Drug List and Metabolism Flashcards
Neuromuscular Agents (categories)
Presynaptic drugs, toxins and venoms
Postsynaptic agents
Presynaptic drugs, toxins and venoms
Tetrodotoxin (TTX)
Mg2+ and other polyvalent cations
Botulinum Toxin Type A
Black Widow Spider Venom (latrotoxin)
Aminoglycoside antibiotics (side effect)
Hemicholinium
Postsynaptic agents (categories)
(1) Non-depolarizing blockers
(2) Depolarizing blockers
(3) Indirect-acting stimulants (anticholinesterases)
(4) Anticholinesterase antagonists
(5) Other peripherally-acting muscle relaxants
Non-depolarizing blockers
Tubocurarine
Pancuronium (PavulonR)
Vecuronium (NorcuronR)
Atracurium (TracriumR)
Cisatracurium (NimbexR)
Rocuronium (ZemuronR)
Agents with__curonium and _curium suffixes
Depolarizing blockers
Acetylcholine
Succinylcholine (AnectineR)
Nicotine
Carbachol
Indirect-acting stimulants (anticholinesterases)
Edrophonium (TensilonR)
Neostigmine (ProstigmineR)
Physostigmine (EserineR)
Pyridostigmine (MestinonR)
DFP (Diisopropylphosphorofluoridate)
Parathion
Malathion
Sarin
Ambenonium (MytelaseR)
Ecothiophate (PhospholineR)
VX
Anticholinesterase antagonists
oximes such as: Pralidoxime (2-PAMR ,ProtopamR)
Other peripherally-acting muscle relaxants
Dantrolene
Autonomic Agents - Cholinergic (categories)
Parasympathomimetics-direct action on Muscarinic Receptors
Parasympathomimetics: indirect-acting
Parasympathetic antagonists (anti-muscarinics)
Ganglionic blockers
Parasympathomimetics-direct action on Muscarinic Receptors
Acetylcholine
Methacholine
Bethanechol (UrecholineR)
Pilocarpine
Cevimeline (EvoxacR)
Carbachol
Muscarine
Parasympathetic antagonists (anti-muscarinics)
Atropine (and Homatropine)
Airways:
Ipratropium (AtroventR)
Tiotropium (SpirivaR)
Overactive bladder:
Tolterodine (DetrolR)
Fesoterodine (ToviazR)
Oxybutynin (DitropanR)
Solifenacin (VESIcareR)
Darifenacin (EnablexR)
Ocular:
Tropicamide (MydriacilR)
Cyclopentolate (CyclogylR)
Depolarizing ganglionic blockers
acetylcholine
nicotine
Direct acting Adrenergic receptor agonists (categories)
Non-selective prototypes
‘Selective’ α1 agonists
‘Selective’ α2 agonists
‘Selective’ β1 agonist
‘Selective’ β2 agonists
Dopamine receptor agonists
Non-selective prototypes
Norepinephrine
Epinephrine
Isoproterenol (IsoprenalineR, IsuprelR)
Dopamine (InotropinR)
‘Selective’ α1 agonists
Phenylephrine (NeosynephrineR)
Imidazolines such as: Oxymetazoline (AfrinR) Xylometazoline
Midodrine
‘Selective’ α2 agonists’
Clonidine (CatapresR)
α-Methyldopa (AldometR)
Guanfacine (TenexR)
Guanabenz (WytensinR)
Apraclonidine (IopidineR)
Brimonidine (AlphaganR)
‘Selective’ β1 agonist
Dobutamine (DobutrexR)
‘Selective’ β2 agonists
Albuterol (VentolinR)
Terbutaline (BrethineR)
Ritodrine (YutoparR)
Salmeterol (SereventR)
Formoterol (ForadilR)
Dopamine receptor agonists
Dopamine (IntropinR)
Autonomic Agents – Adrenergic (categories)
Direct acting receptor agonists
Indirect-acting sympathomimetic amines
Mixed (direct and indirect) acting sympathomimetic amines
Adrenergic receptor antagonists
Phosphodiesterase (PDE) inhibitors
Prostaglandin analogues
Indirect-acting sympathomimetic amines
Tyramine
Amphetamines
Mixed (direct and indirect) acting sympathomimetic amines
Ephedrine-Pseudoephedrine (SudafedR)
Adrenergic receptor antagonists (categories)
Non-selective α blockers
α1 blockers
α2 blocker
Non-selective β blockers
β1 blockers
β2 blocker
α+ β blockers
Non-selective α blockers
Phenoxybenzamine (DibenzylineR)
Phentolamine (RegitineR)
α1 blockers
Prazosin (MinipressR)
Tamsulosin (Flomax)
Alfuzosin (UroXatralR)
Silodosin (RapafloR)
any other agents with an azosin suffix e.g. Terazosin (HytrinR), Doxazosin (CarduraR)
α2 blocker
