time.
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What is the significance of the volume of distribution?
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It's needed to calculate a loading dose; when Vd is low, a high fraction of the drug is bound to proteins; when Vd is high, a big fraction of the drug is being sequestered in tissues.
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Relationship between plasma concentration and volume of distribution
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Inversely proportional. The higher the plasma concetration, the lower the volume of distribution
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Relationship between dose and plasma concentration
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Directly proportional.
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What is redistribution?
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Is when a lipid-soluble drug gets temporarily stored in fat tissue before being eliminated.
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What is the significance of the redistribution rate?
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A second dose of a CNS drug redistributes to fat in lesser amount because fat is "saturated" therefore allowing more drug to enter the CNS and increasing the duration of action.
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What is biotransformation?
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Is the conversion of a drug to a more water-soluble form to be excreted. A metabolite may or may not have pharmacologic action.
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What is phase I biotransformation?
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Modification of the drug via oxidation, reduction or hydrolysis.
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What is microsomal metabolism?
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Cytochrome P450 isoenzymes in the SER require NADPH for oxidation and reduction of drugs.
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General inducers of the P450 enzymes
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Anticonvulsants (barbiturates, phenytoin, carbamazepine), antibiotics (rifampin), chronic alcohol, glucocorticoids.
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General inhibitors of the P450 enzymes
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Proton pump inhibitors (cimetidine, omeprazole), antibiotics (chloramphenicol, macrolides, ritonavir, ketoconazole), acute alcohol, grapefruit juice, isoniazid
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What is nonmicrosomal metabolism?
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Hydrolysis reactions by esterases and amidases; MAO; alcohol dehydrogenases.
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What is phase II biotransformation?
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Modification of the drug by transferases via glucoronidation, acetylation, sulfation, gluthathione conjugation.
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What are the major modes of drug elimination?
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Biotransformation to inactive metabolites, excretion via the kidney, bile ducts, lungs and sweat.
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What is the elimination half-life (t1/2)?
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t1/2 is the time to eliminate 50% of a given amount of drug.
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What is zero-order elimination rate kinetics?
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A constant amount is eliminated per unit time. Independent of plasma concentration, variable t1/2.
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What is first-order elimination rate kinetics?
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A constant percentage of the drug is eliminated per unit time. t1/2 is constant, directly porportional to plasma levels.
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Rate of elimination
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Equals to GFR + active secretion - reabsorption
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Clearance
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Equals to free fraction * GFR or 0.7 * Vd/half life
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What is steady state and when is it achieved?
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Its when the rate in = rate out. 50% of SS is achieved at 1 t1/2; 90% at 3.3 t1/2; 95% at 4-5 t1/2.
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How does rate of infusion affect steady state and plasma levels at steady state?
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It takes the same amout of time to reach steady state but if rate of infusion increases the plasma levels at steady state will increase.
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Formula: volume of distribution
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Vd = D/C0
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Formula: half life
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t1/2 = 0.7/k or t1/2 = 0.7 x Vd/Cl
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Formula: clearance
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Cl = k x Vd
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Formula: infusion rate
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k0 = Cl x Css
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Formula: loading dose
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LD = Vd x Css
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Formula: Maintenance dose
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MD = Cl x Css x t
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Relationship between half-life and elimination
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Inversely proportional
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Relationship between half-life and clearance
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Inversely proportional
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Relationship between half-life and volume of distribution
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Directly proportional.
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Relationship between clearance and volume of distribution
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Inversely proportional
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Relationship between infusion rate and clearance
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Directly proportional.
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Relationship between infusion rate and steady state concentration
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Directly proportional.
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Relationship between steady state concentration and clearance
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Inversely proportional.
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What is pharmacodynamics?
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The effects of drugs in the body and drug receptor binding.
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Affinity
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Ability of the drug to bind its receptor. The closer to the y axis, the more affinity.
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Potency
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The quanity of drug required to produce a desired effect. The closer to the y axis, the more potent.
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Efficacy
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The maximal effect an agonist can achieve at the highest practical concentration. The taller the curve, the more efficacy.
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What is meant by the "duality" of partial agonists?
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Partial agonists can compete with full agonists for its receptor, lowering the maximal response, therefore it acts as an antagonist in the presence of a full agonist.
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Effect of a competitive antagonist
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Parallel shift of the dose-response curve to the right; appears to increase potency; also increases Km; reversed by increasing agonist dose
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Effect of a noncompetitive antagonist
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Non-parallel shift to the right; appears to decrease efficacy of agonist; partially reversed by increasing agonist dose; decreases Vmax
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Physiologic antagonism
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Two agonists with opposing actions antagonize each other: vasoconstrictor Vs. vasodilator
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Chemical antagonism
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Agonist-chemical complex lowers effect of agonist
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Potentiation
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Parallel shift of the curve to the left; appears to increase potency of agonist.
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TD50
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Dose that causes toxicity in 50% of the population
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ED50
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Effective dose in 50% of the population
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Therapeutic index
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TD50/ED50; gives a measure of the relative safety of a drug
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ANS receptors and their second messenger systems
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"qiss qiq siq sqs". α1, α2, β1, β2, M1, M2, M3, D1, D2, H1, H2, V1, V2
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Substances with intracellular receptors
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Glucocorticoids, vitamin D, thyroid hormones, gonadal steroids
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Substances with ion channel receptors
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Nicotine, choline esters (ACh), ganglion blockers, skeletal muscle relaxants.
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Substances that interact with Gs receptors
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Catecholamines, dopamine, glucagon, histamine, prostacyclin. "qiss qiq siq sqs"
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Substances that interact with Gi receptors
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Epinephrine, norepinephrine, Ach, dopamine. "qiss qiq siq sqs"
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Substances that interact with Gq receptors
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Ach, norepinephrine, angiotensin II
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Phase 1 clinical testing
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Dose-response studies on small group of volunteers without disease. Includes pharmacokinetics characterization.
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Phase 2 clinical testing
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Dose-response studies on 100 patients in comparison with placebo and a positive control. Single or double blind.
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Phase 3 clinical testing
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Dose-response studies on 1000 patients in comparison to placebo and positive control. Usually double blind
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Phase 4 clinical testing
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New drug application, marketing approval and post-marketing surveillance.
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Zero-order kinetics curve
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Linear kinetics or exponential kinetics on log graph
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First-order kinetics curve
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Exponential kinetics or linear kinetics on log graph
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Dose-response curve
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Bell curve. Shows absoption phase, distribution, metabolism and elimination phases.
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Neurotransmitter of preganglionic neurons
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Acetylcholine
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Neurotransmitters of postganglionic neurons
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Acetylcholine, norepinephrine, epinephrine, dopamine
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Mechanism of miosis
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Sphincter muscle of the pupilla has M3 receptors. Muscarinic agonists causes contraction and miosis. Muscarinic antagonists cause relaxation and mydriasis with cycloplegia.
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Mechanism of mydriasis
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Dilator muscle of the pupilla has α1 receptors. α1 agonists cause contraction and mydriasis without cycloplegia. Also muscarinic blockers.
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Mechanism of accomodation
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Ciliary muscle has M3 receptors. Muscarinic agonists cause contraction and widening of the lens for close vision. Muscarinic antagonists cause cycloplegia and stretching of the lens for far vision.
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Muscarinic receptors of the eye
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Sphincter of the pupilla and cilliary muscles --> M3 --> miosis and accomodation
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Muscarinic receptors of the heart
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SA node and AV node --> M2 --> decrease heart rate, decrease conduction velocity
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Muscarinic receptors of the lungs
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Bronchioles and glands --> M3 --> bronchospasm and gland secretion
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Muscarinic receptors in the GI tract
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Stomach, intestines --> M3 --> increased motility, cramps, diarrhea; GI glands --> M1 --> gland secretion
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Muscarinic receptors of the bladder
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M3 --> contraction of detrusor, relaxation of the trigone/sphincter --> urination and urinary incontinence
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Muscarinic receptors of sphincters (GI, GU)
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M3 --> relaxation, excep LES which contracts
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Muscarinic receptors of glands
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M3 --> gland secretion --> sweat, salivation, lacrimation
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Muscarinic receptors in endothelium
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M3 --> cause vasodilation via release of NO
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Location of M3 receptros
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Eye (sphincter and cilliary), smooth muscle of bronchioles, GU and GI, glands except GI, sphicters, endothelium.
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Net effects of M3 receptor activation
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Miosis, accomodation, salivation, lacrimation, sweating, bronchoconstriction, increased GI motility, relaxation of sphincters (except LES), release of NO (indirect vasodilation).
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Net effects of M2 receptor activation
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Decreased heart rate, decreased conduction velocity of AV node.
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Net effects of M1 receptor activation
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Gland secretions of the GI tract.
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Receptors in the adrenal medulla
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Nn --> secretion of epinephrine and norepinephrine
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Receptors at the neuromuscular junction
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Nm --> muscle depolarization and contraction
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Receptors in autonomic ganglia
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Nn --> net effects depend on PANS/SANS dominance
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Muscarinic receptor mechanisms and second messenger systems
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M1, M3 --> Gq; M2 --> Gi; Nn, Nm --> Na/K channels
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Hemicholinium
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Inhibits reuptake of choline decreasing Ach synthesis (anticholinergic)
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Botulinum toxin
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Blocks release of ACh. Used in blepharospasm, strabismus, dystonia, cosmetics.
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Direct muscarinic agonists
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ACh, bethanecol, methacholine, pilocarpine
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Properties and use of acethylcholine
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Acts on muscarinic and nicotinic receptors. Strongly hydrolised by AChE. No clinical use.
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Properties and use of bethanecol
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Acts on muscarinic receptors. No AChE hydrolisis. Rx.: paralytic ileus, urinary retention
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Properties and use of methacholine
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More muscarinic than nicotinic actions. Weakly hydrolised by AChE. Used to Dx. Bronchial hyperreactivity.
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Properties and use of pilocarpine
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Acts on muscarinic receptors. Not hydrolyzed by AChE. Used for Rx. of glaucoma and xerostomia.
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Rx. of paralytic ileus
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Bethanecol, neostigmine, pyridostigmine
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Rx. of urinary retention
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Bethanecol, neostigmine, pyridostigmine
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Dx of bronchial hyperreactivity
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Methacholine
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Rx of glaucoma and xerostomia
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Pilocarpine, physostigmine
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Acetylcholinesterase inhibitors
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Edrophonium, physostigmine, neostigmine, pyridostigmine, donepezil, tacrine, organophosphates (irreversible)
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Properties and use of edrophonium
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Short acting AChE inhibitor. Dx myasthenia gravis
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Properties and use of physostigmine
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Tertiary amine AChE inhibitor. Rx glaucoma, antidote in atropine overdose
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Properties and use of neostigmine and pyridostigmine
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Cuaternary amines AChE inhibitors. Rx paralytic ileus, urinary retention, myasthenia, reversal of nondepolarizing NM blockers
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Properties and use of donepezil and tacrine
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Lipid-soluble AChE inhibitor enters CNS. Rx Alzheimer disease.
