Pharm 2 Flashcards
bactericidal drugs
penicillins cephalosporins aminoglycosides vancomycin aztreonam imipenem fluroroquinolones metronidazole polymyxins quinupristin-dalfopristin bacitracin
bacteriostatic drugs
erythromycin (macrolides) clindamycin tetracycline chloramphenicol sulfonamides trimethoprim nitrofurantoin
narrow spectrum
only G+ or G-: isoniazid against mycobacterium
extended spectrum
G+, some G- i.e. ampicillin
broad spec
wide variety of G+ and G-: tetracycline, chloramphenicol, imipenem
expense of drug administration
IV>IM>oral (cheapest)
drugs that inhibit synthesis of bacterial cell walls: PCN (B-lactam): natural penicillins
G, V Potassium, G Procaine, G Benzathine, G Benzathine + Penicillin G Procaine
drugs that inhibit synthesis of bacterial cell walls: PCN (B-lactam): Penicillinase resistant Penicillins (anti-staph)
methicillin
nafcillin
oxacillin
drugs that inhibit synthesis of bacterial cell walls: PCN (B-lactam): ext. spec PNC
ampicillin
amoxicillin
drugs that inhibit synthesis of bacterial cell walls: PCN (B-lactam): antipseudomonal
Ticarcillin + clavulanate potassium (Timentin)
Piperacillin + Tazobactam (Zosyn)
drugs that inhibit synthesis of bacterial cell walls: PCN (B-lactam): monobactams
aztreonam
drugs that inhibit synthesis of bacterial cell walls: PCN (B-lactam): carbapenems
Imipenem + Cilastatin
drugs that inhibit synthesis of bacterial cell walls: PCN (B-lactam): B-lactamase inhibitors
Clavulanic acid, Tazobactam
drugs that inhibit synthesis of bacterial cell walls: cephalosporin (B-lactam): 1st gen
Cefazolin
Cephalexin
drugs that inhibit synthesis of bacterial cell walls: cephalosporin (B-lactam): 2nd gen
Cefaclor
Cefoxitin
Cefuroxime
Cefprozil
drugs that inhibit synthesis of bacterial cell walls: cephalosporin (B-lactam): 3rd gen
Ceftriaxone
Cefixime
Cefotaxime
Ceftazidime
drugs that inhibit synthesis of bacterial cell walls: cephalosporin (B-lactam): 4th gen
Cefepime
drugs that inhibit synthesis of bacterial cell walls: cephalosporin (B-lactam): 5th gen
Ceftaroline
other drugs that inhibit bacterial cell wall synthesis
vancomycin
bacitracin
drugs that alter cell membrane permeability
Polymyxin B
Daptomycin
drugs that inhibit bacterial protein synthesis: Tetracyclines
short-acting: Tetracycline
long-acting: Doxycycline, Minocycline
new: Tigecycline
drugs that inhibit bacterial protein synthesis: Macrolides
Erythromycin base " Estolate, " Stearate, " Ethylsuccinate, " Lactobionate Clarithromycin Azithromycin Telithromycin
drugs that inhibit bacterial protein synthesis: Aminoglycosides
Gentamicin; generic: Garamycin, Jenamicin Tobramycin; generic: Nebcin Amikacin; generic: Amikin Streptomycin Neomycin
drugs that inhibit bacterial protein synthesis: Misc.
Clindamycin
Quinupristin/Dalfopristin
Linezolid
act on 50S ribosomal subunit
Cloramphenicol, macrolides, clindamycin, quinupristin/dalfopristin, linezolid
act on 30S ribosomal subunit
Aminoglycosides, Tetracyclines
drugs that act as anti-metabolites: Sulfonamindes
Silver Sulfadiazine (SILVADINE): topical Trimethoprim-sulfamethoxazole
drugs that inhibit nucleic acid synthesis: Fluoroquinolones
Ciprofloxacin (CIPRO)
Levofloxacin (LEVAQUIN)
Moxifloxacin (AVELOX)
Misc. drugs that act via nucleic acids
Metronidazole
Nitrofurantoin
Rifampin
empirical therapy
“best guess” therapy, br. spec/combo abx
guided by Gs, site of inf, clinical experience, local hospital antibiogram susc. reports
-should be changed to rational therapy (narrow spec) when susc. tests performed and org. ID’d
epsilometer (E) test:
also determines MIC, plastic strip containing gradient of known conc. abc placed on agar plate containing pt’s bac. isolate
how to monitor antimicrobial activity in vivo
serum inhibitory titer: greatest dilution of pt’s serum that inhibits visible growth of pt’s infecting pathogen
bactericidal titer: plate out above no-growth samples onto abx-free plates
min. drug conc. at infected site should be..