Yohimbine (YohimexR)
Non-selective β blockers
Propranolol (InderalR)
Timolol (TimopticR)
various other agents ending in a vowel + lol (e.g. Nadolol, Alprenolol, Pindolol)
β1 blockers
Metoprolol (LopressorR)
Betaxolol (BetopticR)
Atenolol (TenorminR)
Esmolol (BreviblocR)
α+ β blockers
Labetalol (NormodyneR)
Carvedilol (CoregR)
Phosphodiesterase (PDE) inhibitors
Sildenafil (ViagraR)
Other ___afils such as Vardenafil (LevitraR),Tadalafil (CialisR) caffeine, theophylline and other _phyllines (generally better as adenosine receptor blockers than PDE inhibitors)
Prostaglandin analogues
Lananoprost (XalatanR) and other __oprosts such as Bimatoprost (LatisseR ) (These are PGF2a analogs)
Tetrodotoxin (TTX)
Presynaptic Blocking Agent Blocks Na+ channels in nerve terminals and in skeletal muscle responsible for AP upstroke
Puffer fish toxin
Mg2+, polyvalent cations
Presynaptic Blocking Agent Compete with Ca2+ at the external mouth of the Ca2+ channel
Reduces neurally-evoked ACh release, normal MEPPs, low EPPs
Aminoglycosides
Presynaptic Blocking Agent
Reduce Ca2+ entry through Ca2+ channels DO NOT USE WITH MG PTS – COULD KILL!!
Reduce ACh release, normal MEPPs, low EPPs (neomycin> kanamycin > amikacin > gentamicin > tobramycin)
Black Widow Spider Venom (alpha-latrotoxin)
Presynaptic Blocking Agent Forms Ca2+ channels in the membrane causing an asynchronous barrage of MEPPs and increased exocytosis of Ach
this is followed by a lack of vesicles &
increased of surface area of nerve terminal (overall effect: transmission block)
Fasciculations followed by dead post-synaptic membrane
Hemicholinium-3
Presynaptic Blocking Agent
Competitively inhibits uptake of choline via the choline transporter (thus inhibiting the synthesis of Ach)
MEPPs are extremely small, but sensitivity of muscle to Ach is normal
just smaller amount of Ach in the vesicles than usual
Tubocurarine
Postsynaptic Non-Depolarizing Blocker
Competitive inhibitor of Ach at nicotinic receptors, surmountable by increasing [Ach], Ach-like with stabilizing ring structure. Category prototype but obsolete clinically (except for So. American Indians)
RENAL clearance mostly (also in bile)
All neuromuscular blockers are used for: duration of sx’s muscle relaxation, initial phases of endotracheal intubation (masseter & lateral cricoarytenoid muscles), diagnostic procedures (-scopys)
Side Effects: 1. Histamine release (vasodilatation), 2. Ganglionic block @ higher doses (anti-hypertensives) -> fall in blood pressure
Pancuronium (Pavulon)
Postsynaptic Non-Depolarizing Blocker
2 AChs attached to steroid nucleus, favors non-depolarizing competitive inhibition, selective for neuromuscular junction
RENAL clearance
Pancuronium produces MG-like effects, DO NOT use with aminoglycosides (could kill pt)
Not used at NMH (might still be used in community hospitals & death row (cheap drug), long duration of action ~1 hr, 5-10X more potent than tubocurarine, no histamine release, minimal ganglionic block
Side effect: blocks parasympathetic vagal tone, causing tachycardia
Vecuronium (Norcuron)
Postsynaptic Non-Depolarizing Blocker
Same as pancuronium w/o a methyl grp
monoquaternary 85% BILIARY clearance 15% RENAL clearance
intermediate duration of action 30-40 min
no vagal block/tachycardia, no histamine release, devoid of CV effects
Atracurium (Tracrium)
Postsynaptic Non-Depolarizing Blocker
Prototype benzylisoquinolinium (benzyl + isoquino + Ach-like)
HOFFMAN ELIMINATION in plasma, rapid non-enzymatic dequaternization, pH/temp-dependent and by plasma esterases and ubiquitous carboxylases
NOT ELIMINATED BY KIDNEY or LIVER
Intermediate duration of action 20-30 min
no vagal block, no ganglionic block
