Pharm 1 - Pharmacokenetics/dynamics/ANS p232-246 Flashcards
How do competitive inhibitors affect Km?
Increase Km (dec affinity)
The further to the right the x-intercept (ie, closer to zero), the greater the ___ and the lower ______.
The further to the right the x-intercept (ie, closer to zero), the greater the Km and the lower the affinity.
Which type of inhibitor will cross x-intercept of an unihibited substrate?
What does that x-intercept represent?
non competitive inhibitor
X-intercept = 1/-Km
What type of inhibitor will cross the y-intercept of an unihibited substrate? What is that y-intercept = to?
competitive inhibitor
y-intercept = 1/Vmax
Competitive (-)’r of Diazepam? What is the rec’r?
Flumazenil
GABAA- R
Competitive (-)’r vs organophosphates?
Atropine
Competitive (-)’r of xanthine oxidase?
Allopurinol
ex of competitive ACh antagonist
neuromuscular blocking drugs
Atracurium, cisatracurium, pancuronium, rocuronium, tubocurarine, vecuronium
competitive aldosterone receptor antagonists in cortical collecting tubule?
Spironolactone, Eplerenone
Competitive inhibitors of progestins at progesterone receptors?
Mifepristone, ulipristal.
Nonsteroidal competitive inhibitor at androgen receptors? use?
Flutamide; Prostate carcinoma
How does competitive antagonists affect efficacy and potency?
dec potency; doesn’t change efficacy
How does a non competitive antagonist affect potency and efficacy?
dec potency and efficacy
How does partial agonist affect potency?
It doesn’t - it is independent of it.
How does efficacy of a partial agonist compare vs a full agonist?
It has less efficacy than a full agonist
How to calc loading dose?
(Cp × Vd) / F
Cp - plasma conc
Vd - Vol of distribution
F = bioavail
How to calc maintenance dose?
Maintenance dose =
(Cp × CL × τ )/ F
Cp = target plasma concentration at steady state
Cl = clearence τ = dosage interval (time between doses), if not administered continuousl
F = bioavail
In renal or liver disease, maintenance dose ____ and loading dose is usually ______.
In renal or liver disease, maintenance dose Dec and loading dose is usually unchanged.
Time to steady state depends primarily on _____ and is independent of ____ and _____ ________.
Time to steady state depends primarily on t1/2 and is independent of dose and dosing frequency.
How to calc t1/2?
t1/2 = (0.7 × Vd)/Cl in first-order elimination
Drugs with narrow therapeutic index?
Warfarin, Theophylline, Digoxin, Lithium, anti-epitleptics
Warning, These Drugs are lethal
Two drugs with additive effects? What does that mean?
Effect of substance A and B together is equal to the sum of their individual effects
Aspirin and acetaminophen
Give ex of a drug that has a permissive effect on another? what does that mean?
Presence of substance A is required for the full effects of substance B
Cortisol has a permissive effect on catecholamines, as it upregulates α1-receptors on arterioles, making them more sensitive to Epi/NE (leading to inc BP)
Give ex of two synergistic drugs? define.
Effect of substance A and B together is greater than the sum of their individual effects
Clopidogrel with aspirin
What is a tachyphylactic drug interaction?
Acute decrease in response to a drug after initial/repeated administration
ex/
Nitrates, niacin, phenylephrine, LSD, MDMA
In regards to drug elimination, _______ are trapped in urine and cleared quickly. ____ ______ can be reabsorbed
Ionized species are trapped in urine and cleared quickly. Neutral forms can be reabsorbed
Examples of Weak acids (4)
Weak acids
Asprin, Methotrexate, Phenobarbital, Warfarin
WAMP - you’re hit with a Weak Acid
W-arfarin
A-sprin
M-ethotrexate
P-henobarbital
If TCAs are weak bases, why do we treat TCA overdose with sodium bicarbonate (instead of maybe ammonium chloride to acidify the urine and inc elimination of the weak base)
TCA toxicity is generally treated with sodium bicarbonate to overcome the sodium channelblocking activity of TCAs, but not for accelerating drug elimination.
Examples of Weak Bases
TCAs, Amphetamines
Weak Bases = MAT DACes
(Allopurinol, Diazepam, Cocaine, Methyldopa)
What drugs would be cleared by acidifying the urine?
