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176 Cards in this Set
- Front
- Back
What is volume of distribution?
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Volume of distribution: relates the amount of drug in the body to the plasma concentration.
Vd = amount of drug in the body / plasma drug concentration Low Vd -> Drug in blood High Vd -> Drug in tissues |
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What is clearance?
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Clearance: relates the rate of elimination to the plasma concentration.
Cl = rate of elimination of drug / plasma drug concentration Cl = Vd x Ke |
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What is half-life?
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Half-life: the time required to half the amount of drug in a body.
t1/2 = 0.7 x Vd / Cl |
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What is the formula for a loading dose?
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Loading Dose = Cp x Vd / F
Where Cp is the desired plasma concentration |
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What is the formula for a maintenance dose?
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Maintenance dose = Cp x Cl / F
Where Cp is the desired plasma concentration |
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Your patient has increasingly impaired renal function and is starting on a drug that is excreted via the kidneys. How should the loading dose be adjusted compared to a patient with normal kidneys? How should the maintenance dose be adjusted?
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Loading Dose - Does NOT change
Maintenance Dose - Decreases |
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What are some examples of drugs that follow zero-order elimination?
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Examples: Phenytoin, Ethanol and Aspirin
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How do you treat an overdose of a drug that is a weak acid?
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Bicarbonate
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How do you treat an overdose of a drug that is a weak base?
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Ammonium chloride
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What kinds of reactions are classified as Phase I reactions?
What kinds of substances are the end products of Phase I reactions? |
Kinds of reactions:
Reductions, oxidations, hydrolysis Products: Slightly polar, water-soluble metabolites (can be still active) |
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What kinds of reactions are classified as Phase II reactions?
What kinds of substances are the end products of Phase II reactions? |
Kinds of reactions:
Acetylation, glucuronidation, sulfation Products: Very polar, inactive metabolites (renally excreted) |
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What is the efficacy of a drug?
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The maximal effect a drug can produce.
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What is the potency of a drug?
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The amount of drug needed for a given effect.
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A competitive antagonist will do what to the efficacy and potency of a drug?
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Efficacy: No change
Potency: Decreased |
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An irreversible antagonist will do what to the efficiency and potency of a drug?
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Efficacy: Decreased
Potency: No change |
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What is the therapeutic index?
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Its a measurement of drug safety.
TI = LD50 / ED50 TI = median toxic dose / median effective dose Safer drugs have higher TI values |
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What kind of receptors are found on ganglion cells that accept signals from the CNS?
What neurotransmitter activates those receptors? How do those receptors transmit the signal? |
Nicotinic ACh receptors are ligand-gated Na+/K+ channels
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What kind of receptors accept signals from parasympathetic ganglions?
What neurotransmitter activates those receptors? How do those receptors transmit the signal? |
Muscarinic ACh receptors are G-protein-coupled receptors that act through 2nd messengers.
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What kind of receptors are in sweat glands and accept signals from sympathetic ganglions?
What neurotransmitter activates those receptors? How do those receptors transmit the signal? |
Muscarinic ACh receptors are G-protein-coupled receptors that act through 2nd messengers.
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What kind of receptors are in cardiac/smooth muscle, gland cells and nerve terminals and accept signals from sympathetic ganglions?
What neurotransmitter activates those receptors? How do those receptors transmit the signal? |
α, β NE receptors are G-protein-coupled receptors that act through 2nd messengers.
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What kind of receptors are in renal vascular smooth muscle and accept signals from sympathetic ganglions?
What neurotransmitter activates those receptors? How do those receptors transmit the signal? |
D1 Dopamine receptors are G-protein-coupled receptors that act through 2nd messengers.
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What kind of receptors are in the adrenal medulla?
What neurotransmitter activates those receptors? How do those receptors transmit the signal? |
Nicotinic ACh receptors are ligand-gated Na+/K+ channels
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What kind of receptors are in skeletal muscle?
What neurotransmitter activates those receptors? How do those receptors transmit the signal? |
Nicotinic ACh receptors are ligand-gated Na+/K+ channels
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The sympathetic receptors are α1, α2, β1, and β2.
What G-protein classes are these receptors? What are the major functions of these receptors? |
α1 - q - increased vascular smooth muscle contraction, increased pupillary dialator muscle contraction
α2 - i - decreased sympathetic outflow, decreased insulin release β1 - s - increased heart rate, increased contractility, increased renin release, increased lipolysis β2 - 2 - vasodilation, bronchodilation, increased heart rate, increased contractility, increased lipolysis, increased glucagon release, decreased uterine tone |
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The parasympathetic receptors are M1, M2 and M3.