Side Effects: some histamine release, may produce laudanosine in isomer mixture that causes seizures
Cisatracurium (Nimbex)
Postsynaptic Non-Depolarizing Blocker
Properties similar to atracurium, but is only one stereoisomer rather than 10 stereoisomers
Atracurium side effects minimized
Rocuronium (Zemuron)
Postsynaptic Non-Depolarizing Blocker
~~“very fast vecuronium”
Essentially 100% BILIARY clearance
Rapid onset, intermediate duration, no histamine release, very popular for intubation
Acetylcholine (Ach)
Postsynaptic Depolarizing Blocker
Nicotinic receptor agonists in exogenously high concentrations can block transmission
Ganglionic Blockers – Depolarizing:
@ high []s, PI-PII Block as in NMJ
Succinylcholine (SUX)
Postsynaptic Depolarizing Blocker
Nicotinic receptor agonist SUX = 2 Ach, hydrolyzed by ChE in 2 steps when used for long periods of time, can cause sustained depolarization and densensitization of nicotinic receptor/Na+ channel
RAPIDLY REVERSIBLE DO NOT USE FOR THE DURATION OF SURGICAL PROCEDURE – muscle damage caused by enormous fasiculations and continued release of pain producing substances (prostaglandins, potassium, ATP, etc) – remember story of 17 yo girl 1 wk of pain post-op rape accusation
Easy to control duration & intensity of effects; short duration & rapid onset (large doses can be used), used for early anesthesia & intubation to produce rapid by brief periods of block (generally Phase I); Fastest-acting for intubation, lasts increased serum K+ & CV collapse, arrhythmias, liver disease or
genetic ChE deficiency -> prolonged apnea due to Phase II block requires respirator HYDROLYZED in two stages by plasma CHE (Phase I, Hydrolysis)
Nicotine
Postsynaptic Depolarizing Blocker Depolarizing blocker at neuromuscular junction, discussed later in CNS section PI-PII block
Carbachol
Postsynaptic Depolarizing Blocker Nicotinic and muscarinic agonist
Neostigmine (Prostigmine)
Indirect-acting Stimulants (anticholinesterases) / Parasympathomimetics – indirect-acting
Quaternary (no CNS effects), prevent degradation of Ach by binding to cholinesterase 2-4 hr duration, oral/parenteral @ skeletal NMJ: Treat MG patients, reverse residual non-depolarizing block after surgery
Autonomic: like pilocarpine – miotic & glaucoma tx; like bethanechol – tx for urinary retention and GI stasis
FYI Drug Metabolism: HYDROLYZED SLOWLY BY CHE (Phase I, Hydrolysis) and then Phase II glucuronide)
Edrophonium (Tensilon)
Indirect-acting Stimulants (anticholinesterases) / Parasympathomimetics – indirect-acting
Short-acting, rapid onset Reversible anticholinesterases are hydrolyzed by liver cholinesterase
Quaternary agents have direct stimulatory action on the Ach receptor in addition to inhibiting cholinesterase
Test for MG –if injection causes pt to perk up briefly then MG (shown in “House” clip), else no effect and probably cholinergic crisis
Same contraindications as bethanechol
Physostigmine (Eserine)
Indirect-acting Stimulants (anticholinesterases) / Parasympathomimetics – indirect-acting
Tertiary amine, can cross BBB, duration 1-2 hrs, oral/parenteral
In Calibar or ordeal bean-muscarinic control of emesis (if fast ingestion), death (if slow ingestion)
Used for glaucoma therapy (topically), antidote for atropine toxicity!! (the salicylate salt is known as Antilirium)
Pyridostigmine Bromide (PB) (Mestinon)
Indirect-acting Stimulants (anticholinesterases) / Parasympathomimetics – indirect-acting
Same as neostigmine except slow release form has long-lasting 4-12 hr oral effect (useful @ bedtime)Most popular to treat MG
was given as a pretreatment in Persian Gulf war troops (doesn’t work with Sarin, made it worse!)