> = MIC, ideally 2-4x MIC
abscesses must be drained
BBB may prevent..
penetration of drug into CSF
-but during infection BBB is diminished (opened up tight junctions of cerebral capillaries)–>inc. penetration
this may prevent abx penetration to site of action (and dec. levels of free drug)
abx binding to plasma proteins
med doses may need to be adjusted for..
renal/hepatic failure
newborns
oral vs. parenteral admin
bactericidal or bacteriostatic?
cidal is better, esp. if immunecomp
strains of these are resistant to all known drugs
Enterococci
Pseudomonas
Enterobacter
bacterial resistance factors
indiscrim. use (misuse)
delay in optimal tx
admin of subopt. dose
tx during dormant stage
inability to reach inf. site (CNS, eye, prostate, abscess)
defective funct. status of host defense mech
agricult. used of abx in livestock
how microorganisms produce resistance
mutation and selection
i. e. resistance to:
- strep (ribosomal mut.)
- quinolone (DNA gyrase)
- linezolid (rRNA)
- rifampin (RNA polymerase)
- M. tuberculosis
resistance mediated by genetic exchange
HGT:
transformation (PCN res. in pneumo.)
transduction (Staph, penicillinase)
conjugation
conjugation
2 sets of genes transferred: R-determinant (resistance) and resistance transfer factor (RTF)–>ind or combine to for R-factor
- can have >1 abx resis. gene!
- *>50% ppl have int. bac containing R-factors
transposon
DNA sequences that can “jump from place to place”, can carry drug resis. genes
plasmid–>plasmid
plasmid–>chromosome (and vis versa)
biochem mechs of drug resistance
- dec. perm. of org to drug: porins do not allow in anymore (G-) OR active efflux (tetras)
- inactivation of abx by enzymes: (PCN, Chloramphenicol, Aminoglycosides): B-lactamases (+ and -) acetyl/phosphoryl/adenylate drug (amino glycosides, G-)
- altered drug target site: PBP w/ altered affinity for drug, mut. in FQ target (DNA gyrase)
forms of synergism seen with combo abx tx
- block of seq. steps in metabolic pathway (Trimethoprim + Sulfamethosazole–>folic acid)
- inhib. enz. inact. of abx (B-lactamase inhibitor)
- enhanced abx uptake by bac (aminoglycoside + B-lactam)
synergism
4x or greater reduction in MIC or MBC when drug combined
antagonism
> 50% MIC of each drug needed to produce inhibition of growth
antagonism exs.
bacteriostatic antags. bactericidal (need actively growing org) (PCN + chlortetracycline)
induction of enz. inact.: imipenem (induces B-lactamase) + piperacillin (susc. to B-lactamase)
combo abx tx uses
mixed bac inf
unknown specific cause-empirical tx (i.e. pneumonia: macrolides for M. pneumo + ceftriaxone for G-)
synergism may be nec. to kill org. (PCN + AMGS better tx for enterococcal endocarditis)
may prevent resistances (bismuth salts + amos/tetra/or clarithro + metronidazole for H. pylori)
disadv. of combo abx tx
inc. toxic side effects
selection of orgs resis. to >1 abx
possible antag. effect if wrong combo
abx ppx
- post-exposure to certain microorgs: gon, syph, anthrax
- prevent recurrent dis. in susc. pt: artific. heart valve undergoing dental proc. to prevent bac endocarditis, emphysema pts to prevent chron. bronchitis, frequent UTIs
- surgical procedures: 0-2 hrs before, during, 3-4 hrs after
- trauma contam wounds
abx ppx approved surgical procedures
contam, clean-contam operations, dirty wounds, prosthetic placement, immune comp host (any proc)
superinfections
new infection appears during chemotx for other infection
why do superinfections occur?
doses of abx can inhibit NF growth–>other orgs uninhibited
superinfection orgs
enterobacteriaceae, pseudomonas, candida, fungi
inc. risk of superinfection w/
brd spec abx, longer course, oral admin over IM/IV
abx misuse
- for viral infection (fever 2 wks which could be tb, intra-abd. abscess, inf. endocarditis, Ca
- undetermined cause (NOT antipyretics)
- improp. dosage
- abx has to reach inf. site (get rid of pus and kidney stones)
- lack of adeq. bac info: more testing!