Acidifying urine –> inc ionization of weak bases to inc renal elimination.
What do we give to alkalinize urine?
NaHCO3, potassium citrate
What do we give to acidify urine?
Ammonium chloride, Vitamin C, Cranberry juice
Drugs with zero order kinetics?
Rate of elimination is constant regardless of Cp (ie, constant amount of drug eliminated per unit time). Cp decreases linearly with time.
high dose or toxic concentration
- Phenytoin
- Ethanol
- aspirin
Toxic dose
Salicylates, Cisplatin, Flouxetin, Omeprazole
What happens in phase I drug metabolism?
Reduction, Oxidation, Hydrolysis with cytochrome P-450 usually yield slightly polar, water-soluble metabolites (often still active).
R-OH = Phase I
What happens in phase II drug metabolism?
Conjugation (Methylation, Glucuronidation, Acetylation, Sulfation) usually yields very polar, inactive metabolites (renally excreted).
Which phase of drug metabolism do the elderly lose first?
Phase I
Patients who are slow acetylators have ___ side effects from certain drugs because of _____rate of metabolism (eg, isoniazid).
Patients who are slow acetylators have inc side effects from certain drugs because of dec rate of metabolism (eg, isoniazid).
What value of a drug curve represents efficacy?
y-intercept = Vmax
the higher the Y intercept, the higher the Vmax, the higher the efficacy
How is efficacy related to potency?
Unrelated to potency (ie, efficacious drugs can have high or low potency)
Safer drugs have higher _____ values.
Safer drugs have higher TI values.
What are drugs with lower TI values that req monitoring?
- *W**arfarin, Theophylline, Digoxin, Antiepileptic drugs, Lithium;
- *W**arning! These Drugs Are Lethal!).
Adrenal medulla is directly innervated by __________ __________ ________.
Adrenal medulla is directly innervated by preganglionic sympathetic fibers.
Sweat glands are part of the______ _____ but are innervated by _________ _______
Sweat glands are part of the sympathetic pathway but are innervated by cholinergic fibers
What is the channel assoc with nicotinic Ach receptors?
ligand gated Na/K channels
Subtypes of nicotinic Ach receptors
Two subtypes: NN (found in autonomic ganglia, adrenal medulla) and NM (found in neuromuscular junction of skeletal muscle).
Muscarinic Ach Receptors work through which receptors?
Muscarinic ACh receptors are G-protein–coupled receptors that usually act through 2nd messengers
Subtypes of Muscarinic Ach-R
5 subtypes: M1–5 found in heart, smooth muscle, brain, exocrine glands, and on sweat glands (cholinergic sympathetic).
G protein class of α1 & α2 rec’r?
α1 - Gq
α2 - Gi
Major fxn of α1-R?
Inc vascular smooth muscle contraction
Inc pupillary dilator muscle contraction (mydriasis)
Inc intestinal and bladder sphincter muscle contraction
Major fxn of α2-R?
dec sympathetic (adrenergic) outflow
dec insulin release,
dec lipolysis,
dec aqueous humor production
Inc platelet aggregation,
G protein class of β1, β2, β3 - R?
All are Gs
What g proteins are affiliated with M1-3 receptors?
M1R = Gq
M2R = Gi
M3R = Gq
Fxn of M1R
Mediates higher cognitive functions, stimulates enteric nervous system
Fxn of M2R
dec heart rate and contractility of atria
M3R fxn?
- Inc exocrine gland secretions (eg, lacrimal, sweat, salivary, gastric acid)
- Inc gut peristalsis,
- Inc bladder contraction,
- bronchoconstriction,
- Inc pupillary sphincter muscle contraction (miosis), ciliary muscle contraction (accommodation),
- Inc insulin release,
- endothelium-mediated vasodilation
The two dopamine receptors have what g proteins as 2nd messangers?
D1R - Gs
D2R - Gi
Fxn of D1R & D2R
D1R - Relaxes renal vascular smooth muscle, activates direct pathway of striatum
D2R - Modulates transmitter release, especially in brain, inhibits indirect pathway of striatum
What g proteins are associated with histamine receptors?