DFP (Diisopropylphosphorofluoridate)
Indirect-acting Stimulants (anticholinesterases) / Parasympathomimetics – indirect-acting Irreversible anticholinesterase
phosphorylates esteratic site > 6 hrs, oily liquid well absorbed by every route, including skin. Effects similar to physostigmine Enzyme is stuck in phosphorylated state-resynthesis of the enzyme is necessary
Sarin
Indirect-acting Stimulants (anticholinesterases) / Parasympathomimetics – indirect-acting
“weteye,” GB Examples of Japanese subway attack, US soldiers in Gulf War, Syria in 2013
Parathion
Indirect-acting Stimulants (anticholinesterases) / Parasympathomimetics – indirect-acting
metabolized into paraoxon the toxic form that inhibits ChE Agricultural insecticide, Example of methyl derivative sprayed indoors in Chicago homes causing an environmental nightmare
FYI: CYP3A4 metabolizes parathion into paraoxon
Malathion
Indirect-acting Stimulants (anticholinesterases) / Parasympathomimetics – indirect-acting
higher animals can metabolize drug faster than parathion; some selectivity towards insects Slightly safer than parathion as birds and mammals (but not fish) have carboxylase to inactivate. Examples of Medflies, spraying in suburban areas Tx use: in Prioderm lotion for head lice
Oximes (Pralidoxime: 2-PAM/Protopam)
Anticholinesterase Antagonists
Enzyme reactivation, binds anionic site, lifts phosphorylated residue off esteric site
reverses skeletal muscle effects w/relief within 1-2 min
Antidote for anticholinesterase attack (SLUD syndrome)
Dantrolene
Other Peripheral Muscle Relaxants
Blocks Ca2+ release from SR To treat malignant hyperthermia (such as caused by SUX)
Acetylcholine
Parasympathomimetic – Direct
mimics parasympathetic stimulation by acting upon muscarinic receptors @ parasympathetic targets as well as sympathetic cholinergic targets (eccrine sweat glands), accommodation
CARDIAC:
- SA node: 1) increased K+ current (via βγ subunits of G protein 2) inhibits If 3) inhibits L-type Ca2+ currents
- AV node: increased gk and conductance, decreased BP -> vasodilatation via receptors on endothelium -> EDRF (NO) -> increased GMP in smooth muscle cells -> relaxation
Has 2 “faces” – muscarinic 4.4 A, nicotinic 5.9 A Non-specific, rapid hydrolysis, not used clinically
Methacholine
Parasympathomimetic – Direct
Specific for muscarinic receptors, no hydrolysis by ChE but hydrolyzed slowly by AChE
Methacholine challenge test for bronchial asthma (no effect on normal people, intense bronchoconstriction & decreased vital capacity in asthmatics)
Bethanechol (Urecholine)
Parasympathomimetic – Direct
Specific for muscarinic receptors, resistant to hydrolysis by esterases
Used for GI tract treatment of surgery/med-induced low bowel tone “adynamic ileus” to restore peristalsis
Also for treatment of urinary retention
Contraindications: IV/IM – could produce shock (like Ach+neostigmine), asthmatics, hyperthyroid b/c susceptible to arrhythmias, peptic ulcers, intestinal/bladder obstruction
Pilocarpine
Parasympathomimetic – Direct
Tertiary amine w/4.4A selectivity for muscarinic receptors, not hydrolyzed by cholinesterases
Narrow angle: contracts circular muscle fibers, pulls iris toward center of eye & uncrowds angle
Open angle: improves trabecular tone by contracting circular and ciliary muscles, opening pores & increasing AH outflow
Tx of open angle glaucoma w/Ocusert 3rd line drug, for surgery of narrow angle glaucoma, pilocarpine is used as pretreatment along with anti-cholinesterase, acetazolamide/methazolamide/dichlorphenamide (carbonic anhydrase inhibitors inhibit AH synthesis), and mannitol/glycerol (osmotically decreases AH)
Cevimeline (Evoxac)
Parasympathomimetic – Direct Muscarinic agonist
used orally to treat Sjogren’s syndrome (currently preferred to pilocarpine)
FYI:Metabolism: CYP3A4 and CYP 2D6 (Phase I)
Non-depolarizing ganglionic blockers
Trimethaphan (ArfonadR) Mecamylamine (InversineR) Tubocurarine
β2 blocker
Butoxamine (you are not responsible for this; it is just to let you know that such a drug exists)
Atropine (Hyoscyamine, Levsin, Levbid, Nulev)
Parasympathetic Antagonists
MUSCARINIC RECEPTOR BLOCKER Alkaloid from Atropa belladonna prototype, competitive inhibitor of Ach at muscarinic receptors
tertiary TOXICITIES (Jimson Weed):
- DRY as a bone - decreased secretions, urinary retention
- HOT as a stove - increased body temp by decreased eccrine sweating
- RED as a beet – histamine release -> cut. Vasodil.