What G-protein classes are these receptors? What are the major functions of these receptors? |
M1 - q - CNS, enteric nervous system
M2 - i - decreased heart rate and contractility of atria M3 - q - increased exocrine gland secretions, increased gut peristalsis, increased bladder contraction, bronchoconstriction, increased pupillary sphincter muscle contraction (miosis), ciliary muscle contraction (accommodation) |
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The Dopamine receptors are D1 and D2.
What G-protein classes are these receptors? What are the major functions of these receptors? |
D1 - s - Relaxes renal vascular smooth muscle
D2 - i - Modulates transmitter release, especially in brain |
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The Histamine receptors are H1 and H2
What G-protein classes are these receptors? What are the major functions of these receptors? |
H1 - q - increased nasal and bronchial mucus production, contraction of bronchioles, pruritus and pain
H2 - s - increased gastric acid secretion |
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The Vasopressin receptors are V1 and V2
What G-protein classes are these receptors? What are the major functions of these receptors? |
V1 - q - increased vascular smooth muscle contraction
V2 - s - increased water permeability and reabsorption in the collecting tubules of the kidney |
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What receptors utilize Gq proteins?
Walk through the Gq signaling pathway. |
H1, α1, V1, M1, M3
(HAVe 1 M&M) Receptor activates Gq Gq activates phospholipase C phospholipase C turns lipids into PIP2 PIP2 splits into IP3 and DAG IP3 increases Ca+2 levels DAG increases protein kinase C |
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What receptors utilize Gs proteins?
Walk through the Gs signaling pathway. |
β1, β2, D1, H2 and V2
Receptor activates Gs Gs increases adenylyl cyclase Adenylyl cyclase turns ATP into cAMP cAMP increases protein kinase A |
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What receptors utilize Gi proteins?
Walk through the Gi signaling pathway. |
M2, α2, and D2
(MAD 2s) Receptor activates Gi Gi decreases adenylyl cyclase Decreased adenylyl cyclase decreases cAMP Decreased cAMP decreases protein kinase A |
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The autonomic drug hemicholinium does what?
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Blocks choline reuptake from the synaptic cleft
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The autonomic drug vesamicol does what?
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Blocks ACh uptake into synaptic vesicles
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The autonomic drug botulinum does what?
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Blocks the release of ACh by blocking the binding of synaptic vesicles to the cell membrane
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The autonomic drug metyrosine does what?
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Blocks the conversion of Tyrosine to DOPA
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The autonomic drug reserpine does what?
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Blocks Dopamine uptake into synaptic vesicles
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The autonomic drug tricyclic antidepressants does what?
What illegal drug has the same function? |
Blocks NE reuptake
Cocaine |
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The autonomic drug Guanethidine does what?
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Blocks the release of NE from synaptic vesicles
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The autonomic drug Amphetamine does what?
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Increases the release of NE from synaptic vesicles
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Bethanechol
Clinical applications Actions |
Uses for postoperative and neurogenic ileus and urinary retention
Activates bowel and bladder smooth muscle, resistant to AChE |
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Carbachol
Clinical applications Actions |
Glaucoma, pupillary contraction, and release of intraocular pressure
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Pilocarpine
Clinical applications Actions |
Potent stimulator of sweat, tears and saliva
contracts ciliary muscles of eye (open angle), pupillary sphincter (narrow angle); resistant to AChE |
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Methacholine
Clinical applications Actions |
Challenge test for diagnosis of asthma
Stimulates muscarinic receptors in airway when inhaled |
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Neostigmine
Clinical applications Actions |
Postoperative and neurogenic ileus and urinary retention, myathenia gravis, reversal of neuromuscular junction blockade (postoperative)
Increases endogenous ACh (AChE inhibitor) No CNS involvement |
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Pyridostigmine
Clinical applications Actions |
Myasthenia gravis (long acting)
Increases endogenous ACh, increases strength (AChE inhibitor) No CNS involvement |
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Edrophonium
Clinical applications Actions |
Diagnosis of myasthenia gravis (extremely short acting)
Increases endogenous ACh, increases strength (AChE inhibitor) |
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Physostigmine
Clinical applications Actions |
Glaucoma and atropine overdose
Increases endogenous ACh, increases strength (AChE inhibitor) Crosses bbb (CNS effect) |
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Echothiophate
Clinical applications Actions |
Glaucoma
Increases endogenous ACh, increases strength (AChE inhibitor) |
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What are the symptoms of cholinesterase inhibitor poisoning?