H1R - Gq
H2R - Gs
Fxn of H1R & H2R
H1R
inc nasal and bronchial mucus production, vascular permeability, bronchoconstriction, pruritus, pain
H2R
inc gastric acid secretion
one - lung, two - stomach
Vasopressin receptors - what g protein?
V1R - Gq
V2R - Gs
Fxn of V1R & V2R?
V1R - Inc vascular smooth muscle contraction
V2R - inc H2O permeability and reabsorption via upregulating aquaporin-2 in collecting twobules (tubules) of kidney, inc release of vWF
Release of norepinephrine from a sympathetic nerve ending is modulated by ___ itself, acting on ______ ___________
Release of norepinephrine from a sympathetic nerve ending is modulated by NE itself, acting on presynaptic α2-autoreceptors –> negative feedback.
With cholinomimetic drugs - what should one be on the look out for?
Watch for exacerbation of COPD, asthma, and peptic ulcers in susceptible patients.
Rx used for urinary retention - MoA?
Bethanechol - Activates bladder smooth muscle; resistant to AChE. No nicotinic activity
Cholinomimetic rx used to relieve intaocular pressure in open angle glaucoma?
Carbachol - Carbon copy of acetylcholine (but resistant to AChE).
Carbachol for glauComa
Used to test for asthma? MoA?
Methacholine - asthma challenge test - (+) muscarinic receptor in airway when inhaled
Cholinomimetic rx that is used to treat glaucoma and the dry mouth of Sjogren?
Pilocarpine
MoA of Pilocarpine?
Contracts ciliary muscle of eye (open-angle glaucoma), pupillary sphincter (closed-angle glaucoma);
resistant to AChE, can cross bloodbrain barrier (tertiary amine).
“You cry, drool, and sweat on your ‘pilow.’ ”
Rx 1st line for Alzheimer disease
Donepezil, rivastigmine, galantamine
Rx that was used to Dx MG? What is used now?
Edrophonium;
replaced by anti-AchR Ab
Use of Neostigmine?
- Postoperative and neurogenic ileus and urinary retention,
- myasthenia gravis
- reversal of neuromuscular junction blockade (postoperative).
NEO - NEuromusc NEurogenic retention post Op
Tx for anticholinergic toxicity?
Physostigmine
“Phy-xes” (Fixes) anticholingeric tox
Physo-therapy for anticholinergic tox
What drugs are used to control the side effects of Pyridostigmine?
Used with glycopyrrolate, hyoscyamine, or propantheline to control pyridostigmine side effects.
Use GHP drugs to put Pyrido to sleep (Like GHB)
Pyridostigmine used for what disease? and why?
MG; long acting, does not penetrate CNS
Affects of organophosphates
How to reverse organophosphate poisoning?
Diarrhea
Urination,
Miosis,
Bronchospasm,
Bradycardia,
Emesis,
Lacrimation,
Sweating,
Salivation.
DUMBBELSS
Rx/ Atropine
What are the nicotinic effects of organophosphate poisoning?
Neuromuscular blockade;
like succinyl choline
How to reverse the nicotinic effects of organophosphates?
Pralidoxime; regenerates AchE if given early
How to rev. nicotinic effects of organophosphates.
PraLID O - Put a LID on nicOtinic effects.
CNS effects of organophosphate poisoning?
respiratory depression,
lethargy,
seizures, coma
Atropine, homatropine, tropicamide works on what body part? used for what?
Atropine, homatropine, tropicamide:
to produce mydriasis and cycloplegia
Benztropine; trihexyphenidyl has what site of action and application?
Benztropine; trihexyphenidyl
used in CNS, for Parkinsons and acute dystonia
Try to Park my Benz
Glycopyrrolate has what use in the body?
Glycopyrrolate
Parenteral: preoperative use to reduce airway secretions.
Oral: drooling, peptic ulcer.
Hyoscyamine
Dicyclomine
Hyoscyamine Dicyclomine:
HolD the spasms
GI - antispasmodics for IBS
Ipratropium and tiotropium
respiratory;
COPD, asthma (“I pray I can breathe soon!”)
What muscarinic antagonist is used against bladder spasms and urge urinary incontinence?