- BLIND as a bat – mydriasis and cycloplegia
- MAD as a hatter – delirium, hallucinations
- …eventually coma and death
Effects, uses, and contraindications: predictable from ANS effects (oppose parasympathetics, produce sympathetic effects) – mydriasis and cycloplegia,** **bronchiolar tx of COPD and asthma, GI and urinary colic, block secretions (respiratory, acid, adjunct to surgery by blocking autonomic effects of neostigmine), increases HR during stage 2 and spinal anesthesia, antidote for anti-ChE poisoning, Parkinsonism (as an adjunct to L-dopa) Tx of toxicities – emesis, gastric lavage, activated charcoal ANTIDOTE for severe neuro effects: salicylate salt of PHYSOSTIGMINE (aka ANTILIRIUM)
Homatropine (Novatran) / Eucatropine (Euphthalmine)
Parasympathetic Antagonists MUSCARINIC RECEPTOR BLOCKER
Shorter duration of action Drug of choice at NU for ciliary spasm due to injury
Scopolamine (1-hyoscine)
Parasympathetic Antagonists MUSCARINIC RECEPTOR BLOCKER
Similar to atropine, w/more CNS depressant effects @ usual therapeutic doses
Remember muscarinic blockers produce anti-emesis via vestibular nucleus and vomiting center, sedation via basal forebrain and mesopontine nuclei, amnesia via septo-hippocampal projection Tx of motion sickness
Previously used for “twilight sleep” during labor
Tolterodine (Detrol)
Parasympathetic Antagonists MUSCARINIC RECEPTOR BLOCKER
Active by itself but also metabolized to another active drug-5-OHmethyltolterodine by CYP2D6
Tx of overactive bladder (OAB) and bladder spasms / urinary incontinence and enuresis, reduced sedation, and dry mouth
Contraindications: urinary retention, GI retention, narrow-angle glaucoma
FYI Metabolism: Phase I via CYP3A4, Phase II by glucuronide
Fesoterodine (Toviaz)
Parasympathetic Antagonists MUSCARINIC RECEPTOR BLOCKER
INACTIVE by itself but metabolized to same active drug 5-OHmethyltolterodine as tolterodine but by non specific esterases
Tx OAB and bladder spasm glaucoma
FYI Metabolism: active metabolite further metabolized by Phase I via CYP3A4and CYP2D6, Phase II by glucuronide
Solifenacin (Vesicare)
Parasympathetic Antagonists MUSCARINIC RECEPTOR BLOCKER
Superior to tolterodine
Tx OAB and bladder spasms
FYI Metabolism for _fenacins: Phase I via CYP3A4 and CYP2D6, Phase II by glucuronide
Darifenacin (Enablex)
Parasympathetic Antagonists MUSCARINIC RECEPTOR BLOCKER
Tx for bladder spasms
Oxybutynin (Ditropan)
Parasympathetic Antagonists MUSCARINIC RECEPTOR BLOCKER
Just another uninteresting drug to treat OAB and bladder spasms
Tropicamide (Mydriacyl)
Parasympathetic Antagonists MUSCARINIC RECEPTOR BLOCKER
Ocular effects (b/c atropine is too long-lasting) For older patients
Ipratropium (Atrovent)
Parasympathetic Antagonists MUSCARINIC RECEPTOR BLOCKER
Quaternary (also blocks ganglia), effective bronchiolar dilation w/o impairing mucociliary clearance – muscarinic receptors are located in larger, more centrally-located airways while
2 adrenoreceptors are located in fine branchelets of the bronchioles 1st line tx for COPD
M1 and M2!