What is the antidote? What can cause cholinesterase inhibitor poisoning? |
Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Excitation of skeletal muscle and CNS, Lacrimation, Sweating and Salivation (DUMBBELSS)
Antidote - atropine plus parlidoxime Parathion and other organophosphates |
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Atropine (homatropine, tropicamide)
Receptor and effect Organ system affected Clinical Use Toxic effects |
Muscarninic antagonist
Eye - increased pupil dilation, cycloplegia Airway - decreased secretions Stomach - decreased acid secretion Gut - decreased motility Bladder - decreased urgency in cystitis Produce mydriasis and cycloplegia Increased body temperature, rapid pulse, dry mouth, dry flushed skin, cycloplegia, constipation, disorientation Can cause acute angle-closure glaucoma in elderly, urinary retention in men with prostatic hyperplasia and hyperthermia in infants |
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Benztropine
Organ system affected Clinical Use |
CNS
Used to treat Parkinsons |
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Scopolamine
Organ system affected Clinical Use |
CNS
Motion Sickness |
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Ipratropium
Organ system affected Clinical Use |
Respiratory
Asthma, COPD |
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Oxybutynin (glycopyrrolate)
Organ system affected Clinical Use |
Genitourinary
Reduce urgency in mild cystitis and reduce bladder spasms |
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Methscopolamine (pirenzepine, propantheline)
Organ system affected Clinical Use |
GI
Peptic ulcer treatment |
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Hexamethonium
Receptor and effects Clinical use Toxicity |
Nicotinic antagonist
Ganglionic blocker, used in experimental models to prevent vagal reflex responses to changes in blood pressure - eg. prevents reflex bradycardia caused by NE Severe orthostatic hypotension, blurred vision, constipation, sexual dysfunction |
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Epinephrine
What receptors is it specific for? What are the applications? |
α1, α2, β1, β2
Anaphylaxis, glaucoma (open angle), asthma, hypotension |
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Norepinephrine
What receptors is it specific for? What are the applications? |
α1, α2 > β1
Hypotension (decreased renal perfusion |
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Isoproterenol
What receptors is it specific for? What are the applications? |
β1 = β2
AV block |
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Dopamine
What receptors is it specific for? What are the applications? |
D1 = D2 > β > α
Shock (increased renal perfusion), heart failure |
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Dobutamine
What receptors is it specific for? What are the applications? |
β1 > β2, inotropic but not chronotropic
Shock, heart failure, cardiac stress testing |
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Albuterol, terbutaline
What receptors is it specific for? What are the applications? |
β2 > β1
Albuterol for acute asthma Terbutaline reduces premature uterine contractions |
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Ritodrine
What receptors is it specific for? What are the applications? |
β2
Reduces premature uterine contractions |
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Amphetamine
Mechanism Clinical applications |
Indirect general agonist, releases stored catecholamines
Narcolepsy, obesity, ADD |
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Ephedrine
Mechanism Clinical applications |
Indirect general agonist, releases stored catecholamines
Nasal decongestion, urinary incontinence, hypotension |
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Cocaine
Mechanism Clinical applications |
Indirect general agonist, uptake inhibitor
Causes vasoconstriction and local anesthesia |
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Clonidine, α-methyldopa
Mechanism Clinical applications |
Centrally acting α2-agonist, decreased central adrenergic outflow
Hypertension, especially with renal diseas (no decrease in blood flow to kidney) |
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What are some selective β2-agonists?
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Metaproterenol, Albuterol, Salmetrerol, Terbutaline
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What is a non-selective, irreversible α-blocker?
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Phenoxybenzamine
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What is a non-selective, reversible α-blocker?
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Phentolamine
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What is a α1-selective, α-blocker?
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Prazosin, terazosin, doxazosin
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What is a α2-selective, α-blocker?