Bladder spasms and urinary incontinence
Solifenacin
Tolterodine
Oxybutynin
STOP urinary incontinence
Ephedrine (pseudophedrine)
used for motion sickness
Scopolamine
Atropine effects on?
Atropine blocks ______ effects of anticholinesterases, but not the _____ effects.
Atropine blocks muscarinic effects (DUMBBeLSS) of anticholinesterases, but not the nicotinic effects.
SE of Atropine
inc body temperature (due to dec sweating); Inc HR; dry mouth; dry, flushed skin; cycloplegia; constipation; disorientation
Hot as a hare
Dry as a bone
Red as a beet
Blind as a bat
Mad as a hatter
Full as a flask
What can atropine use lead to in the elderly, in men, and infants?
Atropine use causes:
Can cause acute angle-closure glaucoma in elderly (due to mydriasis), urinary retention in men with prostatic hyperplasia, and hyperthermia in infants.
Albuterol,salmeterol, and terbutaline works on which receptors? used for?
β2 > β1
Albuterol for Acute asthma/COPD.
Salmeterol for Serial (long-term) asthma/COPD.
Terbutaline for acute bronchospasm in asthma and tocolysis.
Dobutamine - rec’r and use?
β1 \> β2, α Heart failure (HF), cardiogenic shock (inotropic \> chronotropic), cardiac stress testing.
Dopamine - which rec’r and use?
D1 = D2 > β > α
Unstable bradycardia, HF, shock;
inotropic and chronotropic effects at lower doses due to β effects;
vasoconstriction at high doses due to α effects
Difference between Epi/NE and receptors they use?
Epi = β > α
NE = α1 > α2 > β
Epi and NE used for?
Epi - Anaphylaxis, asthma, open-angle glaucoma; α effects predominate at high doses. Significantly stronger effect at β2-receptor than norepinephrine.
NE - Hypotension, septic shock
Fenoldopam - which rec’r and use?
D1 R
Postoperative hypertension, hypertensive crisis. Vasodilator (coronary, peripheral, renal, and splanchnic).
Promotes natriuresis.
Can cause hypotension and tachycardia.
Fenoldopam - FENd Off serious HTN
Isoproterenol - affect which rec’r ? use?
β1 = β2
Electrophysiologic evaluation of tachyarrhythmias. Can worsen ischemia.
Has negligible α effect.
rec’r used by Midodrine, what use?
α1
Autonomic insufficiency and postural hypotension. May exacerbate supine hypertension
Mirabegron - rec’r and use?
Mirabegron
β3
urinary incontinence, overactive bladder
Beta 3 = inc lipolysis, thermogenesis, bladder relaxation
Phenylephrine - rec’r and use?
α1 > α2
Hypotension (vasoconstrictor), ocular procedures (mydriatic), rhinitis (decongestant), ischemic priapism.
vascular smooth muscle contraction, pupillary dilator muscle contraction (mydriasis), intestinal and bladder sphincter muscle contraction
List 3 indirect sympathomimetics
Amphetamine
Cocaine
Ephedrine
(TCAs)
List the mechanisms of Amphetamine, Cocain, Ephedrine
Amphetamine - Indirect general agonist, reuptake inhibitor, also releases stored catecholamines
Cocaine - Indirect general agonist, reuptake inhibitor Ephedrine - Indirect general agonist, releases stored catecholamines
Why is it dangerous to give BB to a cocaine user?
Caution when giving β-blockers if cocaine intoxication is suspected (can lead to unopposed α1 activation –> extreme hypertension, coronary vasospasm).
Use of Ephedrine
Nasal decongestion (pseudoephedrine), urinary incontinence, hypotension
used for hypertension in pregnancy
α-methyldopa
SE of α-methyldopa
Direct Coombs ⊕ hemolysis, drug-induced lupus
α-methyldopa
Other drugs that cause drug (+)’d lupus
Drugs that cause COOMBS (+) hemolysis
Lupus
Methyldopa, Minocycline, Hydralazine,
Isoniazid, Phenytoin, Sulfa drugs, Etanercept,
Procainamide
Lupus Makes My HIPS Extremely Painful
M SHIPPE
Coombs: Penicillin, methylDopa, Cephalosporins
sympatholytic that relieves spasticity
Tizanidine
Spastic Tizan
Clonidine and Guanfacine applications
Clonidine and Guanfacine - alpha 2 agonists
( dec sympathetic (adrenergic) outflow, dec insulin release, dec lipolysis, dec aqueous humor production, INC plat aggregation)
Hypertensive urgency (limited situations), ADHD, Tourette syndrome, symptom control in opioid withdrawa
if one abruptly stops taking clonidine/guanfacine, what is the side effect
rebound hypertension
side effects of α-methyldopa
Direct Coombs ⊕ hemolysis, drug-induced lupus
Use of Tizanidine & SE.