Tiotropium (Spiriva)
Parasympathetic Antagonists
MUSCARINIC RECEPTOR BLOCKER In the bronchioles, there are presynaptic inhibitory M2 autoreceptors as well as postsynaptic M1s. Blocking M2 inhibitory synapses will increase Ach release (defeating the purpose of muscarnic block). Tiotropium blocks only M1s; Ipratropium blocks both M1s and M2s so not as effective Superior to ipatropium for COPD tx
Norepinephrine (Levophed)
Non-selective Autonomic Adrenergic Receptor Agonist - Direct-acting
Orally ineffective, poor absorption from SQ, usually given by IV but quickly inactivated
Good stimulant of alpha & beta1, essentially no beta2
For tx of severe hypotension in ICU (only clinical use of NE)
Ephinephrine
Non-selective Autonomic Adrenergic Receptor Agonist - Direct-acting
Oral absorption satisfactory, but metabolized by MAO by gut/liver, so oral EPI has little effect
Good stimulant of alpha, beta1, & beta2
EPI inhaler for asthma attacks, intracardiac EPI is useful for cardiac arrest (for both alpha & beta1 vasoconstriction + cardiac stimulatory effects to increase perfusion), to treat anaphylactic shock-see the antihistamine lecture
Isoproterenol (Isoprenaline, Isuprel)
Non-selective Autonomic Adrenergic Receptor Agonist - Direct-acting
Poor substrate for MAO so longer-acting Good stimulant of beta1 & beta2, essentially no alpha
Inhaler for asthma attack, but not selective
Dopamine (Inotropin)
Non-selective Autonomic Adrenergic Receptor Agonist - Direct-acting
Low dose increases cardiac output; high dose may cause tachycardia & vasoconstriction
Direct vasodilator effect to relieve oliguria Also used for cardiogenic shock if systolics <80
Phenylephrine
‘Selective’ alpha1 Agonist
Identical to EPI minus 4-OH (resistant to COMT for longer duration of action), selective but not very potent (need high doses), little effect on myocardium “get the red out” vasoconstrictor mechanism or nasal decongestants, also marketed for pupillary dilation
FYI: MAO metabolism
Imidazolines (Naphazoline, Tetrahydrozoline, Oxymetazoline)
‘Selective’ alpha1 Agonist
5-membered rings, not catechol or amine. Long-acting because not substrates for MAO or COMT, @ low doses alpha1 agonists, @ high doses alpha2 agonists
Nasal spray or eye drops May cause severe depressant effects in kids! alpha2 constriction can cause structural damage to nasal mucosa due to loss of blood flow
FYI Metabolism: Phase I via CYP2D6
Midodrine
‘Selective’ alpha1 Agonist
Metabolized by unknown peptidase to desglymidodrine, alpha1 constriction, increased BP in severe liver or kidney disease, occasionally used for postural hypotension
FYI Metabolism: Phase I via CYP2C19, Phase II by glucuronide
Clonidine (Catapres)
‘Selective’ alpha2 Agonist
Reduces sympathetic tone in medulla & hypothalamus, decreasing sympathetic activity from CNS to periphery @ higher doses -> stimulate peripheral post-syn alpha2 receptors w/initial vasoconstriction decreased HR & decreased TPR (decreased NE)
Used in past as anti-hypertensive, with diuretic/direct vasodilator
CLONIDINE SUPPRESSION TEST: distinguish essential Htn from pheochromocytoma
Abrupt discontinuation – risk of rebound Htn
Side effects: sedation, constipation, sexual dysfxn
FYI: Metabolism:excreted largely unchanged in urine
alpha-methyldopa (Aldomet)
‘Selective’ alpha2 Agonist
Produces alpha methyl NE that acts as an alpha2 agonist
An anti-hypertensive of choice for pregnancy (but not at NMH)
FYI: Metabolism: metabolized by Sulfation.