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Properties and use of organophosphates
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Lipid soluble irreversible AChE inhibitors. Rx glaucoma. Also insecticides parathion, malathion and nerve gas sarin.
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Dx and Rx of myasthenia gravis
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Edrophonium (Dx), neostigmine, pyridostigmine (Rx)
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Rx Alzheimer disease
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Donepezil, tacrine
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Signs and symptoms of organophosphate intoxication
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"Dumbbelss" Diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation, lacrimation, salivation, sweating.
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Rx of organophosphate intoxication
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Atropine + pralidoxime for regeneration of non-aged AChE.
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MOA pralidoxime
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Removes organophosphate group from AChE thus regenerating it. Aged AChE that have just a phosphate attached cannot be regenerated.
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Muscarinic blockers
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Atropine, tropicamide, ipratropium, scopolamine, benztropine
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Effects of muscarinic blockers
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Decreased salivary, bronchiolar and sweat secretions, mydriasis and cycloplegia, hyperthermia, tachychardia, sedation, urinary retention, constipation, hallucinations
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Rx of muscarinic blocker intoxication
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Physostigmine
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Uses of atropine
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Anesthesia, management of organophosphate toxicity
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Uses of propicamide
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Opthalmologic mydriasis
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Uses of ipratropium
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Inhaled in asthma and COPD. Doesn’t enter CNS.
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Uses of scopolamine
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Motion sickness, sedation, short-term memory block.
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Uses of benztropine
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Lipid-soluble, enters CNS. Used in parkinsonism and acute extrapyramidal symptoms of antipsychotics.
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Effects of ganglion blockers
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Reduce the predominant autonomic tone. PANS is dominant in heart, pupil, GI, GU and sphincters. SANS is dominant in blood vessels and sweat glands.
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Synthesis of catecholamines
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Tyrosine + tyrosine hydroxylase --> dopa + dopa decarboxylase --> dopamine + dopamine β hydroxylase --> norepinephrine + SAM + methyltransferase --> epinephrine
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MAO
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Located in outer mitochondrial membrane, degrades catecholamines by oxidative deamination. MAO-A: mainly in liver metabolizes NE, 5HT and tyramine. MAO-B mainly in brain, metabolizes DA.
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COMT
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Located in postsynaptic membrane, degrades catecholamines by methylations (requires SAM).
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Distribution of α1 receptors
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Pupil dilator muscle, arterioles of skin and viscera, veins, bladder trigone and sphincter, vas deferens, liver, kidney
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Distribution of α2 receptors
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Presynaptic terminal, platelets, pancreas
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Distribution of β1 receptors
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Heart SA node, AV node, atrial and ventricular muscle, His-Purkinje, kidney
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Distribution of β2 receptors
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All blood vessels, uterus, bronchioles, skeletal muscle, liver, pancreas
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Distribution of D1 receptors
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Renal, mesenteric, coronary vasculature
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α1 effects
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Mydriasis, increases TPR, diastolic pressure, afterload, venous return, preload, reflex bradycardia, urinary retention, ejaculation, glycogenolysis, decreases renin release
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α2 effects
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Decreases NE synthesis and release, promotes platelet aggregation, decreases insulin secretion
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β1 effects
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Increases HR, conduction velocity, contractility, CO, oxygen consumption and renin release
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β2 effects
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Vasodilation, decreases TPR, diastolic pressure and afterload, uterine relaxation, bronchodilation, increases glycogenolysis in liver and muscle, increases insulin secretion
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D1 effects
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Vasodilation of renal, mesenteric, coronary vasculatures, increases RBF, GFR
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α1 agonists
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Phenylephrine, methoxamine
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Uses of phenylephrine
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Nasal decongestant and opthalmologic mydriasis without cycloplegia
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α2 agonists
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Clonidine, methyldopa
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Uses of clonidine
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Mild to moderate hypertension
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Uses of methyldopa
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Mild to moderate hypertension
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Effects of β agonists on CV system
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β1: increase HR, CO, pulse pressure; β2: decrease TPR, BP.
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β agonists
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Isopreterenol, dobutamine
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β2 selective agonists
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Salmeterol, albuterol, terbutaline
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Uses of β2 selective agonists
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Asthma and ritodrine in premature labor
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Uses of isoproterenol
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β1=β2: used in bronchospasms, heart blocks and bradyarrhythmias. Side effects: flushing, angina, arrhythmias
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Uses of dobutamine
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β1 > β2: congestive heart failure
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Effects of norepinephrine on CV system
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Acts on α1 (increases TPR, BP), α2 and β1 (increases HR, CO, pulse pressure). Potential reflex bradycardia.
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Effects of low dose of epinephrine on CV and respiratory systems
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Acts on β1 (increases HR, SV, CO, pulse pressure), β2 (decreases TPR, BP, bronchodilation)
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Effects of medium dose epinephrine on CV and respiratory systems
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Acts on β1 (increases HR, SV, CO, pulse pressure), β2 (decreases TPR, BP, bronchodilation), α1 (increases TPR, BP)
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Effects of high dose epinephrine on CV and respiratory systems
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Acts on α1 (increases TPR, BP), β1 (increases HR, CO, pulse pressure), β2 (decreases TPR, BP, bronchodilation). Potential reflex bradycardia.
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Effect of adding α1 blocker to epinephrine
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Reverses hypertension to hypotension. Use this to differentiate from norepinephrine.
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Uses of epinephrine
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Cardiac arrest, adjunct to local anesthetic, hypotension, anaphylaxis, asthma
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Uses of norepinephrine
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Cardiac arrest, adjunct to local anesthetic, hypotension
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Indirect acting adrenergic agonists
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Releasers of catecolamines: Tyramine, amphetamines (methylphenidate), ephedrine. Reuptake inhibitors: cocaine, tricyclic antidepressants. MAO-A inhibitors interaction can cause hypertensive crisis.
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Effects of α blockers
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Decrease TPR and BP. May cause reflex tachychardia and salt/water retention.
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Uses of α blockers
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Hypertension, pheochromocytoma, BPH (selective α1 blocker)
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Nonselective α blockers
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Phentolamine (reversible), phenoxybenzamine (irreversible)
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Selective α1 blockers
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Prazosin, doxazosin, terazosin, tamsulosin
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Selective α2 blockers
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Yohimbe (used in hypotension and impotence), mirtazapine (depression)
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Effects of β1 blockers
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Decresed HR, SV, CO, renin, aqueous humor production
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Side effects of β2 blockers
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Bronchospasm in asthmatics, vasospasm, decreased glycogenolysis, gluneogenesis, increased LDLs, TGs
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Selective β1 blockers
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Acebutolol, atenolol, metroprolol
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Nonselective β blockers
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Pindolol, propranolol, timolol
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β blockers that raise blood lipids
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Atenolol (β1), metroprolol (β1), propranolol, timolol
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β blockers that cause the most sedation
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Propranolol, timolol
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β blockers with intrinsic sympathomimetic activity
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Act as partial agonists, less bradycardia, slight vasodilation, bronchodilation, minimal change in lipids: acebutolol, pindolol
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General uses of β blockers
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Angina, hypertension, post-MI
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β blockers used as antiarrhythmics
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Propranolol, acebutolol, esmolol
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Specific uses of timolol
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Glaucoma
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Specific uses of propranolol
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Migraine, thyrotoxicosis, performance anxiety, essential tremor
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Combined α1 and β blockers
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Labetalol, carvedilol. Used in CHF.
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Combined K channel and β blockers
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Sotalol. Class III antiarrhythmic.
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Phase 0 of the cardiac action potential
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Fast Na channels open causing depolarization. Class I antiarrhythmics slow or block phase 0.
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Phase 1 of the cardiac action potential
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Overshoot. Na channels inactivated, transient outward K currents.
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Phase 2 of the cardiac action potential
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Plateau phase. Slow influx of Ca and late-appearing outward K current.
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Phase 3 of the cardiac action potential
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Repolarization. Delayed rectifier K outward current. Class III antiarrhythmics slow repolarization.
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Phase 4 of the cardiac action potential
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Resting membrane potential. Maintained by the Na/K ATPase pump.
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Phase 0 of the pacemaker action potential
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Depolarization depends on Ca channels. Class IV antiarrhythmics slow or block this phase.
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Phase 3 of the pacemaker action potential
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Repolarization. Ca currents are opposed by outward delayed K currents.
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Phase 4 of the pacemaker action potential
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Spontaneous depolarization caused by Na funny current, Ca inward curents and K outward currents. Class II and IV antiarrhythmics slow this phase.
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Effective refractory period
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No stimulus can elicit a response. Lasts into phase 3 due to Na channel inactivation. K channel blockers prolong ERP.
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Relative refractory period
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Only a strong stimulus can elicit a response. Associated with arrhythmias.
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Innervation of the SA and AV nodes
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Parasympathetic via M2 receptors. Sympathetic via β1 receptors.
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What effect does sympathetic stimulation have on SA and AV nodes
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β1 activation increases cAMP, increasing upstroke velocity by increase of Ca conductance. Shortens action potential duration by increase of K conductance. Increases HR by increase of Na funny currents and increased phase 4 slope.
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What effect does parasympathetic stimulation have on SA and AV nodes
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M2 activation decreases cAMP. Decrease upstroke velocity by decreasing Ca conductance. Prolongs action potential duration by decrease of K conductance. Decreases HR by decrease of Na funny current and by increase K conductance.
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Class 1A antiarrhythmics
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Quinidine, procainamide
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1A antiarrhythmics MOA
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Block fast Na channels in the open state (decreases excitability and phase 0 slope) increasing APD and ERP. Block K channels which prolongs repolarization (decrease phase 3 slope).
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Quinidine pharmacokinetics
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Orally effective weak base enhanced absorption and toxicity by antacids. In atrial fibrilation needs intitial digitalization.
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Quinidine pharmacodynamics
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Class 1A effects plus muscarinic receptor blockade (increase HR and AV conduction); vasodilation via alpha block with reflex tachychardia.
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Quinidine adverse effects
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Cinchonism (GI, tinnitus, ocular dysfunction, CNS excitation), hypotension, QRS and QT prolongation associated with syncope torsades
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Quinidine drug interactions
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Hyperkalemia enhances effects and vice versa. Displaces digoxin from tissue binding sites, enhancing toxicity.
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Procainamide pharmacokinetics
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Phase 2 acetylation by N-acetyltransferase to N-acetylprocainamide (NAPA) active metabolite. Subject to genotypic variation/slow acetylators/drug-induced lupus.
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Procainamide adverse effects
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SLE-like syndrome (30%) in slow acetylators. Thrombocytopenia, agranulocytosis, torsades.