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Mirtazapine
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Phenoxybenzamine
Receptors targeted Clinical applications Toxicity |
α1, α2 blocker irreversible
Pheochromocytoma Orthostatic hypotension, reflex tachycardia |
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Phentolamine
Receptors targeted Clinical applications Toxicity |
α1, α2 blocker reversible
Pheochromocytoma Orthostatic hypotension, reflex tachycardia |
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Prazosin, terazosin, doxazosin
Receptors targeted Clinical applications Toxicity |
α1 selective blocker
Hypertension, urinary retention in BPH 1st-dose orthostatic hypotension, dizziness, headache |
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Mirtazapine
Receptors targeted Clinical applications Toxicity |
α2 selective blocker
Depression Sedation, increased serum cholesterol, increased appetite |
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What are some β-blockers?
What are some clinical applications of β-blockers? What are the physiologic effects of β-blockers What are the toxic effects of β-blockers? |
-lol
Hypertension Angina pectoris MI SVT (propranolol, esmolol) CHF Glaucoma (timolol) Decrease cardiac output Decrease renin secretion Decrease heart rate and contractility Decrease AV conduction velocity Decreases secretion of aqueous humor Impotence Exacerbation of asthma Bradycardia, AV block, CHF Sedation, sleep alterations |
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What are some non-selective β antagonists?
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Propranolol, timolol, nadolol, pindolol, labetalol
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What are some β1-selective antagonists?
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Acebutolol, betaxolol, esmolol, atenolol, metoprolol
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What are some non-selective α and β antagonists?
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Carvedilol, labetalol
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Antidote for acetaminophen overdose?
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NAC (N-acetylcysteine)
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Antidote for salicylate overdose?
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NaHCO3 (alkalinize urine), dialysis
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Antidote for amphetamines overdose?
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NH4Cl (acidify urine)
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Antidote for anticholinesterase or organophosphate overdose?
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Atropine + pralidoxime
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Antidote for antimuscarinic, anticholinergic agents overdose?
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Physostigmine salicylate
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Antidote for β-blocker overdose?
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Glucagon
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Antidote for Digitalis overdose?
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Normalize K+, lidocaine, anti-digitalis Fab fragments, Mg2+
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Antidote for Iron overdose?
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Deferoxamine
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Antidote for Lead overdose? (4)
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CaEDTA, dimercaprol (BAL), succimer, penicillamine
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Antidote for Mercury overdose?
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Dimercaprol (BAL), succimer
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Antidote for arsenic overdose?
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Dimercaprol (BAL), succimer, penicillamine
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Antidote for gold overdose?
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Dimercaprol (BAL), succimer, penicillamine
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Antidote for copper overdose?
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Penicillamine
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Antidote for Cyanide overdose?
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Nitrite, hydroxocobalamine, thiosulfate
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Antidote for methemoglobin overdose?
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Methylene blue, vitamin C
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Antidote for carbon monoxide overdose?
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100% O2, hyperbaric O2
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Antidote for Methanol overdose?
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Ethanol, dialysis, fomepizole
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Antidote for ethylene glycol overdose?
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Ethanol, dialysis, fomepizole
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Antidote for opioids overdose?
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Naloxone/naltrexone
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Antidote for benzodiazepines overdose?
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Flumazenil
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Antidote for TCA overdose?
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NaHCO3 (serum alkalinization)
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Antidote for Heparin overdose?
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Protamine
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Antidote for Warfarin overdose?
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Vitamin K, fresh frozen plasma
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Antidote for tPA overdose?
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Aminocaproic acid
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Antidote for streptokinase overdose?
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Aminocaproic acid
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Antidote for theophylline overdose?
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β-blocker
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Symptoms of lead poisoning?
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Lead Lines on gingivae (called Burton's lines) and on epiphyses of long bones on x-ray
Encephalopathy and Erythrocyte basophilic stippling Abdominal colic and sideroblastic Anemia Drops - wrist and foot drop. Dimercaprol and EDTA 1st line of treatment. Succimer for kids. LLEEAADD |
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Mechanism of iron poisoning?