Apraclonidine (Iodpidine) & Brimonidine (Alphagan)
‘Selective’ alpha2 Agonist
Inhibit secretion of AH 2nd line drug for stubborn glaucoma (remember pilocarpine is 3rd line drug)
Dobutamine (Dobutrex)
‘Selective’ beta1 Agonist
Catecholamine that looks like dopamine w/bulky grp on N atom. increased Cardiac contraction w/minimal effect on HR
@ low []s mechanism complex-see Katzung for details. Useful for CHF or cardiogenic shock to increased CO, can also be used as chemical agent for stress echo Initial agent of choice for systolic >80mmHg; for MI when you don’t want alpha1 effects
FYI Metabolism: via COMT
Albuterol (Ventolin)
‘Selective’ beta2 Agonist
Prototype, most selective
Rescue inhaler
FYI: Metabolism: Phase II Sulfation
Terbutaline (Brethine)
‘Selective’ beta2 Agonist
Resorcinol w/more selectivity, only one available for parenteral & oral use
‘TERB’ - Successful bronchodilator (orally) -> poor MAO substrate
Uterine relaxation during premature labor @ NU
FYI Metabolism: Phase II Sulfation as described in the Drug Metabolism lectures
Ritodrine (Yutopar)
‘Selective’ beta2 Agonist
Not very selective
Highly popularized in media, only one currently approved for prevention/delay of premature labor
Potential for serious metabolic/CV effects (fetal and maternal HR), Not used at NMH
FYI Metabolism: Phase II Sulfation
Salmeterol (Serevent) & Formoterol (Foradil)
‘Selective’ beta2 Agonist
As selective as albuterol but long-lasting (12+ hours, inhaler), not as rapid onset
Do not use alone -> caused deaths in asthmatics! Used in combination with corticosteroids
FYI Metabolism: Phase I CYP3A4
Dopamine (Intropin)
Dopamine Receptor Agonist
increased CO beta1 effect, some increased HR, dilate renal beds via D1 dopamine receptors, vasoconstrictive alpha1 effects
@ high doses Systolics <80 mmHg, oliguria (but tachycardia & increased TPR may worsen myocardial ischemia)
Tyramine
Sympathomimetic Amine – Indirect
Enters nerve terminal via Uptake 1, displacing NE (increased release of NE), degraded by MAO
Found in aged cheese, ripe fruit, processed meat, etc. Tachyphylaxis, inhibitors of uptake can block effects
MAO inhibitors like Phenylzine (Nardil) can potentiate & produce hypertensive crisis Uptake 1 inhibitors: cocaine, tricyclic antidepressants, methylphenidate Metabolism: MAO
Amphetamines
Sympathomimetic Amine – Indirect
Release of biogenic amines (NE, dopamine, serotonin) from nerve endings Tachyphylaxis, inhibitors of uptake can block effects,
FYI Metabolism: Phase I via CYP2D6, Phase II by glucuronide. MAO inhibitors like Phenylzine (Nardil) can potentiate
Ephedrine-Pseudoephedrine (Sudafed)
Sympathomimetic Amine – Mixed Direct
agonist on alpha & beta receptors (esp. beta2), indirect release of NE from nerve terminals; resistant to COMT & MAO
“oral EPI,” less potent than EPI, CNS stimulant effect, tolerance develops (tachyphylaxis), long duration OTC nasal decongestants (alpha1) OTC anti-asthma preps (beta2)
Toxicity: peripheral vasoconstriction, cardiac stimulation, CNS (nervousness, anxiety, tremor, irritability, insomnia)
@ very high doses -> HTN (possibly leading to stroke), tachycardia, nausea & vomiting, fever, psychosis, respiratory depression, convulsions, & coma
FYI Metabolism: as much as 74% unchanged in urine , some (unknown) CYP mediated N-dealkylation
Phenoxybenzamine (Dibenzyline)
Non-selective alpha Blocker
Has some selectivity for alpha1; irreversibly alkylates receptors, decreased BP
Used to manage pheochromocytoma, tx of sexual dysfunction (increased NO, mediator of NANC release),
Phentolamine (Reglitine)
Non-selective alpha Blocker
alpha1 = alpha2 selectivity; short-acting, competitive; v. good against circulating catecholamines Used to test for pheochromocytoma (decreased BP if injected), but less useful than testing urinary metabolites
tx of sexual dysfunction (but must be injected into the corpus cavernosum—ouch…also nonselective & causes priapism due to blocking detumescence so phenylephrine is needed)
Drug of choice for hypertensive crisis induced by tyramine + MAOI
The ___azosins Prazosin (Minipress), also Terazosin Doxazosin & Trimazosin
alpha1 Blocker
All are non-selective alpha1 blockers - decreased BP w/o persistent tachycardia, decreased urinary outflow resistance in bladder neck, prostate, & urethra Rare use for Htn (combine with diuretic + beta blocker for moderate htn)
Also used to treat BPH, but not really used anymore because of severe orthostatic hypotension (block of alpha1B on blood vessels FYI Metabolism: Phase I via CYP3A4, Phase II by glucuronide
Tamsulosin (Flomax), Alfuzosin (Uroxatral), Silodosin
alpha1 Blocker
Selective alpha1A antagonists Very useful treatment for BPH
FYI Metabolism: Phase I via CYP3A4, Phase II by glucuronide (silodosin also uses CYP2D6)
Yohimibine (Yohimex)
alpha2 Blocker
Disinhibition of synaptic transmission – similar effects as nerve stimulation -> persistent tachycardia, increased GI motility
Popular in drug culture b/c of CNS stimulatory effects + aphrodisiac quality; used to treat impotence in diabetics (decreased inhibition of presyn relaxation -> increased release of NANC -> increased vasodilation
Propanolol (Inderal)
Non-selective beta Blocker
Prototype blocker of cardiac beta1 receptors: decreased HR, decreased CO, generally less or no change in BP after prolonged use
Main currently accepted mechanism as an antihypertensive is a block of renin release (recall rennin produces Angiotensin II, which is one of the most potent vasoconstrictors) Anti-arrythmic, anti-anginal, antihypertensive, pheochromocytoma (+ phenoxybenzamine), stage fright, prophylaxis of migraines.