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Class 1B antiarrhythmics
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Lidocaine, mexiletine, tocainide
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Class 1B antiarrhythmics MOA
|
Block fast Na channels in the inactive state, preferentially in hypoxic tissues results in increased threshold for excitation and less excitability of hypoxic heart muscle. Block of slow Na window currents with decreased APD (decreased phase 2 of AP). Increases dyastole and time for recovery (leads to asystolia)
|
|
Uses and side effects of lidocaine
|
Post MI, open heart surgery, digoxin toxicity. Seizures, least cardiotoxic antiarrhythmic. IV because of first-pass metabolism.
|
|
Class 1C antiarrhythmics MOA
|
Block fast Na channels specially in His-Purkinje fibers without altering the APD (decreases phase 0 slope at the expense of shortening phase 2 duration)
|
|
Flecainide
|
Class 1C antiarrhythmic. Limited use because of proarrhythmogenic effects. Increased risk of sudden death post-MI.
|
|
Effects of class 1A antiarrhythmics on action potential
|
Decrease slope of phase 0; increase APD and ERP.
|
|
Effects of class 1B antiarrhythmics on action potential
|
Decrease length of phase 2 (plateau) with no change in phase 0 or 3 which decreases APD.
|
|
Effects of class 1C antiarrhythmics on action potential
|
Decrease slope of phase 0 and decrease length of phase 2 which cancels out effect on APD.
|
|
Class II antiarrhythmics MOA
|
Block β1 receptors in the heart decreasing cAMP; Decrease upstroke velocity by decreasing Ca conductance (decreased phase 4). Prolongs action potential duration by decrease of K conductance (decreased phase 3 slope). Decreases HR by decrease of Na funny current and by increase K/ACh conductance (decreased phase 4)
|
|
Class II antiarrhythmics
|
Propranolol (nonselective), acebutolol, esmolol (β1 selective)
|
|
Uses of class II antiarrhythmics
|
Prophylaxis post MI, supraventricular tachyarrhythmias
|
|
Properties of propranolol
|
Nonselective β blocker, no sympathicomimetic activity, produces sedation and increases blood lipids.
|
|
Properties of acebutolol
|
Selective β1 blocker with intrinsic sympathicomimetic activity, no sedation, no increase in blood lipids.
|
|
Class III antiarrhythmics MOA
|
Decreased delayed rectifier K currents which slows phase 3 and increases APD and ERP.
|
|
Class III antiarrhythmics
|
Amiodarone, sotalol (combined K channel and β1 blocker)
|
|
Amiodarone pharmacokinetics
|
t1/2 > 80 days, large Vd.
|
|
Amiodarone pharmacodynamics
|
Blocks K channels in many tissues. Mimics class I, II and IV antiarrhythmics. Increases APD and ERP.
|
|
Amiodarone side effects
|
Large Vd affects many tissues: pulmonary fibrosis, blue pigmentation of skin, phototoxicity, corneal deposits, hepatic necrosis, thyroid dysfunction.
|
|
Sotalol MOA
|
Blocks K channels decreasing phase 3 of AP (increases APD); blocks β1 which decreases phase 4 and phase 3 slopes in pacemaker cells (which decreases HR and conduction)
|
|
Class IV antiarrhythmics MOA
|
Block slow Ca channels in pacemaker cells which decreases phase 4 and 0 slopes, which decreases HR.
|
|
Class IV antiarrhythmics
|
Verapamil, diltiazem
|
|
Uses of verapamil
|
Supraventricular tachyarhythmias
|
|
Verapamil side effects
|
Constipation, dizziness, flushing, hypotension, AV block
|
|
Verapamil drug interactions
|
Additive AV block with β-blockers and digoxin; displaces digoxin from tissue-binding sites.
|
|
Properties of adenosine
|
Activates adenosine receptors coupled to Gi, decreasing cAMP, decreasing SA and AV node activity. Used for paroxysmal supraventricular tachyarrhythmias. t1/2 < 10 seconds. Side effects: flushing, sedation, dyspnea. Antagonized by theophylline.
|
|
Drugs that cause torsades
|
Class IA (quinidine) and III (sotalol) antiarrhythmics, antipsychotics (ziprasidone), tricylic antidepressants.
|
|
Drugs that displace digoxin
|
Verapamil, quinidine
|
|
Drugs that cause drug-induced lupus
|
Hydralazine > procainamide > isoniazid (slow acetylators)
|
|
Effects of hyperkalemia on heart
|
Decreases K efflux reducing repolarization. Membrane is depolarized. Can cause heart stop on systole. Peaked T waves.
|
|
Effects of hypokalemia on heart
|
Increases K conductance and hyperpolarization. Heart stops of dyastole.
|
|
What is the strategy to treat hypertension
|
Decrease TPR (α2 agonists, α1 blockers), decrease CO (β-blockers), decrease body fluids (diuretics), vasodilation (hydralazine, nitirites, ACEIs, ARBs).
|
|
α2 agonists
|
Clonidine, methyldopa
|
|
Uses and side effects of clonidine
|
Uses: Mild to moderate hypertension, opiate withdrawal; Side effects: CNS depression, edema.
|
|
Uses and side effects of methyldopa
|
Uses: mild to moderate hypertension, hypertension management in pregnancy; Side effects: positive Coombs test, CNS depression, edema.
|
|
Reserpine MOA and side effects
|
Destroys catecolamine vesicles leading to decrease in CNS and peripheral levels. Side effects: depression, edema.
|
|
Guanethidine MOA and side effects
|
Accumulates into nerve endings by reuptake, binds catecolamine vesicles and inhibits release of NE; Side effects: diarrhea, edema. Tricyclics block reuptake and actions of guanethidine
|
|
α1 blockers
|
Prazosin, doxazosin, terazosin
|
|
α1 blockers MOA
|
Decrease arteriolar and venous resistance. Decrease prostate and urinary sphincter tone.
|
|
α1 blockers side effects
|
First dose syncope, orthostatic hypotension, urinary incontincence
|
|
β-blockers cautions in use
|
Asthma, vasospastic disorders (atherosclerosis, Raynauds), diabetics (hypoglycemia normally induces tachychardia which is perceived by patient, but β-blockers prevent tachychardia warning signs).
|
|
Properties of hydralazine
|
Direct vasodilator as nitric oxide donor. Decreases TPR. Use in moderate to severe hypertension. Side effects: Drug-induced lupus in slow acetylators, edema, reflex tachychardia.
|
|
Drugs metabolized by acetylation
|
Hydralazine > procainamide > isoniazid (slow acetylators)
|
|
Nitroprusside
|
Nitric oxide donor vasodilates arterioles and venules. Used for hypertensive emergencies. Releases cyanide thus coadminister thiosulfate to form nontoxic thiocyanate. In case of cyanide poisoning give nitrites.
|
|
Direct vasodilators
|
Hydralazine (NO), nitroprusside (NO), minoxidil (opens K channels --> hyperpolarization --> vasodilation)
|
|
Minoxidil
|
Opens K channels in smooth muscle --> hyperpolarization --> vasodilation. Use in severe hypertension and alopecia. Side effects: hypertrichosis, edema, reflex tachychardia.
|
|
Diazoxide
|
Opens K channels in smooth muscle --> hyperpolarization --> vasodilation. Use in hypertensive emergencies. Side effects: hyperglycemia (decreases insulin release)
|
|
Arteriolar vasodilators
|
Ca channel blockers (nifedipine), hydralazine, K channel openers (minoxidil)
|
|
Venular vasodilation
|
Nitrates (nitroprusside)
|
|
Orthostatic hypotension
|
Due to venular dilation not arteriolar. Usually from α1 blockers.
|
|
Calcium channel blockers MOA
|
Block L-type Ca channels in heart and blood vessels smooth muscle --> decrease intracellular Ca --> decreased CO and TPR.
|
|
Calcium channel blockers
|
Verapamil, diltiazem, nifedipines and derivatives.
|
|
Uses of calcium channel blockers
|
Hypertension, angina, antiarrhythmics (verapamil, diltiazem)
|
|
Side effects of calcium channel blockers
|
Reflex tachychardia (nifedipine and derivatives), gingival hyperplasia (nifedipine and derivatives), constipation (verapamil)
|
|
ACE inhibitors MOA
|
Block formation of angiotensin II --> no AT-1 receptor stimulation --> decreased aldosterone secretion and vasodilation; also prevent bradykinin degradation by ACE (dry cough). Captopril and other -prils
|
|
Angiotensin receptor blockers MOA
|
Block angiotensin receptors --> decreased aldosterone secretion and vasodilation. Losartan and other -sartans
|
|
Uses of ACEIs and ARBs
|
Mild to moderate hypertension, protective of diabetic neprhopathy, CHF
|
|
ACEIs side effects
|
Dry cough (no degradation of bradykinin), hyperkalemia (no aldosterone), acute renal failure in renal artery stenosis (angiotensin maintains RBF), angioedema, rash
|
|
ARBs side effects
|
Hyperkalemia (no aldosterone), acute renal failure in renal artery stenosis (angiotensin maintains RBF), angioedema
|
|
Treatment strategy for heart failure
|
Decrease preload (diuretics, ACEIs, ARBs, venodilators), decrease afterload (ACEIs, ARBs, arteriodilators), increase contractility (digoxin, beta agonists), decrease cardiac remodeling (ACEIs, ARBs, spironolactone)
|
|
What drugs are beneficial in CHF and why?
|
ACEIs, ARBs and spironolactone prevent cardiac remodeling
|
|
Digoxin MOA
|
Inhibits cardiac Na/K ATPase --> increase intracellular Na --> decrease Na/Ca exchange --> increase intracellular Ca --> increase Ca release on sarcoplasmic reticulum --> increase contractile force. It also inhibits neuronal Na/K ATPase which increases vagal and sympathetic stimulation.
|
|
Digoxin pharmacokinetics
|
Long t1/2 needs loading dose; renal clearance; large Vd and displacement by verapamil and quinidine
|
|
Uses of digoxin
|
CHF and supraventricular tachychardias except Wolff-Parkinson-White syndrome
|
|
Wolff-Parkinson-White syndrome
|
Prexcitation of the ventricles due to accesory conduction bundle of Kent. Block accessory path with class IA or III antiarrhythmics, avoid β-blockers, CCBs and adenosine
|
|
Digoxin side effects
|
Anorexia, nausea, ECG changes, disorientation, visual halos, cardiac arrhythmias
|
|
Digoxin toxicity
|
Can cause cardiac arrhythmias. Use Fab antibodies against digoxin and class IB antiarrhythmics.
|
|
Digoxin drug interactions
|
Quinidine, verapamil displace digoxin; sympathicomimetics; diuretics
|
|
Phosphodiesterase inhibitors MOA
|
Inamrinone, milrinone. Phosphodiesterase normally converts cAMP into AMP, inhibitors increase cAMP and inotropy in heart and relax smooth muscle cells which leads to decreased TPR
|
|
Antianginal drugs
|
Nitroglycerin, isosorbide, CCBs (nifedipine), β-blockers and carvedilol
|
|
Nitrates MOA
|
Pro drugs of nitric oxide; NO activates smooth muscle guanylyl cyclase --> increase cGMP --> relaxation --> venodilation --> decrease preload --> decrease cardiac work and oxygen requirements
|
|
Nitroglycerin side effects
|
flushing, headache, orthostatic hypotension, reflex tachychardia, methhemoglobinemia.
