General Pharmacology Flashcards
Michaelis-menten kinetics:
Km is ____ related to the affinity of the enzyme for its substrate
Vmax is _____ proportional to the enzyme concentration
Most enzymatic reactions follow a hyperbolic curve (i.e., Michaelis menten kinetics); however, enzymatic reactions that exhibit a ______ curve usually indicate cooperative kinetics (e.g., Hgb)
Inversely
Directly
Sigmoid
On a lineweaver-burk plot, the further to the right the x-intercept (i.e., the closer to zero), the _____ the Km and the _____ the affinity
Greater; lower
Reversible competitive inhibitors effects on Vmax and Km
Vmax unchanged
Km increased
[decrease the potency of the substrate, but can be overcome by increase substrate concentration]
Irreversible competitive inhibitors effects on Vmax and Km
Vmax decreased
Km unchanged
[decrease the efficacy of the substrate]
Noncompetitive inhibitors effects on Vmax and Km
Vmax decreased
Km unchanged
[decrease the efficacy of the substrate]
Fraction of administered drug reaching systemic circulation unchanged; equal to 100% for an IV dose
Bioavailability
Theoretical volume occupied by a total amount of the drug in the body relative to its plasma concentration
Volume of distribution (Vd)
Apparent Vd of plasma protein-bound drugs can be altered by liver and kidney disease (decreased protein binding, increased Vd); drugs may distribute in more than one compartment.
How is Vd calculated?
Vd = amount of drug in the body/plasma drug concentration
Large/charged molecules and plasma-protein bound drugs in the intravascular compartment are associated with a ______ Vd
Low
Small lipophilic molecules, especially if bound to tissue protein, found in all tissues including fat are associated with a _____ Vd
High
Small hydrophilic drugs found in the ECF are associated with a ____ Vd
Medium
Volume of plasma cleared of drug per unit time; may be imapired with defects in cardiac, hepatic, or renal function
Clearance (CL)
Clearance (CL) calculation (2 equations)
CL = Rate of elimination of drug/plasma drug concentration
[or]
CL =Vd x Ke (elimination constant)
1/2 life is the amount of time required to change the amount of drug in the body by 1/2 during elimination
in first order kinetics, a drug infused at a constant rate takes _____ half-lives to reach a steady state. It takes 3.3 half lives to reach ____ of the steady-state level
4-5; 90%
Calculation for half life in first order elimination
t(1/2) = [0.7 x Vd]/CL
Percent of drug remaining after 1, 2, 3, and 4 half lives in first order kinetics
50% remaining after 1 half life
25% remaining after 2 half lives
- 5% remaining after 3 half lives
- 25% remaining after 4 half lives
Calculation for loading dose
Loading dose = [Cp x Vd]/F
Cp = target plasma concentration at steady state
Calculation for maintenance dose
Maintenance dose = [Cp x CL x tau]/F
Cp = target plasma concentration at steady state
Tau = dosage interval (time between doses) if not administered continuously
In renal or liver disease, the maintenance dose typically ______ and the loading dose is ______
Time to steady state depends primarily on _______ and is independent of dose and dosing frequency
Decreases; unchanged
t(1/2)
Aspirin and acetaminophen are an example of a _______ drug interaction in which the effect of substance A and B together is equal to the sum of their individual parts
Additive
The effect of cortisol on catecholamine responsiveness is an example of a _______ drug interaction in which presence of substance A is required for the full effects of substance B
Permissive
Clopidogrel with aspirin is an example of a _______ drug interaction in which effect of substance A and B together is greater than the sum of their individual effects
Synergistic
Nitrates, niacin, phenylephrine, LSD, and MDMA are an example of a _______ drug interaction in which there is an acute decrease in response to a drug after initial/repeated adminstration
Tachyphylactic (aka tolerance)
What is zero-order elimination?