Symptoms of iron poisoning? |
Cell death due to peroxidation of membrane lipids
Acute - gastric bleeding Chronic - metabolic acidosis, scarring leading to GI obstruction |
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Drug reactions - Cardiovascular
Atropine-like side effects |
Tricyclic anti-depressants
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Drug reactions - Cardiovascular
Coronary vasospasm |
Cocaine, sumatriptan
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Drug reactions - Cardiovascular
Cutaneous flushing |
Niacin, Ca2+ channel blockers, adenosine, vancomycin
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Drug reactions - Cardiovascular
Dilated cardiomyopathy |
Doxorubicin (Adriamycin), daunorubicin
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Drug reactions - Cardiovascular
Torsades de pointes |
Class III (sotalol), class IA (quinidine) antiarrhythmics, cispride
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Drug reactions - Hematologic
Agranulocytosis |
Clozapine, carbamazepine, colchicine, propylthiouracil, methimazole
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Drug reactions - Hematologic
Aplastic anemia |
Chloramphenicol, benzene, NSAIDs, propylthiouracil, methimazole
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Drug reactions - Hematologic
Direct Coombs-positive hemolytic anemia |
Methyldopa
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Drug reactions - Hematologic
Gray baby syndrome |
Chloramphenicol
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Drug reactions - Hematologic
Hemolysis in G6PD-deficient patients |
Isoniazid, Sulfonamides, Primaquine, Aspirin, Ibuprofen, Nitrofurantoin
Mnemonic hint: hemolysis IS PAIN |
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Drug reactions - Hematologic
Megaloblastic anemia |
Phenytoin, Methotrexate, Sulfa drugs
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Drug reactions - Hematologic
Thrombotic complications |
OCPs (estrogens and progestins)
|
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Drug reactions - Respiratory
Cough |
ACE inhibitors (ARBs like losartan - no cough)
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Drug reactions - Respiratory
Pulmonary fibrosis |
Bleomycin, busulfan, amiodarone
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Drug reactions - GI
Acute cholestatic hepatitis |
Macrolides
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Drug reactions - GI
Focal to massive hepatic necrosis |
Halothane, valproic acid, acetaminophen, Amanita phalloides
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Drug reactions - GI
Hepatitis |
Isoniazid
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Drug reactions - GI
Pseudomembranous colitis |
Clindamycin, ampicillin
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Drug reactions - Reproductive/endocrine
Adrenocortical insufficiency |
Glucocorticoid withdrawal (HPA suppression)
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Drug reactions - Reproductive/endocrine
Gynecomastia |
Spironolactone, Digitalis, Cimetidine, chronic Alcohol use, estrogens, Ketoconazole
Mnemonic hint: (Some Drugs Create Awesome Knockers) |
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Drug reactions - Reproductive/endocrine
Hot flashes |
Tamoxifen, clomiphene
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Drug reactions - Musculoskeletal/connective tissue
Gingival hyperplasia |
Phenytoin
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Drug reactions - Musculoskeletal/connective tissue
Gout |
Furosemide, thiazides
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Drug reactions - Musculoskeletal/connective tissue
Osteoporosis |
Corticosteroids, heparin
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Drug reactions - Musculoskeletal/connective tissue
Photosensitivity |
Sulfonamides, Amiodarone, Tetracycline
Mnemonic hint: SAT for a photo |
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Drug reactions - Musculoskeletal/connective tissue
Rash (Stevens-Johnson syndrome) |
Ethosuximide, lamotrigine, carbamazepine, phenobarbital, phenytoin, sulfa drugs, penicillin, allopurinol
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Drug reactions - Musculoskeletal/connective tissue
SLE-like syndrome |
Hydralazine, Isoniazid, Procainamide, Phenytoin
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Drug reactions - Musculoskeletal/connective tissue
Tendonitis, tendon rupture and cartilage damage (kids) |
Fluoroquinolones
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Drug reactions - Renal
Fanconi's syndrome |
Expired tetracycline
|
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Drug reactions - Renal
Interstitial nephritis |
Methicillin, NSAIDs, furosemide
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Drug reactions - Renal
Hemorrhagic cystitis |
Cyclophosphamide, ifosfamide (prevent by coadministrating with MESNA)
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Drug reactions - Neurologic
Cinchonism |
Quinidine, quinine
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Drug reactions - Neurologic
Diabetes insipidus |
Lithium, demeclocycline
|
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Drug reactions - Neurologic