|
|
Nitroglycerin interactions
|
Cardiovascular toxicity with sildenafil
|
|
Sildenafil MOA
|
Inhibits PDE5 in blood vessels of corpora cavernosa --> increase cGMP --> vasodilation --> erection
|
|
Uses and side effects of manitol
|
Decreases IOP in glaucoma, decreases intracerebral pressure in cerebral edema. Side effects: hypovolemia
|
|
Carbonic anhydrase inhibitors drugs
|
Acetazolamide, dorzolamide
|
|
Azetazolamide MOA
|
Decreases H+ formation in PCT --> decrease Na/H+ antiport --> increases Na and HCO3 in lumen --> diuresis
|
|
Uses of azetazolamide and CA inhibitors
|
Glaucoma, acute moutain sickness (acidosis stimulates ventilation), metabolic alkalosis
|
|
Azetazolamide and CA inhibitors side effects
|
Bicarbonaturia/acidosis, hypokalemia (increases Na load dowstream), hyperchloremia, paresthesia, renal stones (alkalinizes urine), sulfa hypersensitivity
|
|
Loop diuretic drugs
|
Ethacrynic acid, furosemide
|
|
Loop diuretics MOA
|
Inhibit Na/K/2Cl cotransporter --> decrease intracell K+ --> decrease positive potential --> decrease reabsorption of Ca, Mg --> increased diuresis
|
|
Uses of loop diuretics
|
Acute pulmonary edema, CHF, hypertension, refractory edema, acute renal failure, anion overdose, hypercalcemia
|
|
Loop diuretic side effects
|
Sulfonamide hypersensitivity (except ethacrynic acid), hypokalemia, alkalosis, hypocalcemia, hypomagnasemia, hyperuricemia, ototoxicity (ethacrynic acid > furosemide)
|
|
Loop diuretics drug interactions
|
Enhanced ototoxicity with aminoglycosides; decrease clearance of lithium, increase digoxin toxicity
|
|
Thiazide drugs
|
Hydrochlorothiazide, indapamide
|
|
Thiazides MOA
|
Inhibit Na/Cl transporter in DCT --> increases Na and Cl in the lumen --> increase diuresis
|
|
Uses of thiazides
|
Hypertension, CHF, nephrolithiasis (calcium stones), nephrogenic diabetes insipidus
|
|
Thiazides side effects
|
Sulfonamide hypersensitivity, hypokalemia, alkalosis, hypercalcemia, hyperuricemia, hyperglycemia, hyperlipidemia
|
|
Thiazide drug interactions
|
Increase digoxin toxicity, avoid in diabetics
|
|
K+ sparing agents
|
Spironolactone, eplerenone, amiloride, triamterene
|
|
MOA spironolactone
|
Aldosterone receptor antagonist --> no sodium reabsorption --> no K+ secretion
|
|
Uses of spironolactone
|
Hyperaldosteronism, adjunct to K+ wasting diuretics, hirsutism, CHF
|
|
Spironolactone side effects
|
Hyperkalemia, acidosis, antiandrogenic (except eplerenone)
|
|
MOA amiloride/triamterene
|
Blocks Na+ channels in principal cells of collecting ducts --> decreased Na+ reabsorption and K+ secretion
|
|
Uses of K+ sparing agents
|
Adjunct to K+ wasting diuretics, lithium-induced nephrogenic diabetes insipidus (amiloride)
|
|
Side effects of K+ sparing agents
|
Hyperkalemia, acidosis, antiandrogenic (except epleronone)
|
|
Electrolytes excreted by acetazolamide
|
Na, K, HCO3
|
|
Electrolytes excreted by loop diuretics
|
Na, K, Ca, Mg, Cl
|
|
Electrolytes excreted by thiazides
|
Na, K, Cl; Ca is reabsorbed
|
|
Electrolytes excreted by K+ sparing agents
|
Na; K is not secreted
|
|
Statins MOA
|
Inhibition of HMG-CoA-Reductase --> decreased cholesterol --> increased LDL receptor expression --> decresed LDLs
|
|
Statins side effects
|
Myalgia, myopathy, rhabdomyolysis due to decrease in farnesyl ppi
|
|
Statins drug interactions
|
Gemfribozil increases rhabdomyolysis; P450 inhibitors enhance toxicity
|
|
Bile acid sequestrant drugs
|
Cholestyramine, colestipol
|
|
MOA of bile acid sequestrants
|
Decreased enterohepatic circulation --> increased new bile salts in liver --> decreased liver cholesterol --> increased LDL receptor expression --> decreased blood LDL
|
|
Side effects of bile acid sequestrants
|
Increased VLDL and triglycerides; gastrointestinal disturbances; malabsorption of lipid-soluble vitamins
|
|
Drug interactions of bile acid sequestrants
|
Interact with orally administered drugs
|
|
Contraindications of bile acid sequestrants
|
Hypertriglyceridemia
|
|
Niacin MOA
|
Inhibits VLDL synthesis --> decreased plasma VLDL --> decreases LDL --> increases HDL
|
|
Niacin side effects
|
Flushing, pruritus, rashes, hepatotoxicity
|
|
Gemfibozil MOA
|
Activates lipoprotein lipase --> decreases VLDL and IDL --> decreases LDL --> increases HDL
|
|
Uses of gemfibrozil
|
Hypertriglyceridemia
|
|
Ezetimibe MOA
|
Prevents intestinal reabsorption of cholesterol --> decreased LDL
|
|
Which antihyperlipidemic: increased cholesterol
|
Cholestyramine, colestipol, ezetimibe
|
|
Which antihyperlipidemic: increased triglycerides
|
Gemfibrozil
|
|
Which antihyperlipidemic: increased cholesterol and triglycerides
|
Statins, niacin, ezetimibe
|
|
Properties of benzodiazepines
|
Bind to gamma subunit of GABAa complex to increase frequency of Cl- channel opening; no GABAmimetic activity; BZ1 mediates sedation; BZ2 mediates antianxiety and impairment of cognitive functions
|
|
Benzodiazepine drugs
|
Alprazolam, diazepam, lorazepam, midazolam, temazepam, oxazepam
|
|
Uses of alprazolam
|
Anxiety, phobias, panic attacks
|
|
Uses of diazepam
|
Anxiety, preop sedation, muscle relaxation, withdrawal states
|
|
Uses of lorazepam
|
Anxiety, preop sedation, status epilepticus
|
|
Uses of midazolam
|
Preop sedation and anesthesia, anterograde amnesia
|
|
Uses of temazepam
|
Sleep disorders
|
|
Uses of oxazepam
|
Sleep disorder and anxiety
|
|
Pharmacokinetics of benzodiazepines
|
Liver metabolized to active compounds except oxazepam, temazepam, lorazepam; t1/2: diazepam > lorazepam > alprazolam > temazepam > oxazepam > midazolam
|
|
Uses of barbiturates
|
Phenobarbital for seizures; thiopental for induction of anesthesia
|
|
Properties of barbiturates
|
Prolong GABA activity; increase duration of Cl- channel opening; GABAmimetic activity at high doses; bind to beta subunit of GABA(a) complex; inhibit complex I of ETC, induces P450
|
|
Pharmacokinetics of barbiturates
|
General inducers of P450; contraindicated in porphyrias
|
|
Withdrawal signs of benzodiazepines
|
Rebound insomnia, anxiety, seizures
|
|
Withdrawal signs of barbiturates and ethanol
|
Anxiety, agitation, life threatening seizures
|
|
Drug interactions of GABA drugs
|
Life threatening respiratory depression if used with other CNS depressants (antihistaminics, opiates, beta blockers); Barbiturates induce metabolism of lipid-soluble drugs (oral contraceptives, carbamazepine, phenytoin, warfarin)
|
|
Flumazenil
|
Benzodiazepine receptor antagonist. Used as antidote for benzodiazepine overdose.
|
|
Zolpidem
|
BZ1 receptor agonist used in sleep disorders. No cognitive impairment (no BZ2 actions), overdose reversed by flumazenil, less tolerance and abuse liability
|
|
Buspirone
|
No effect on GABA, 5-HT1a partial agonist, used for generalized anxiety, nonsedative, 1-2 weeks for effects
|
|
Effects of alcohols
|
GABA mimetic activity causes CNS depression; metabolic acidosis; fetal alcohol syndrome
|
|
Metabolism of ethylene glycol
|
Ethylene glycol + alcohol DH --> glycoaldehyde + aldehyde DH --> glycolic acid --> oxalic acid
|
|
Effects of ethylene glycol
|
CNS depression, severe metabolic acidosis, nephrotoxicity
|
|
Metabolism of methanol
|
Methanol + alcohol DH --> formaldehyde + aldehyde DH --> formic acid
|
|
Effects of methanol
|
Respiratory failure, severe anion gap metabolic acidosis, ocular damage
|
|
Treatment of alcohol overdose
|
Fomepizole (alcohol DH inhibitor) and hemodialisis
|
|
Metabolism of ethanol
|
Ethanol + alcohol DH --> acetaldehyde + NADH + acetaldehyde DH --> acetic acid + NADH
|
|
Effects of ethanol
|
CNS depression, metabolic acidosis, acetaldehyde toxicity
|
|
Acetaldehyde toxicity
|
Nausea, vomit, headache, hypotension, inactivates folate, decreases availability of thiamine
|
|
Drugs that cause disulfram-like effects
|
Disulfram-like effects = acetaldehyde toxicity. Disulfram inhibits acetaldehyde DH. Metronidazole, cefamandole, cefoperazone, cefotetan, chlorpropamide
|
|
Anticonvulsant drugs
|
Phenytoin, carbamazepine, benzodiazepines, barbiturates, lamotrigine, topiramate, felbamate, ethosuximide, valproic acid
|
|
Drugs used for partial seizures
|
Valproic acid, phenytoin, carbamazepine
|
|
Drugs used for general tonic-clonic seizures
|
Valproic acid, phenytoin, carbamazepine
|
|
Drugs used for absence seizures
|
Ethosuximide
|
|
Drugs used for status epilepticus
|
Lorazepam, diazepam, phenytoin
|
|
Phenytoin MOA
|
Inhibits fast Na channels in axons which decreases conduction and prevents seizure propagation
|
|
Pharmacokinetics of phenytoin
|
Variable absorption, nonlinear kinetics at low doses, zero-order kinetics at high doses, inducer of P450
|
|
Phenytoin side effects
|
CNS depression, gingival hyperplasia, hirsutism, osteomalacia (decreases vitamin D), megaloblastic anemia (decreases folate), aplastic anemia, teratogenic (cleft lip and palate).