Rate of elimination is constant regardless of amount of drug eliminated per unit time
Cp decreases linearly with time
Examples include Phenytoin, Ethanol, and ASA (at high or toxic concentrations)
The rate of first-order elimination is directly proportional to _____
The drug concentration
[constant fraction of drug eliminated per unit time; Cp decreases exponentially with time — applies to most drugs]
Phenobarbital, methotrexate, and aspirin (salicylates) are examples of _____ ____ in which overdoses can be treated with sodium bicarbonate to _______ urine
Weak acids; alkalinize
TCAs and amphetamines are examples of ____ ____ in which overdoses can be treated with ___ ____ to acidify urine
Weak bases; ammonium chloride
[note that TCA toxicity is generally treated with sodium bicarbonate to overcome the sodium channel-blocking activity of TCAs, but not for accelerating drug elimination]
Phase I drug metabolism
Reduction, oxidation, hydrolysis with cytochrome P450 usually yield slightly polar, water-soluble metabolites (often still active)
[geriatric pts lose phase I first R-OH]
Phase II drug metabolism
Conjugation (methylation, glucuronidation, acetylation, sulfation) usually yields very polar, inactive metabolites (renally excreted)
[geriatric pts retain phase II, pts who are slow acetylators have increased side effects from certain drugs because of low rate of metabolism (e.g. INH)]
Therapeutic index (TD50/ED50) is a measure of drug safety; safer drugs have _____ TI values
Higher
[TD = median toxic dose, ED50 = median effective dose]
G-protein class and major functions α-1 sympathetic receptors
Gq
Increase vascular smooth muscle contraction
Increase pupillary dilator muscle contraction (mydriasis)
Increased intestinal and bladder sphincter muscle contraction
G-protein class and major functions α-2 sympathetic receptors
Gi
Decreased sympathetic (adrenergic) outflow
Decreased insulin release
Decreased lipolysis
Increased platelet agg
Decreased aqueous humor production
G-protein class and major functions β1 sympathetic receptors
Gs
Increased heart rate, contractility, renin release, and lipolysis
G-protein class and major functions β2 sympathetic receptors
Gs
Vasodilation, bronchodilation
Increased lipolysis, increased insulin release, increased glycogenolysis, decreased uterine tone (tocolysis), increased aqueous humor production, increased cellular K+ uptake
G-protein class and major functions β3 sympathetic receptors
Gs
Increased lipolysis, thermogenesis in skeletal muscle, and bladder relaxation
G-protein class and major functions M1 parasympathetic receptors
Gq
Mediates higher cognitive functions, stimulates enteric nervous system
G-protein class and major functions M2 parasympathetic receptors
Gi
Decreased heart rate and contractility of atria
G-protein class and major functions M3 parasympathetic receptors
Gq
Increased exocrine gland secretions (e.g., lacrimal, sweat, salivary, gastric acid), increased gut peristalsis, increased bladder contraction, bronchoconstriction, increased pupillary sphincter muscle contraction (miosis), ciliary muscle contraction (accomodation), increased insulin release, endothelium-mediated vasodilation
G-protein class and major functions D1 receptors
Gs
Relaxes renal vascular smooth muscle
Activates direct pathway of striatum
G-protein class and major functions D2 receptors
Gi
Modulates transmitter release, esp in the brain, inhibits direct pathway of striatum
G-protein class and major functions H1 receptors
Gq
Increased nasal and bronchial mucous production
Increased vascular permeability
Bronchoconstriction, pruritis, pain
G-protein class and major functions H2 receptors
Gs
Increased gastric acid secretion
G-protein class and major functions V1 receptors
Gq
Increased vascular smooth muscle contraction
G-protein class and major functions V2 receptors
Gs
Increased H2O permeability and reabsorption via upregulating aquaporin-2 in collecting tubules of kidney; increased release of vWF
Cholinomimetic direct acting agonist that activates bladder smooth muscle; resistant to AChE. No nicotinic activity.
Treatment for urinary retention
Bethanechol
Cholinomimetic direct acting agonist that works like ACh but is resistant to AChE; constricts pupils and relieves intraocular pressure in open-angle glaucoma
Carbachol
Cholinomimetic direct acting agonist that stimulates muscarinic receptors in airway when inhaled; used in challenge test for dx of asthma
Methacholine
Cholinomimetic direct acting agonist that contracts ciliary muscle of eye (open-angle glaucoma), pupillary sphincter (closed-angle glaucoma); resistant to AChE, can cross BBB (tertiary amine)
Potent stimulator of sweat, tears, and saliva; treats open and close-angle glaucoma as well as xerostomia found in Sjogren syndrome
Pilocarpine
Cholinomimetic indirect acting agonist (AChE’s) that are first-line for Alzheimer disease
Donepezil
Rivastigmine
Galantamine
Cholinomimetic indirect acting agonist (AChE’s) historically used to diagnose to dx myasthenia gravis; replaced by Anti-AChR Ab test
Edrophonium
Cholinomimetic indirect acting agonist (AChE’s) that does not penetrate the CNS; used to tx postop and neurogenic ileus and urinary retention, myasthenia gravis, reversal of neuromuscular blockade (postop)
Neostigmine
Cholinomimetic indirect acting agonist (AChE’s) that freely crosses the BBB —> CNS (tertiary amine); antidote for anticholinergic toxicity (e.g., atropine overdose)
Physostigmine
Cholinomimetic indirect acting agonist (AChE’s) that increases muscle strength; often used with glycopyrrolate, hyoscyamine, or propantheline to control its side effects; used to tx Myasthenia gravis (long acting); does not penetrate CNS (quaternary amine)
Pyridostigmine
Use of cholinomimetic agents should prompt you to watch for exacerbation of what 3 conditions in susceptible patients?