Relief of spasticity
Hypotension, weakness, xerostomia
Diff b/w Phenoxybenzamine & Phentolamine
Phenoxybenzamine - irreversible α-blocker
Phentolamine - reversible α-blocker
Use of Phenoxybenzamine
Pheochromocytoma (used preoperatively) to prevent catecholamine (hypertensive) crisis
α2 selective (-)’r and use
Mirtazapine, use for depression
MirtAZapine = α2
(DEC sympathetic (adrenergic) outflow, insulin release, lipolysis, , aqueous humor production INC platelet aggregation)
Examples of partial agonists?
- Danazol - partial agonist at androgen receptor
- acebutalol - B1 sel partial agonist
- pindalol - BB, nonselective
- Tamoxifen - partial agonist in endometrium (SERM)
- Buprenorphine - partial agonist at opiod receptor
- Aripiprazole - D2 partial agonist
- Varenicline - nACh-R partial agonist
- Vilazodone - 5HT1A-R partial agonist
- Buspirone - 5HT1A-R partial agonist
- Butorphanol - mu partial agonist (mixed opiod receptor)
- Pentazocine - mu antagonist/partial agonist (mixed opiod)
Which beta blockers dec mortality in heart failure?
Bisoprolol, Carvedilol, Metoprolol (β-blockers Curb Mortality
In HTN how do BB help?
dec cardiac output, dec renin secretion (due to β1 receptor blockade on JG cells)
BB used in hyperthyroidism, actions?
Propranolol
Symptom control (dec heart rate, dec tremor), thyroid storm
How do BB help in hypertrophic cardiomyopathy
dec heart rate –> inc filling time, relieving obstruction
How do BB help in MI?
dec o2 demand
dec mortality
Which BB used for SVT? how do they help?
metoprolol
esmolol
dec AV conduction velocity (class II antiarrhythmic)
MESsVT - Metoprolol & Esmolol for SVT
BB used in variceal bleeding? MoA?
Nadolol, propranolol, carvedilol
dec hepatic venous pressure gradient and portal hypertension (prophylactic use)
Portal VariCeal hypertensioN
P - propranolol
C- Carvedilol
N- nadolol
Adverse effects of BB
- Erectile dysfunction
- cardiovascular (bradycardia, AV block, HF),
- CNS (seizures, sleep alterations)
- dyslipidemia (metoprolol)
- asthma/COPD exacerbations
Why must one be wary of using BB in cocaine assoc chest pain?
Use of β-blockers for acute cocaine-associated chest pain remains controversial due to unsubstantiated concern for unopposed α-adrenergic stimulation.
Ex of B1R (-)’rs?
β1-selective antagonists (β1 > β2)—acebutolol (partial agonist), atenolol, betaxolol, bisoprolol, esmolol, metoprolol
Nonselective α- and β-antagonists?
carvedilol
labetalol
Unique features of Nebivolol?
Nebivolol combines cardiac-selective β1-adrenergic blockade with stimulation of β3-receptors (activate nitric oxide synthase in the vasculature and dec SVR)
Nebivolol inc NO
What type of foods can lead to histamine poisoning?
Spoiled dark-meat fish such as tuna, mahimahi, mackerel, and bonito.
Action of histamine in scombroid poisoning, and sx?
Bacterial histidine decarboxylase converts histidine to histamine. Frequently misdiagnosed as fish allergy.
Mimics anaphylaxis: acute burning sensation of mouth, flushing of face, erythema, urticaria, itching. May progress to bronchospasm, angioedema, hypotension.
Tx of Histamine poisoning?
Antihistamines. Albuterol and epinephrine if needed.
Tetrodotoxin - found in what food? MoA?