|
|
Carbamazepine MOA
|
Inhibits fast Na channels in axons which decreases conduction and prevents seizure propagation
|
|
Pharmacokinetics of carbamazepine
|
Induces P450
|
|
Carbamazepine side effects
|
CNS depression, osteomalacia, megaloblastic anemia, aplastic anemia, exfoliative dermatitis, increases ADH secretion (dilutional hyponatremia), teratogenic (cleft lip and palate, spina bifida)
|
|
Valproic acid MOA
|
Inhibits fast Na channels in axons which decreases conduction and prevents seizure propagation; Inhibits GABA transaminase; Blocks presynaptic Ca+ channels
|
|
Uses of valproic acid
|
Seizures, bipolar mania, migraines
|
|
Pharmacokinetics of valproic acid
|
Inhibits P450
|
|
Valproic acid side effects
|
Hepatotoxic metabolite, thrombocytopenia, pancreatitis, alopecia, spina bifida
|
|
Ethosuxamide MOA
|
Blocks presynaptic T-type Ca+ channels in thalamic neurons
|
|
Lamotrigine MOA
|
Blocks Na+ channels and glutamate receptors. Side effect: Steven-Johnson
|
|
Inhaled anesthetic drugs
|
Nitrous oxide, halothane
|
|
Properties of halothane
|
High potency (0.8% MAC), high blood-gas ratio (2.3), sensitizes heart to catecholamines
|
|
Side effects of halothane
|
Malignant hyperthermia, hepatitis, cardiac arrhythmias
|
|
What is MAC?
|
Minimal alveolar concentration is the amount of anesthetic at which 50% of patients don't respond to surgical stimulus. Analogous to ED50, measures potency, the more lipid soluble the lower the MAC, lower in elderly
|
|
What is the blood-gas ratio?
|
Measure of the onset of recovery. The more soluble in the blood the slower the anesthesia and recovery.
|
|
Intravenous anesthetic drugs
|
Midazolam, thiopental, propofol, fentanyl, ketamine
|
|
General anesthesia protocol
|
Includes sedation and anterograde amnesia (midazolam), induction (propofol), analgesia (fentanyl), muscle relaxant for intubation (succinylcholine) and may or may not include atropine in case of CV depression due to propofol
|
|
Naloxone
|
Antidote for opiods
|
|
Neostigmine
|
AChE inhibitor reverses non-depolarizing muscle relaxants
|
|
What are the ester local anesthetics?
|
Procaine, cocaine, benzocaine. Metabolized by plasma esterases. All have only one "i"
|
|
What are the amide local anesthetics?
|
Lidocaine, bupivacaine, mepivacaine. Metabolized by liver amidases. All have two "i".
|
|
MOA of local anesthetics
|
Nonionized form crosses axonal membrane --> ionized form blocks inactivated Na+ channel --> prevent propagation of action potentials
|
|
Side effects of local anesthetics
|
Neurotoxicity, cardiovascular toxicity, allergies. Use alpha-1 agonists to prevent absorption.
|
|
Skeletal muscle relaxants MOA
|
Nicotinic antagonists (competitive, nondepolarizing); Nicotinic agonists (noncompetitive, depolarizing)
|
|
Non-depolarizing muscle relaxant drugs
|
Atracurium, mivacurium, tubocurarine
|
|
Non-depolarizing muscle relaxant properties
|
Nicotinic antagonists, reversible with AChE inhibitors, progressive paralysis, no effects on heart or CNS
|
|
Properties of succinylcholine
|
Depolarizing muscle relaxant, nicotinic agonist; Phase I: depolarization, fasciculation, flaccid paralysis; Phase II: desensitization. Caution in atypical pseudocholineeterase, hyperkalemia, malignant hyperthermia
|
|
Malignant hyperthermia
|
Succinylcholine side effect in genetically susceptible people. Muscle rigidity, hyperthermia, hypertension, acidosis, hyperkalemia. Rx.: dantrolene
|
|
Opiod analgesic drugs
|
Morphine, meperidine, methadone, codeine, fentanyl
|
|
Contraindications of opiod analgesics
|
Head injuries, pulmonary dysfunction, hepatic or renal dysfunction, adrenal or thyroid deficiencies, pregnancy
|
|
Effects of morphine
|
Analgesia, sedation, respiratory depression (decreased response to PCO2), miosis, cough supression, nausea, vomiting
|
|
Pharmacokinetics of morphine
|
Phase 2 metabolism by glucoronidation. Caution in renal dysfunction as morphine-6-glucoronide is highly active
|
|
Opiod toxicity
|
Pinpoint pupils, repiratory depression and coma. Rx. Naloxone
|
|
Meperidine
|
Opiod without miosis or spasms. Metabolized via P450 to normeperidine which can cause seizures
|
|
Methadone
|
Used for opiate withdrawal in addicts
|
|
Codeine
|
Cough suppressant, analgesia, use in combination with NSAIDs
|
|
Symptoms of opiod withdrawal
|
Yawning, lacrimation, rhinorrea, salivation, anxiety, muscle spasms and CNS-originating pain. Rx.: methadone
|
|
Drugs used in Parkinson disease
|
Levodopa, tolcapone, selegiline, bromocriptine, benztropine, amantadine
|
|
Levodopa
|
Crosses CNS barrier. Converted to dopamine in CNS and periphery, so use tolcapone, carbidopa and selegiline
|
|
Tolcapone
|
Inhibits COMT which blocks levodopa conversion to methyldopa which has no pharm actions
|
|
Carbidopa
|
Inhibits conversion of levodopa to dopamine in peripheral tissues, increasing CNS availability
|
|
Selegiline
|
MAOb selective inhibitor, adjunt to levodopa to decrease dopamine metabolism in CNS
|
|
Bromocriptine
|
Dopamine-receptor agonist used in hyperprolactinemia, acromegaly
|
|
Benztropine
|
Muscarinic blocker used to decrease Ach activity in Parkinson. Decreases tremor and rigidity but not bradykinesia
|
|
Atypical antipsychotics
|
Clozapine, olanzapine, risperidone, aripiprazole, quetiapine, ziprasidone, paliperidone
|
|
Atypical antipsychotic MOA
|
Inhibition of dopamine and 5HT2 receptors
|
|
Side effects of antipsychotic drugs
|
Extrapyramidal symptoms, akathisia, tardive dyskinesia, dysphoria, endocrine dysfunction, weight gain, hypotension, muscarinic blockade tachychardia
|
|
Specific side effects of thioridazine
|
Torsades, retinal deposits
|
|
Typical antipsychotics
|
Chlorpromazine, thioridazine, fluphenazine, haloperidol
|
|
Specific side effects of haloperidol
|
Neuroleptic malignant syndrome, tardive diskynesia
|
|
Specific side effects of clozapine
|
Agranylocytosis, seizures, salivation
|
|
MAO inhibitor drugs
|
phenelzine, tranylcypromine
|
|
Drug interaction of MAO inhibitors
|
Tyramine, TCAs, alpha-1 agonists, levodopa: increase NE --> hypertensive crisis; Serotonin syndrome with SSRI, TCA, meperidine --> sweating, rigidity, myoclonus, hyperthermia
|
|
Tricyclic antidepressant drugs
|
Amitriptyline, imipramine, clomipramine
|
|
TCAs MOA
|
Nonspecific blockade of 5HT and NE reuptake
|
|
Side effects of TCAs
|
Muscarinic blockade, alpha blockade, serotonin syndrome, hypertensive crisis
|
|
SSRI drugs
|
Fluoxetine, sertraline, paroxetine, citalopram
|
|
Side effects of SSRI
|
Anxiety, agitation, bruxism, sexual dysfunction, weight loss, serotonin syndrome
|
|
Serotonin syndrome
|
Sweating, rigidity, myoclonus, hyperthermia. Interaction between MAOi, TCAs, SSRIs, meperidine, dextromethorphan
|
|
Drug-induced hypertensive crisis
|
Due to interaction between MAOi, TCAs, alpha-1 agonists
|
|
Venlafaxine
|
Selective reuptake inhibitor of NE and 5HT. Can cause hypertensive crisis and serotonin syndrome
|
|
Bupropion
|
Dopamine reuptake blocker. Used in smoking cessation
|
|
Lithium MOA
|
Prevents recycling of inositol (decreases PIP2), decreases cAMP
|
|
Lithium side effects
|
Narrow therapeutic index requires monitoring, tremor, hypothyroidism (decreases TSH effects and inhibits 5'-deiodinase), nephrogenic diabetes insipidus (manage with amiloride), teratogenic
|
|
Methylphenidate
|
inhibits reuptake of DA and NE. Side effects: agitation, restlessness, insomnia, CV toxicity. Treats ADHD.
|
|
Atomoxetine
|
Selective NE reuptake inhibitor. Treats ADHD.
|
|
MOA of penicillins
|
Bind PBPs to inhibit transpeptidation reactions in peptidoglycan cross-linking --> inhibit cell wall synthesis
|
|
Mechanism of resistance to penicillin
|
Beta-lactamases (staphylococci); structural change in PBPs (MRSA); change in porin structure (pseudomonas)
|
|
Narrow spectrum penicillins
|
Penicillin G and V. Strep, pneumococci, menigococci, treponema
|
|
Very narrow spectrum penicillins
|
Nafcillin, methcillin, oxacillin. Staph. If MRSA use vancomycin.
|
|
Broad spectrum penicillins
|
Ampicillin, amoxicillin. Gram+ cocci (except staph), Listeria, H. influenzae, E. coli., Borrelia and H. pylory: amoxi
|
|
Extended spectrum penicillins
|
Ticarcillin, piperacillin, azlocillin. Increased activity against gram- plus anti-pseudomonal
|
|
Beta-lactamase inhibitors
|
Clavulanic acid, sulbactam. Use in combination with broad and extended spectrum penicillins
|
|
Pharmacokinetics of penicillins
|
Most are eliminated via active tubular secretion. Nafcillin and oxacillin are eliminated in bile. Ampicillin undergoes enterohepatic circulation but is excreted by the kidney. Benzathine penicillin G repository form (t1/2: 2 weeks)
|
|
Side effects of penicillins
|
Hypersensitivity (5-7%). Urticarial skin rash to anaphylaxis. Interstitial nephritis (methicillin).
|
|
First generation cephalosporins
|
Cefazolin, cephalexin. Gram+ cocci (not MRSA), E. coli, Klebsiella pneumoniae, some proteus. Surgical prophylaxis
|
|
Second generation cephalosporins
|
Cefotetan, cefaclor, cefuroxime. Increased gram- coverage, including some anaerobes
|
|
Third generation cephalosporins
|
Ceftriaxone (IM), cefotaxime (IV), cefdinir, cefixime (oral). Gram+ and gram- cocci plus gram- rods. Enter CNS. Use in meningitis, sepsis
|
|
Fourth generation cephalosporins
|
Cefepime (IV). Enter CNS, resistant to betalactamases
|
|
Pharmacokinetics of cephalosporins
|
Active tubular secretion blocked by probenecid. Cefoperazone and ceftriaxone largely eliminated in bile.