COPD
Asthma
Peptic ulcers
Muscarinic effects of anticholinesterase poisoning
DUMBBELSS:
Diarrhea Urination Miosis Bronchospasm Bradycardia Emesis Lacrimation Sweating Salivation
Nicotinic and CNS effects of anticholinesterase poisoning
Nicotinic: neuromuscular blockade (mechanism similar to succinylcholine)
CNS: respiratory depression, lethargy, seizures, coma
Methods for reversal of muscarinic and nicotinic effects of anticholinesterase poisoning
Muscarinic effects reversed by atropine, a competitive inhibitor (can cross BBB to relieve CNS symptoms as well)
Nicotinic effect reversed by pralidoxime, regenerates AChE if given early; pralidoxime does not readily cross BBB
3 muscarinic antagonists that produce mydriasis and cycloplegia
Atropine
Homatropine
Tropicamide
2 muscarinic antagonists that treat Parkinson disease and acute dystonia
Benztropine
Trihexyphenidyl
Muscarinic antagonist that can be used parenterally in pre-op to reduce airway secretions, or orally to treat drooling and peptic ulcer
Glycopyrrolate
2 muscarinic antagonists used as antispasmotics for IBS
Hyoscyamine
Dicyclomine
2 muscarinic antagonists used to treat COPD and asthma
Ipratropium
Tiotropium
3 muscarinic antagonists used to reduce bladder spasms and urge urinary incontinence (overactive bladder)
Oxybutynin
Solifenacin
Tolterodine
Muscarinic antagonist used to treat motion sickness
Scopolamine
Effects of atropine (muscarinic antagonist) on eye, airway, stomach, gut, and bladder
Eye — pupil dilation, cycloplegia
Airway — bronchodilation, decreased secretions
Stomach — decreased acid secretion
Gut — decreased motility
Bladder — decreased urgency in cystitis
AEs of atropine
Increased body temp Increased HR Dry mouth Dry flushed sin Cycloplegia Constipation Disorientation
Can cause acute angle-closure glaucoma in the elderly (due to mydriasis), urinary retention in men with BPH, and hyperthermia in infants
[Hot as a hare, Dry as a bone, Red as a beet, Blind as a bat, Mad as a hatter, Full as a flask]
3 direct sympathomimetics that act at beta2>beta1:
_______ is used for acute asthma/COPD
_______ is used for long-term asthma/COPD
_______ is used for acute bronchospasm in asthma and tocolysis
Albuterol
Salmeterol
Terbutaline
Direct sympathomimetic that acts on beta1>beta2, alpha; applications include heart failure, cardiogenic shock (inotropic>chronotropic), and cardiac stress testing
Dobutamine
Direct sympathomimetic that acts on D1 = D2 > beta > alpha; applications include unstable bradycadia, HF, shock; inotropic and chronotropic effects at lower doses due to beta effects; vasoconstriction at high doses due to alpha effects
Dopamine
Direct sympathomimetic that acts on beta > alpha receptors; applications include anaphylaxis, asthma, open-angle glaucoma; alpha effects predominate at high doses. significantly stronger effect at beta 2 receptors than NE
Epinephrine
Direct sympathomimetic that acts on D1 receptors; treats postop HTN, hypertensive crisis. Acts as a vasodilatory (coronary, peripheral, renal, and splanchnic); promotes natriuresis. Can cause hypotension and tachycardia
Fenoldopam
Direct sympathomimetic that acts on beta 1= beta 2 receptors; applications include electrophysiologic eval of tachyarrythmias. Can worsen ischemia; has negligible alpha effect
Isoproterenol
Direct sympathomimetic that acts on alpha1 receptors; treats autonomic insufficiency and postural hypotension. May exacerbate supine HTN
Midodrine
Direct sympathomimetic that acts on beta3 receptors; treats urinary urge incontinence or overactive bladder
Mirabegron
Direct sympathomimetic that acts on alpha 1> alpha 2 > beta1 receptors; applications include hypotension, septic shock
NE
Direct sympathomimetic that acts on alpha 1 > alpha 2 receptors; treats hypotension, used in ocular procedures (mydriatic), rhinitis (decongestant), and ischemic priapism
Phenylephrine
Indirect sympathomimetic that acts as indirect general agonist, reuptake inhibitor, also releases stored catecholamines; treats narcolepsy, obesity, and ADHD
Amphetamine
Indirect sympathomimetic that acts as an indirect general agonist and reuptake inhibitor; causes vasoconstriction and local anesthesia. Caution when giving beta blockers if intoxication is suspected — can lead to unopposed alpha1 activation —> extreme HTN and coronary vasospasm
Cocaine
Indirect sympathomimetic that acts as indirect general agonist and releases stored catecholamines; applications include nasal decongestion, urinary incontinence, and hypotension
Ephedrine
2 sympatholytics (alpha-2 agonists) that are used in hypertensive urgency (limited situations), ADHD, tourette syndrome, and symptom in opioid withdrawal; AEs include CNS depression, bradycardia, hypotension, respiratory depression, miosis, rebound HTN with abrupt cessation
Clonidine
Guanfacine
Sympatholytic (alpha-2 agonists) that treats HTN in pregnancy; AEs include direct Coombs + hemolysis and drug-induced lupus
Alpha-methyldopa
Sympatholytic (alpha-2 agonists) that is used for relief of spasticity; AEs include hypotension, weakness, xerostomia
Tizanidine