Pufferfish. Highly potent toxin; binds fast voltagegated Na+ channels in cardiac/nerve tissue, preventing depolarization
Sx of TTX poisoning?
Nausea, diarrhea, paresthesias, weakness, dizziness, loss of reflexes.
Ciguatoxin found in what food?
Reef fish such as barracuda, snapper, and moray eel.
MoA and Sx of ciguatoxin?
Opens Na+ channels, causing depolarization.
Nausea, vomiting, diarrhea; perioral numbness; reversal of hot and cold sensations; bradycardia, heart block, hypotension.
What is Beers criteria ?
Widely used criteria developed to reduce potentially inappropriate prescribing and harmful polypharmacy in the geriatric population. Includes > 50 medications that should be avoided in elderly patients due to dec efficacy and/or inc risk of adverse events
Ex of Rx that meet Beers criteria?
- α-blockers (inc risk of hypotension)
- Anticholinergics, antidepressants, antihistamines, opioids (inc risk of delirium, sedation, falls, constipation, urinary retention)
- Benzodiazepines (inc risk of delirium, sedation, falls)
- NSAIDs (inc risk of GI bleeding, especially with concomitant anticoagulation)
- PPIs (inc risk of C difficile infection)
A man presents with kidney issues and pain - what Rx should one be careful giving him? and why?
Morphine - Morphine 6 glucoronide is an active metabolite of morphine and more active than morphine itself. Can be toxic in pt. with kidney issues, since they can’t eliminate it as well
A pt has a clotting issue, but is a poor metabolizer. What anti-clotting Rx should we not give him?
Not Warfarin - Poor metabolizers will bleed.
A pt is on Warfarin but acquires a bacterial infection - which antibiotics would cause bleeding in this patient?
Ciprofloxacin, Macrolides (except azithromycin), Sulfonamides.
5 drugs that cause pulmonary fibrosis?
Bleomycin (w/in weeks -mos), Amiodarone, Busulfan (takes years), Methotrexate, Nitrofurantoin
Pulmonary fibrosis is BBAd, MaN
Why does Crohn’s lead to malabsorption?
Crohn’s has cobblestone mucosa - the thicker membrane is due to fibrosis, decreasing the absorption in SI
What form of a drug is needed to get into the CNS?
lipid soluble, Non-ionized, small
what form of drug is affected by pK and pH?
Ionized, water soluble
Why is Heparin the anticoagulant of choice in pregnancy?
water soluble, won’t cross blood placental barrier
Drug of Choice in hypothyroidism in pregnancy?
PTU, 90% protein bound, wont cross blood placental barrier
Which Rx would decrease Digoxin’s Vd (volume of distribution) (6)
Any Rx that displaces digoxin from its tissue binding site (more tissue bound = greater Vd) - Amiodarone, verapamil, itraconazole, erythromycin, clarithromycin, quinidine.
Disruption of which metabolic pathway will lead to poor drug metabolization by cytochromes?
Pentose phosphate pathway - Cytochrome p450s require NADPH to function
How many half lives does it take to get to 90% of steady state?
3.3
What drug reverses the action of Heparin? (Chemical antagonism)
Protamine sulfate
Which drugs bind to an inhibitory Cl- ion channel in the CNS?
GABAa Receptor - Benzos, Barbiturates,
Which receptors will result in DEC in cAMP? (6)
Gi coupled -
M2R, Alpha2-R, D2R, - People who are 2 MAD (-) themselves
Opiate, GABAb, 5-HT1
Which receptors activate PLC?
Gq coupled -
a1-R, M1-R, M3-R, H1, V1, - HAVE 1 M&M
5-HT2
Example of tyrosine kinase receptor blocker? Used for what diseases?
Imatinib - CML, GI stromal tumors Erlotinib - non small cell lung carcinoma
Single most effective drug for malaria? SE?
Artesunate > Quinidine/Doxycyclin - clears parasitemia faster SE// long QT
______ is directly proportional to the enzyme concentration
Vmax is directly proportional to the enzyme concentration
Max concentration of a drug is proportional to ?
Dose administered
Which antibiotic is contraindicated in neonate because it could lead to kernicterus? why?
Sulfonamides, as they displace bilirubin from albumin binding sites.