|
|
Side effects of cephalosporins
|
Hypersensitivity (2%), rashes, fever, positive Coombs test, disulfram-like effect
|
|
Drugs to use in case of penicillin/cephalosporin allergy
|
Macrolides for gram+, aztreonam for gram- rods
|
|
Imipenem and meropenem
|
Resistant to betalactamases. Active against gram+ cocci, gram- rods and anaerobes. Use in life-threatening infections. Used IV. Imipenem is given with cilastatin to inhibit rapid renal metabolism by dehydropeptidase. Side effect: seizures
|
|
Aztreonam
|
Resistant to betalactamases. Used IV against gram- rods. No cross-allergenicity with penicillins or cephalosporins
|
|
Vancomycin MOA
|
Binds D-Ala-D-Ala pentapeptide to inhibit elongation of peptidoglycan chains. Does not bind PBPs.
|
|
Uses of vancomycin
|
MRSA, enterococci, C. difficile (backup drug)
|
|
Resistance to vancomycin
|
Terminal D-ala is replaced with D-lactate in muramyl pentapeptide
|
|
Pharmacokinetics of vancomycin
|
Used IV and orally (not absorbed) in colitis. Enters most tissues but not CNS. Eliminated by renal filtration. Long t1/2
|
|
Side effects of vancomycin
|
"Red man syndrome" (histamine release); permanent ototoxicity; nephrotoxicity
|
|
Antibiotics that act on 30S ribosomal subunit
|
Aminoglycosides, tetracyclines. "buy AT 30, CCEL at 50".
|
|
Antibiotics that act on 50S ribosomal subunit
|
Chloranphenicol, clindamycin, erythromycin (macrolides), linezolid. "buy AT 30, CCEL at 50"
|
|
Antibiotics that inhibit formation of initiation complex
|
Aminoglycosides (30S), linezolid (50S)
|
|
Antibiotics that block attachment of aminoacyl-tRNA to A site
|
Tetracyclines (30S), dalfopristin (50S)
|
|
Antibiotics that inhibit peptidyltransferase (peptide bond formation)
|
Chloranphenicol (50S)
|
|
Antibiotics that inhibit translocation
|
Macrolides (50S), clindamycin (50S)
|
|
Mecanisms of resistance to macrolides and clindamycin
|
Methyltransferases alter drug binding site on the 50S ribosome; active transport out of cell
|
|
Mechanism of resistance to tetracyclines
|
Tetracycline pumps transport drug out of the cell
|
|
Mechanism of resistance to aminoglycosides
|
Conjugation enzymes
|
|
Mechanism of resistance to sulfonamides
|
Change in target enzyme decreases drug sensitivity; formation of PABA; use of exogenous folic acid
|
|
Mechanism of resistance to fluoroquinolones
|
Change in target enzyme decreases drug sensitivity; pumps transport drugs out of the cell
|
|
Mechanism of resistance to chloranphenicol
|
Formation of inactivating acetyltransferases
|
|
Pharmacokinetics of aminoglycosides
|
Polar compounds not absorbed orally or widly distributed. Renal elimination. Modify in renal dysfunction
|
|
Aminoglycoside drugs
|
Gentamicin, tobramycin, amikacin: gram- aerobic rods; Streptomycin: TB, plague and tularemia; neomycin
|
|
Side effects of aminoglycosides
|
Nephrotoxicity (6-7%), ototoxicity enhanced by loop diuretics.
|
|
Tetracycline drugs
|
Tetracycline, doxycycline, minocycline, demeclocycline
|
|
Uses of tetracyclines
|
Chlamydia, mycoplasma, H. pylory, Rickettsia, Borrelia, Brucella, Vibrio
|
|
Phamacokinetics of tetracyclines
|
Metabolized by kidney (most), and liver (doxycycline). Decrease absorption of divalent cations by chelation.
|
|
Side effects of tetracyclines
|
Tooth enamel dysplasia, decreased bone growth (avoid in children), phototoxicity, contraindicated in pregnancy
|
|
Drugs that cause phototoxicity
|
amiodarone, tetracyclines, sulfonamides, quinolones
|
|
Drugs that are nephrotoxic
|
Vancomycin, aminoglycosides, amphotericin B, cisplatin, cyclosporine
|
|
Drugs that are ototoxic
|
Aminoglycosides, loop diuretics
|
|
Pharmacokinetics of chloranphenicol
|
Orally effective, enters CNS, metabolized by hepatic glucoronidation, inhibits P450
|
|
Side effects of chloranphenicol
|
Dose-dependant bone-marrow suppression, "gray baby" in neonates (decreased glucoronosyl transferase)
|
|
Macrolide drugs
|
Erythromycin, azithromycin, clarithromycin
|
|
Uses of Erythromycin
|
Gram+ cocci, atypicals (chlamydia, mycoplasma, ureaplasma), legionella, campylobacter
|
|
Uses of azithromycin
|
Gram+ cocci, atypicals (chlamydia, mycoplasma, ureaplasma), legionella, campylobacter, more activity in respiratory infections
|
|
Pharmacokinetics of macrolides
|
Erythromycin and clarithromycin: metabolized by liver, excreted in bile, inhibit P450, not safe in pregnancy. Azithromycin: excreted by kidney, doesn't inhibit P450, safer in pregnancy
|
|
Side effects of macrolides
|
Stimulate motilin receptors and cause GI distress, reversible deafness, cholestasis, jaundice
|
|
Drugs to avoid in pregnancy
|
Aminoglycosides, erythromycin, clarithromycin, fluoroquinolones, sulfonamides, tetracyclines
|
|
Uses of clindamycin
|
Gram+ cocci, anaerobes, toxoplasmosis. Use in gram+ osteomyelitis. Can cause pseudomembranous colitis
|
|
Linezolid
|
VRSA, VRE, drug-resistant pneumococci. Side effect: bone marrow suppression (platelets)
|
|
Streptogramin drugs
|
Quinupristin-dalfopristin
|
|
MOA of streptogramins
|
Bind 50S ribosomal subunit
|
|
Uses of streptogramins
|
Vancomycin resistant staph (VRSA), vancomycin resistant enterococci (VRE), drug-resistant gram+ cocci
|
|
Inhibitors of nucleic acid synthesis drugs
|
5-MP, 6-FU, hydroxyurea, methotrexate, sulfonamides, trimethoprim, pyrimethamine
|
|
MOA of sulfonamides
|
Inhibits dihydropteroate synthetase which inhibits folic acid synthesis
|
|
MOA of trimethoprim
|
Inhibits dihydrofolate reductase which inhibits folic acid synthesis
|
|
Uses of trimethoprim-sulfamethoxazole
|
DOC in Nocardiosis; mycobacteria; gram+ cocci, E. coli, Salmonella, Shigella, H. influenzae, P. carinii, toxoplasma
|
|
Pharmacokinetics of sulfonamides
|
Hepatically acetylated; renally excreted metabolites cause crystalluria; high protein binding
|
|
Side effects of sulfonamides
|
Hypersensitivity, Steven Johnson, phototoxicity, GI distress, hemolysis in G6PDH deficiency
|
|
Side effects of trimethoprim
|
Bone marrow suppression, enterocolitis
|
|
Quinolone drugs
|
Norfloxacin, ciprofloxacin, ofloxacin, levofloxacin
|
|
MOA of quinolones
|
Bactericidal. Inhibit topoisomerase II (DNA gyrase).
|
|
Uses of quinolones
|
UTIs resistant to cotrimoxazole, PID (chlamydia, gonococcus), skin and bone infections by gram-, diarrhea to shigella, salmonella, E. coli, campylobacter
|
|
Pharmacokinetics of quinolones
|
Iron and Ca+ limit their absorption, eliminated by kidney active secretion (inhibited by probenecid)
|
|
Side effects of quinolones
|
GI distress, phototoxicity, rashes, tendonitis, increases QT interval, contraindicated in pregnancy and children
|
|
Regimens used in H. pylori infections and ulcers
|
BMT: bismuth, metronidazole, tetracyclines or clarithromycin, amoxicillin, omeprazole
|
|
Uses of metronidazole
|
Giardia, trichomonas, entamoeba, gram- anaerobics, clostridium (DOC pseudomembranous colitis)
|
|
MOA and resistance to isoniazid
|
Inhibits mycolic acid synthesis; prodrug requires conversion by catalase; resistance: deletions if katG gene encodes catalase needed for activation; deletions in inhA gene encodes acyl carrier protein, the target
|
|
Side effects of isoniazid
|
Age-dependant hepatitis, peripheral neuritis (use B6), sideroblastic anemia (use B6), hemolysis in G6PDH deficiency, drug-induced lupus in slow acetylators
|
|
MOA and resistance to rifampin
|
Inhibits DNA-dependant RNA polymerase; resistance via change in enzyme
|
|
Side effects of rifampin
|
Hepatitis, induction of P450, red-orange metabolites
|
|
MOA of ethambutol
|
Inhibits synthesis of cell wall component arabingalactan
|
|
Side effects of ethambutol
|
Dose-dependant retrobulbar neuritis --> decreases visual acuity and red-green discrimination
|
|
Side effects of streptomycin
|
Deafness, vestibular dysfunction, nephrotoxicity
|
|
Polyene drugs
|
Amp B, nystatin
|
|
MOA of polyenes
|
Formation of artificial pores in the ergosterol membranes disrupts membrane permeability
|
|
Uses of amphotericin B
|
Severe infections by Aspergillus, Candida, Cryptococcus, Histoplasma, Mucor, Sporothrix
|
|
Uses of nystatin
|
Topical localized infections; too toxic for systemic use
|
|
Pharmacokinetics of amphotericin B
|
Given by slow IV infusion, does not enter CNS, slow t1/2 > 2 weeks, hepatic metabolism and renal elimination
|
|
Side effects of amphotericin B
|
Infusion-related: fever chills, muscle rigor, hypotension alleviated by NSAIDs, antihistamines, meperidine, steroids. Dose-dependant: nephrotoxicity, decreased GFR, tubular acidosis, anemia
|
|
Azole drugs
|
Ketoconazole, fluconazole, itraconazole, clotrimazole
|
|
MOA of azoles
|
Fungicidal by inhibiting 14-alpha-demethylase which converts lanosterol to ergosterol
|
|
Uses of ketoconazole
|
DOC for Paracoccidioides; backup for Blastomyces, Histoplasma; Oral use in mucocutaneous candidiasis or dermatophytoses
|
|
Uses of fluconazole
|
DOC for esophageal and invasive candidiasis and coccidioidomycoses. Prophylaxis and suppression of cryptococcal meningitis
|
|
Uses of itraconazole
|
DOC in blastomycoses and sporotrichoses
|
|
Uses of clotrimazole
|
Used topically for candidal and dermatophytic infections
|
|
Pharmacokinetics of ketoconazole
|
Orally effective; absorption decreased by antacids; metabolized by liver enzymes; inhibits P450
|
|
Pharmacokinetics of itraconazole
|
Orally effective; absorption increased by food; metabolized by liver enzymes; inhibits P450
|
|
Pharmacokinetics of fluconazole
|
Orally effective; enters CSF; eliminated in the urine in unchanged form
|
|
Side effects of azoles
|
Decreased synthesis of cortisol and testosterone --> decreased libido, gynecomastia, menstrual irregularities; Increased liver function tests and rare hepatotoxicity
|
|
Drugs that block viral penetration and uncoating
|
Amantadine, enfurvitide
|
|
Drugs that inhibit viral DNA polymerases
|
Acyclovir, foscarnet, ganciclovir
|
|
Drugs that inhibit viral RNA polymerases
|
Foscarnet, ribavirin
|
|
Drugs that inhibit viral reverse transcriptase
|
Zidovudine, didanosine, zalcitabine, lamivudine, stavudine, nevirapine, delavirdine, efavirenz
|
|
Drugs that inhibt viral aspartate protease
|
Indinavir, ritonavir, saquinavir, nelfinavir
|
|
Drugs that inhibit viral neuraminidase
|
Zanamivir, oseltamivir
|
|
Drugs used to treat herpes
|
Acyclovir, ganciclovir, foscarnet
|
|
Acyclovir
|
Activated by viral thymidine kinase, inhibitor and chain terminator of DNA polymerase. Use for HSV ans VZV. Side effects: crystalluria, neurotoxicity
|
|
Ganciclovir
|
Activated by viral thymidine kinase, inhibitor and chain terminator of DNA polymerase. Use for HSV, VZV, CMV, AIDS retinitis and transplant patients. Side effects: hematotoxicity, crystalluria, rash
|
|
Foscarnet
|
Inhibits viral DNA and RNA polymerases. Use for HSV, VZV, CMV, AIDS retinitis, transplant patients. Side effects: nephrotoxic acute tubular necrosis, hypocalcemia (tremors, seizures)
|
|
Zidovudine (ZDV, AZT)
|
Converted to triphosphate that inhibits reverse transcriptase and causes chain termination. Resistance by mutations of RT gene.