Parkinson-like syndrome |
Haloperidol, chlorpromazine, reserpine, metoclopramide
|
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Drug reactions - Neurologic
Seizures |
Bupropion, imipenem.cilastatin, isoniazid
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Drug reactions - Neurologic
Tardive dyskinesia |
Antipsychotics
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Drug reactions - Multiorgan
Disulfiram-like reaction |
Metronidazole, certain cephalosporins, procarbazine, 1st-generation sulfonylureas
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Drug reactions - Multiorgan
Nephrotoxicity/neurotoxicity |
Polymyxins
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Drug reactions - Multiorgan
Nephrotoxicity/ototoxicity |
Aminoglycosides, vancomycin, loop diuretics, cisplatin
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P-450 Inducers
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Quinidine*, Barbiturates, St. John's wort, Phenytoin, Rifampin, Griseofulvin, Carbamazepine
Mnemonic hint: Queen Barb Steals Phen-phen and Refuses Greasy Carbs *Quinidine can both induce and inhibit different isoforms of P-450. Induction is the more important effect |
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P-450 Inhibitors
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Sulfonamides, Isoniazid, Cimetidine, Ketoconazole, Erythromycin, Grapefruit joice
Mnemonic hint: Inhibit yourself from drinking beer from a KEG because it makes you SICk |
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Ethylene glycol degradation pathway
Toxic effects of products |
Ethylene glycol -> Oxalic acid via Alcohol dehydrogenase
Toxic effects - Acidosis, nephrotoxicity |
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Methanol degradation pathway
Toxic effects of products |
Methanol -> Formaldehyde and formic acid via Alcohol dehydrogenase
Toxic effects - Severe acidosis, retinal damage |
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Ethanol degradation pathway
Toxic effects of products |
Ethanol -> Acetaldehyde via Alcohol dehydrogenase (inhibited by Fomepizole)
Acetaldehyde -> Acetic acid via Acetaldehyde dehydrogenase (inhibited by Disulfiram) Toxic effects of Acetaldehyde: Nausea, vomiting, headache, hypotension |
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Sulfa drug allergies
What are the sulfa drugs? What are the symptoms? How variable? |
Celecoxib, furosemide, probenecid, thiazides, TMP-SMX, sulfasalazine, sulfonylureas, sumatriptan
Fever, pruritic rash, Stevens-Johnson syndrome, hemolytic anemia, thrombocytopenia, agranulocytosis, urticaria (hives) Variability - mild to life-threatening |
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Drug name ending -afil
Category of drug Example of drug |
Erectile dysfunction
Sidenafil |
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Drug name ending -ane
Category of drug Example of drug |
Inhalational general anesthetic
Halothane` |
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Drug name ending -azepam
Category of drug Example of drug |
Benzodiazepine
Diazepam |
|
Drug name ending -azine
Category of drug Example of drug |
Phenothiazine (neuroleptic antiemetic)
Chlorpromazine |
|
Drug name ending -azole
Category of drug Example of drug |
Antifungal
Ketoconazole |
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Drug name ending -barbital
Category of drug Example of drug |
Barbituarate
Phenobarbital |
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Drug name ending -caine
Category of drug Example of drug |
Local anesthetic
Lidocaine |
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Drug name ending -cillin
Category of drug Example of drug |
Penicillin
Methicillin |
|
Drug name ending -cycline
Category of drug Example of drug |
Antibiotic, protein synthesis inhibitor
Tetracycline |
|
Drug name ending -etine
Category of drug Example of drug |
SSRI
Fluoxetine |
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Drug name ending -ipramine
Category of drug Example of drug |
TCA
Imipramine |
|
Drug name ending -navir
Category of drug Example of drug |
Protease inhibitor
Saquinavir |
|
Drug name ending -olol
Category of drug Example of drug |
β antagonist
Propranolol |
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Drug name ending -operidol
Category of drug Example of drug |
Butyrophenone (neuroleptic)
Haloperidol |
|
Drug name ending -oxin
Category of drug Example of drug |
Cardiac glycoside (inotropic agent)
Digoxin |
|
Drug name ending -phylline
Category of drug Example of drug |
Methylxanthine
Theophylline |
|
Drug name ending -pril
Category of drug Example of drug |
ACE inhibitor
Captopril |
|
Drug name ending -terol
Category of drug Example of drug |
β2 agonist
Albuterol |
|
Drug name ending -tidine
Category of drug Example of drug |
H2 antagonist
Cimetidine |
|
Drug name ending -triptan
Category of drug Example of drug |
5-HT1A agonists (migrane)
Sumatriptan |
|
Drug name ending -triptyline
Category of drug Example of drug |
TCA
Amitriptyline |
|
Drug name ending -tropin
Category of drug Example of drug |
Pituitary hormone
Somatotropin |
|
Drug name ending -zosin
Category of drug Example of drug |
α1 antagonist
Prazosin |