Contraindications: asthmatics, diabetics (masks signs of severe hypoglycemia & decreased glycogenolysis), in past, disorders in which cardiac contractility is depressed. Now this drug category useful to treat heart failure.
Side effects: fainting lightheadedness, fatigue
Metabolism: Phase I via CYP2D6 and CYP2C19, Phase II by sulfation or glucuronide
Timolol (Timoptic)
Non-selective beta Blocker
Decreases secretion of aqueous humor by ciliary body
Useful to treat all forms of glaucoma, better than pilocarpine b/c no cyclospams, miosis, or impaired vision
Metabolism: Phase I via CYP2D6
Metoprolol (Lopressor)
beta1 Blocker
Equipotent w/propanolol for cardiac arrhythmias, htn, & angina “propanolol for asthmatics”
Metabolism: Phase I via CYP2D6 – important!
Betaxolol (Betoptic)
beta1 Blocker
Can be used in place of timolol to treat glaucoma in pts with airway disease “timolol for asthmatics”
Metabolism: Phase I via CYP2D6
Atenolol (Tenormin)
beta1 Blocker
Was very popularly prescribed, now very much out of favor (little to no metabolism)
Esmolol (Brevibloc)
beta1 Blocker
Short duration of action (hydrolyzed by esterases)
Metabolism: plasma esterases (Phase I)
Labetalol (Normodyne, Trandate)
alpha1 + beta Blocker
Blocks the pressor amines at alpha1 (increased TPR) & beta1 (increasedHR)
Treatment of hypertensive crisis & pheochromocytoma. The current drug of choice for hypertension during pregnancy.
Metabolism: only Phase II via glucuronide demonstrated
Carvedilol (Coreg)
alpha1 + beta Blocker
alpha block to produce vasodilatation, alpha block to decrease adverse effects of sympathetic stimulation -> overall decreased afterload & increased CO in pts w/heart failure
Tx for pts w/mild to moderate heart failure, w/no signif hypotension or pulmonary congestion, already on ACEI, diuretic, & digoxin
Metabolism: Phase I via CYP2D6, Phase II via glucuronide
Sildenafil (Viagra)
Phosphodiesterase (PDE) Inhibitor
Selective inhibitors of phosphodiesterase type 5, the PDE that breaks down cGMP; leads to increased cGMP accumulation
Under Revatio label, used to treat pulmonary hypertension Used to treat erectile dysfunction (along with the other –afils)
_Contraindications: _oral/transdermal nitrates b/c synergy leads to potentiation of hypotension; use with alpha1B blockers leads to bad hypotension; Also, increased cGMP by inhibition of PDE type 6 in retina leads to visual problems
FYI: For all three of these agents-Drug Metabolism: CYP3A4
Lananoprost (Xalatan), and other __oprosts
Prostaglandin Analogue
PGF2alpha agonist increases AH outflow by uveal scleral route
Another 1st line drug tx for glaucoma
Major side effect: production of irreversible darkening of iris + eyelashes in 33% of hazel eyes, also dry eyes & conjunctivitis
Trimethaphan (Arfonad)
Ganglionic BLocker - Non-depolarizing
Block the predominant tone, which is largely PARASYMPATHETIC so effects similar to atropine (don’t forget sweat is sympathetic cholinergic)
used as antihypertensives as sympathectic tone to bvs unopposed
Htn crisis, Dissecting aortic aneurysm, bloodless field