|
|
Drug interaction of zidovudine (ZDV, AZT)
|
Increase levels of ZDV: azoles, cimetidine, indomethacin, probenecid, TMP-SMX. Decrease levels of ZDV: rifampin
|
|
Side effects of ZDV
|
Neutropenia, anemia, granulocytopenia, headache, myalgias, neuropathy, lactic acidosis
|
|
MOA enfuvirtide
|
Binds gp41 and inhibits fusion of HIV-1 to CD4 cells
|
|
Needle stick HIV prophylaxis
|
ZDV + 3TC + indinavir
|
|
Pregnancy HIV prophylaxis
|
ZDV trimester 2 and 3 plus 6 weeks to neonate reduces vertical transmission by 80%. Or ZDV intrapartum reduces transmission by 50-60%
|
|
Amantadine
|
Blocks attachment, penetration and uncoating of Influenza A. May decrease flu symptoms. Side effects: nervousness, insomnia, atropine-like effects
|
|
Uses of interferons
|
Antiviral: HBV, HCV; antiumor: Kaposi, CML, multiple myeloma, renal CA; Immunoregulatory: mutiple sclerosis
|
|
Effects of H1 receptor activation
|
Increased capillary dilation and permeability (hypotension, edema), bronchoconstriction, activation of nociceptive receptors (pain, pruritus)
|
|
Effects of H2 receptor activation
|
Increased gastric acid secretion (ulcers), positive inotropism
|
|
H1 antagonist drugs
|
Diphenhydramine, promethazine, chlorpheniramine, meclizine, hydroxyzine, loratadine, fexofenadine
|
|
Uses of H1 antagonists
|
Hay fever, rhinitis, urticaria, motion sickness and vertigo (meclizine), nausea in pregnancy
|
|
Adverse effects of H1 antagonists
|
M block and sedation, GI distress, allergic reactions.
|
|
Substances that increase proton pump activity
|
ACh, gastrin, histamine (H2 receptors)
|
|
H2 antagonist drugs
|
Cimetidine, ranitidine
|
|
MOA of H2 antagonists
|
Indirectly decrease proton pump activity (histamine increases proton pump activity)
|
|
Uses of H2 antagonists
|
Peptic ulcer disease, GERD, Zollinger-Ellison
|
|
Side effects of H2 antagonists
|
GI distress, dizziness, sommnolence; Cimetidine: inhibits P450 --> increases effects of quinidie, phenytoin, TCAs, warfarin; also decreases androgens --> gynecomastia
|
|
Omeprazole
|
Direct, irreversible proton pump inhibitor. Uses: PUD, GERD, Zollinger-Ellison, H. pylori. Side effects: decreases bioavailability of weak acids (fluoroquinolones, ketoconazole), inhibits P450
|
|
Misoprostol
|
PGE1 analog, increases mucus and bicarbonate, decreases HCL secretion. Use: NSAID-induced ulcers.
|
|
Sulcralfate
|
Polymerizes in stomach to coat ulcers. Increases healing and decreases ulcer recurrence.
|
|
Drugs that require acid stomach pH to be absorbed
|
Azoles, fluoroquinolones, warfarin
|
|
Drugs used as antiemetics
|
5HT3 antagonists (ondansetron), DA antagonists (metoclopramide), H1 blockers (diphenhydramine, meclizine), muscarinic blockers (scopolamine)
|
|
Metabolism of serotonin
|
5HT is metabolized by MAOa to 5-hydroxyinolacetic acid (marker for carcinoid)
|
|
Buspirone
|
Partial 5HT1a agonist used for generalized anxiety disorder
|
|
Sumatriptan
|
5HT1d agonist in cerebral vessels, used for migraine
|
|
Olanzapine
|
Atypical antipsychotic, 5HT2A and D2 receptor antagonist, decreases psychosis. Side effects: weight gain, tardive diskinesia, metabolic syndrome
|
|
Cyproheptadine
|
5HT2 antagonist used in carcinoid
|
|
Ondansetron
|
5HT3 antagonist, used as antiemetic in chemotherapy, radiation and post-op. 5HT3 receptors are found in area postrema
|
|
Ergonovine
|
Uterine muscle contraction after placental delivery
|
|
Ergotamine
|
Partial 5HT2 and alpha agonist causes vasoconstriction to decrease pulsation in migraine acute attack. Side effect is vasoconstriction (prinzmetal)
|
|
Prophylaxis of migraine headaches
|
Propranolol, verapamil, amitriptyline, valproic acid
|
|
PGE2
|
Vasodilation in kidneys, increases renal blood flow, increases gastric mucosal blood flow (mucoprotection), activates osteoclasts, fever, pain, maintains ductus arteriosus
|
|
Prostacyclin (PGI2)
|
Vasodilation and inhibits platelet aggregation
|
|
COX1
|
Constitutive enzyme synthesizes GI PGs and TxA2
|
|
COX2
|
Inducible enzyme synthesizes PGs involved in inflammation, fever and pain.
|
|
Zileuton
|
Lipoxygenase inhibtor used in asthma
|
|
Zafirlukast and -lukasts
|
Leukotriene receptor antagonist used in asthma
|
|
MOA of aspirin
|
Nonselective, irreversible COX inhibitor via acetylation of serine near active site
|
|
Actions of aspirin
|
Low dose: antiplatelet aggregation (post-MI); moderate dose: analgesia, antipiresis, hyperuricemia; High dose: antiinflammatory, uricosuria
|
|
Effects of aspirin on acid-base and electrolytes
|
Antiinflammatory doses: uncoupling of ETC --> increases respiration --> decreased pCO2 --> resp. alkalosis --> renal compensation via HCO3 excretion --> compensated respiratory alkalosis. Toxic doses: inhibits respiratory center --> decreases respiration --> resp. acidosis plus ETC uncoupling --> metabolic acidosis, decreases ATP, hyperthermia, hypokalemia
|
|
Side effects of aspirin
|
Gastritis, ulcers, bleeding, tinnitus, vertigo, decreased hearing, bronchoconstriction, hypersensitivity (asthma, nasal polyps, rhinitis), Reye syndrome, increased bleeding time, renal dysfunction at high doses
|
|
Aspirin overdose management
|
Gastric lavage, alkalinization of urine (zero-order kinetics at toxic doses)
|
|
Celecoxib
|
Selective COX-2 inhibitor. Antiinflammatory. Increases PT when used with warfarin, prothrombotic. Cross hypersensitivity with sulfonamides. Potential cardiotoxicity resulted in withdrawal of rofecoxib.
|
|
Acetaminophen
|
Inhibits COX in CNS only. No antiplatelet activity, not implicated in Reye syndrome, no effects on uric acid, no bronchoconstriction. Metabolized via P450. Hepatotoxic due to reactive metabolite N-acetylbenzoquinonemine, which is inactivated by GSH. Upon GSH depletion, metabolite damages hepatocytes, nausea, vomiting, abdominal pain, centrilobular necrosis. Inducers of P450 enhance toxicity. Management of hepatotoxicity: N-acetylcysteine.
|
|
Hydroxychloroquine
|
Used for rheumatoid arthritis. Stabilizes lysosomes and decreases chemotaxis. Side effects: GI distress, visual dysfunction, hemolysis in G6PDH deficiency
|
|
Methotrexate
|
Used for rheumatoid arthritis. Cytotoxic to lymphocytes. Side effects: hematotoxicity, mucositis, crystalluria
|
|
Sulfasalazine
|
Used for rheumatoid arthritis. Decreases B cell function, possibly inhibits COX. Side effects: GI distress, rash, hemolysis in G6PDH deficiency, drug-induced lupus
|
|
Glucocorticoids
|
Used in rheumatoid arthritis. Decrease LTs and platelet activating factor (PAF). Side effects: ACTH suppression, Cushingoid state, osteoporosis, GI distress, glaucoma
|
|
Gold salts
|
Used in rheumatoid arthritis. Decreases lysosomal and macrophage functions. Side effects: dermatitis, hematotoxicity, nephrotoxicity
|
|
Penicillamine
|
Used in rheumatoid arthritis. Suppresses T cells and circulating rheumatoid factor. Side effects: proteinuria, hematotoxicity, autoimmune disease.
|
|
Etanercept
|
Used in rheumatoid arthritis. Binds TNF. Side effects: hypersensitivity, injection site reactions, infections
|
|
Infliximab
|
Used in rheumatoid arthritis. Monoclonal antibody to TNF. Side effects: infusion reactions, infections
|
|
Anakinra
|
Used in rheumatoid arthritis. IL-1 receptor antagonist. Side effects: infections, injection site reactions
|
|
Colchicine
|
Used in acute gout. Binds tubulin --> decreases microtubular polymerization ; decreases LTB4 and leukocyte/granulocyte migration. Side effects: diarrhea, GI pain, hematuria, myelosuppression, neuropathy
|
|
Allopurinol
|
Prodrug converted by xanthine osidase into alloxanthine which inhibits the enzyme --> decreases purine metabolism --> decreases uric acid. Side effects: GI distress, neuropathy, rash, vasculitis, stones.
|
|
Probenecid
|
Inhibits tubular reabsorption of urate. Interactions: inhibits secretion of acidic drugs (cephalosporins, fluoroquinolones). Side effects: GI distress, rash, nephrotic syndrome, crystallization
|
|
Glucocorticoid drugs
|
Cortisol, prednisone, triamcinolone, betamethasone, dexamethasone
|
|
MOA of glucocorticoids
|
Inhibits leukocyte migration, phagocytosis and capillary permeability, decreases PGs, LTs, expression of COX2, PAF and interleukins
|
|
Uses of glucocorticoids
|
Antiinflammatory and immunosuppressive
|
|
Side effects of glucocorticoids
|
Suppression of ACTH --> cortical atrophy, shock if abruptly withdrawn, cushingoid syndrome, hyperglycemia (increased gluconeogenesis), osteoporosis with vertebral fractures, gastric acid secretion (ulcers), Na+ and H2O retention with edema and hypertension, hypokalemic alkalosis, hypocalcemia, inhibits bone growth in children, decreases wound healing (infections), increased sorbitol (glaucoma, cataracts), mental dysfunction.
|
|
Role of beta agonists in asthma
|
Slective β2 agonists: Relief of acute bronchoconstriction (albuterol, metaproterenol, terbutaline) and prophylaxis of nightime attacks (salmeterol). Side effects include anxiety, tremors and CV toxicity
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Ipratropium
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Muscarinic blocker causes bronchodilation in acute asthma. Safer than β1 agonists in patients with cardiovascular disease. DOC in bronchospasm induced by β-blockers.
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Theophylline
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Inhibits phosphodiesterase --> increases cAMP --> bronchodilation. Also antagonizes adenosine (bronchoconstrictor). Narrow therapeutic index. Side effects: nausea, diarrhea, increases HR, arrhythmias. Increased toxicity with erythromycin, cimetidine and fluoroquinolones.
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Role of glucocorticoids in asthma
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Decreases reactivity by decreasing PGs, LTs and Ils; May cause oropharyngeal candidiasis and retarded bone growth with chronic use; low doses prevent desensitization of β receptors.
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Zafirlukast, mentelukast
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LTD4 antagonists with slow onset. Used prophylactically for antigen, exercise or drug-induced asthma.
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Zileuton
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Selective inhibitor of lypoxygenases --> decreased ILs. Rapid onset, adjunct to steroids.
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first generation sulfonylureas
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tolbutamide, chlorpropamide; block K+ channels of β cells --> depolarization --> ↑Ca+ --> release of insulin
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second generation sulfonylureas
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glipizide, glyburide, glimepiride; block K+ channels of β cells --> depolarization --> ↑Ca+ --> release of insulin
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side effects of sulfonylureas
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hypoglycemia, weight gain, sulfa allergy, hypoglycemia with cimetidine (fisrt generation), disulfram-like (first generation)
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hypoglycemia
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paresthesia, lethargy, confusion, sweats, tremors, tachychardia, coma, seizures
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metformin
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↓ gluconeogenesis; can be used in patients with no islet function; side effect: lactic acidosis
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glitazones
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↑ target cell sensitivity to glucose via PPARs; side effects: weight gain, edema, hepatotoxicity, CV toxicity
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α-glucosidase inhibitors
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acarbose, miglitol; no hypoglycemia; inhibit brush border α-glucosidase; side effects: GI disturbance
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xenatide
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GLP-1 receptor full agonist --> augments insulin secretion; hypoglycemia when used with sulfonylureas
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orlistat
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inhibits pancreatic lipases; used in obesity; side effects: steatorrhea, fat malabsorption
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sibutramine
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serotonin/norepinephrine reuptake inhibitor; obesity management; side effects: tachychardia
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propylthiouracil/methimazole
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inhibits organification and coupling; side effects: agranulocytosis, aplastic anemia, skin rash
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anastrozole
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aromatase inhibitor --> ↓ estrogen synthesis; use: estrogen-dependant postmenopausal breast cancer
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clomiphene
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↓ feedback inhibition --> ↑FHS/LH --> ↑ovulation; fertility drugs; adverse effects: multiple births
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tamoxifen/raloxifene
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estrogen receptor agonist in bone; estrogen receptor antagonist in breast; partial agonist in endometrium
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progestins/estrogens/oral contraceptives
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medroxyprogesterone, norethindrone, desogestrel, estrogens; ↑progesterone --> ↓LH/FSH; side effects: ↑LDL ↓HDL, glucose intolerance, androgenic, antiestrogenic
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mifepristone
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progesterone antagonist --> abortifacient
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methyltestosterone
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ilicit in athletics, used in male hypogonadism; side effects: premature closure of epiphysis, jaundice, aggression
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flutamide
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androgen receptor blocker; used in prostate cancer
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leuprolide
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GnRH analog; prostate cancer
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finasteride
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5-α-reductase inhibitor --> ↓dihydrotestosterone; BPH, baldness; teratogenic
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biphosphonates
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use in Paget, osteoporosis; alendronate, etidronate, pamidronate
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energy source of RBC
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anaerobic glycolysis --> lactate (90%) and HMP shunt (10%)
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antithrombin III
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activated by heparin; inactivates thrombin, IXa, Xa, XIa
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tPA
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tissue plasminogen activator; fibrinolytic; generates plasmin from plasminogen; ↑PT and ↑PTT
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protein C
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inactivates factors Va and VIIIa --> anticoagulation
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factor V leiden
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mutation causes resistance to activated protein C --> hypercoagulable state
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warm agglutinin
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IgG; AIHA seen in SLE, CLL and methyldopa; "Warm weather is GGGreat, Cold ice cream MMM"
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cold agglutinin
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IgM; AIHA seen in mycoplasma or infectious mononucleosis infections; "Warm weather is GGGreat, Cold ice cream MMM"
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heparin
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activates antithrombin III; measure PTT; use: PE, DVT, AMI, DIC; side effects: bleeding, heparin-induced thrombocytopenia, hypersensitivity
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protamine sulfate
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rapid reversal of heparinization; binds negatively-charged heparin
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antithrombin III
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serine protease inhibitor binds to activated clotting factors (IXa, Xa, XIa) to inactivate them
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warfarin antidote
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vitamin K
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warfarin
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epoxide reductase inhibitor decreases vitamin K-dependant factors; slow onset; check PT; SE: skin necrosis; metabolized by P450
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warfarin-induced skin necrosis
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protein C and VIIa have the shortest half-lives --> transient inactivation of protein C and extrinsic pathway while intrinsic path is still active and unopposed due to longer half-lives of factors --> hypercoagulable state --> thrombosis
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platelet activators
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TxA2, ADP, 5HT --> ↑expression of GpIIb/IIIa receptors
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platelet deactivators
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prostacyclin, cAMP, clopidogrel, gpIIb/IIIa blockers (abciximab)
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clopidogrel
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blocks platelet ADP receptors --> ↓platelet activation; SE neutropenia
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abciximab
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gpIIb/IIIa antagonist --> ↓platelet aggregation
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methotrexate
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inhibits dihydrofolate reductase --> ↓dTMP --> ↓DNA synthesis; uses: leukemias, lymphomas, abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis
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5-FU MOA
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inhibits thymidylate synthase --> ↓dTMP --> ↓DNA synthesis; uses: colon cancer and solid tumors, basal cell carcinoma
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6-MP
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activated by HGPRTase --> blocks purine synthesis; uses: leukemias, lymphomas (except CLL or Hodgkin); metabolized by xanthine oxidase (↑toxicity with allopurinol); hepatotoxic
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cytarabine (ara-C)
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DNA polymerase inhibitor; use: AML
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cyclophosphamide
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alkylating agent ---> attacks guanine N7 --> denatures DNA; uses: non-Hodgkin lymphoma, ovarian and breast cancer, neuroblastoma
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cisplatin
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alkylating agent cross-links DNA strands; uses testicular, bladder, ovary and lung carcinomas; nephrotoxic
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doxorubicin
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intercalates DNA inhibits topoisomerase II; uses: Hodgkin's, myelomas, solid tumors; dilated cardiomyopathy
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actinomycin D (dactinomycin)
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intercalates DNA inhibits topoisomerase; uses: Wilm's tumor, Ewing's sarcoma. Rhabdomyosarcoma
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bleomycin
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formation of free radicals cause breaks in DNA strands; uses: testicular cancer, lymphomas; pulmonary fibrosis is side effect
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hydroxyurea
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inhibits ribonucleotidde reductase --> decreases DNA synthesis; uses: melanoma, CML, sickle cell disease
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tamoxifen
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estrogen receptor antagonist in breast, agonist in bone; use: breast cancer
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vincristine
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bind tubulin during M phase blocking polymerization of microtubules and formation of mitotic spindle; uses: lymphoma, Wilm's tumor, choriocarcinoma; neurotoxic
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cyclosporine
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binds cyclophillin --> ↓calcineurin --> ↓IL-2, IL-3, IFN-gamma; use in organ transplants
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tacrolimus
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inhibits calcineurin --> ↓IL-2, IL-3, IFN-gamma; use in organ transplants
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infliximab
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monoclonal Ig against TNF; use in rheumatoid arthritis and Crohn's
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trastuzumab
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erb-B2 antagonist; use in breast cancer
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dacliximab
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blocks IL-2 receptors; use in kidney transplants
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etanercept
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Recombinant TNF receptor binds TNF; uses: rheumatoid arthritis, psoriasis, ankylosing spondylitis
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first generation H1 blockers
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reversible; diphenhydramine, chlorpheniramine; uses: allergy, motion sickness, sleep aid; SE: sedation, antimuscarinic and anti-alpha adrenergic effect
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2nd generation H1 blockers
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loratadine, fexofenadine, desloratadine, cetirizine; use: allergy; less sedation
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salmeterol
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beta2 agonist; long-acting; tremor and arrhythmias
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albuterol
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beta2 agonist; use in acute asthma attack
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theophylline
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inhibits phosphodiesterase and increases cAMP --> bronchodilation; cardiotoxic, neurotoxic, narrow therapeutic index; metabolized by P450
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ipratropium
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antimuscarinic used in asthma and COPD
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cromolyn
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stabilizes mast cell membrane; not effective in acute asthma attack just prophylaxis
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zileuton
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5-lipoxygenase inhibitor --> decreases leukotrienes
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lukasts
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leukotriene receptor antagonists; aspirin-induced asthma
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guainfenesin
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expectorant; doesn’t suppress cough reflex
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colchicine
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use in acute gout; depolymerizes tubulin microtubules, prevents leukocyte chemotaxis and degranulation; SE: GI disturbances
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probenecid
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use in chronic gout; inhibits reabsorption of uric acid in PCT
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allopurinol
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use in chronic gout and leukemia; inhibits xanthine oxidase and decreases uric acid.
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