- improp. duration of tx (finish your abxs!)
receptors at parasympathetic end organs (and symp. sweat glands)
muscarinic: M1-5, 2,3*most common
B1 adrenergic receptor
heart (inc. force, rate)
kidney (mediate renin secr)
brain
B2 adrenergic receptor
airway, BVs of skel music, pregnant uterus
-smooth musc relaxation
B3 adrenergic receptor
bladder smooth musc: relaxation
a1 adrenergic receptor
most BVs, urinary sphincters, eye
-mediate contraction of smooth musc
a2 adrenergic receptor
some end organs, @ adrenergic nerve endings and in CNS
organs that received both parasym and symp innervation
heart, GI, bladder, eye, etc
organs w/ only symp innervation
adrenal medulla, spleen capsule, pilomotor musc, BVs of skin and skeletal muscd
reserpine blocks adrenergic system..
produces exaggerated cholinergic response: inc. GI motility, secretions
atropine blocks cardiac vagal influence..
cardiac acceleration, reduction of GI motility, secretion
eye sympathetics
a1: mydriasis (dilator musc. of iris)
B2: inc. aqueous humor
gland sympathetics
a, B
B2: respiratory secretions
heart sympathetics
B1, B2:
inc. rate (SA node), contractility (ventricles), automaticity, conduction velocity (SA, AV nodes)
BVs sympathetics (mucosa, saliva, skin, splanchnic)
a1, a2: constriction
BVs sympathetics (skeletal musc)
a1: constriction
B2: dilation
BVs parasyms
no PS inn to most vasc beds, but muscarinic rec are present on endo cells: activation of these receptors: NO-med. vasodilation
airway symps
relaxation: B2
GI symps
relaxation: a1, a2, B1, B2
dec. motility
Urinary bladder wall, sphincter, prostate sympathetics
relaxation: B2, B3 (widens out)
contraction: a1 (sphinter)
kidney JG cell symp
inc. renin secretion: B1
uterus symp
contraction: a1
relaxation: B2 (later on)
male sex organs symp
ejaculation: a1
male sex organs PS
erection
liver, fat cells symp
inc. glucose output: B2
inc. FA output: B1
skin pilomotor music and sweat glands symps
contraction: a1
secretion: muscarinic
eye PS
miosis (pupillary sphincter musc)
accommodation- near vision (ciliary musc.)
PS ciliary musc contraction also…
inc. pressure on trabecular meshwork–>inc. outflow of AH in canal of Schlemm and dec. intraocular pressure
PS action on lacrimal gland
inc. tear production
acetylcholine is formed by action of
choline acetyl transferse (choline + acetate)
ACh pathway
stored in vesicles–>AP–>inc. IC [CA2+]–>storage vesicle fuses with plasma mem–>ACh rel. into synapse–>acts on postmen. rec–>activates transduction pathway–>response
nicotinic rec. usually coupled to
Na+ channels
muscarinic rec may be coupled to
phospholipase C, K+ channels
or act thru G-protein mechanism to inhibit adenylate cyclase
actions of ACh terminated by
acetycholinesterase (rapid hydrolysis) choline and acetate recycle to ACh by presyn. nerve ending
specific sites where drugs can modify cholinergic system
- ACh synthesis
- ACh release
- stim or blockade of postmen. receptors
- inhib. of AChesterase
tyrosine–>DOPA–>DA–>NE
- tyrosine hydroxylase* 2. DOPA decarboxylase 3. Dopamine B-hydroxylase
NE acts on postsyn. rec
a1 or B1–>signal transduction pathway
–>response
Noradrenergic signal transduction pathway
typ. involve G-prot. coupled rec.
B-rec: coupled to adenylate cyclase
a-rec: coupled to pholspholipases or ion channels
NE can also act on
a2 rec on presynaptic nerve ending: feedback inhibition on NE release
action of NE terminated mostly by
rapid reuptake into presyn. nerve ending, med. by high affinity transport pump–>broken down by MAO or requestered in storage vesicles
sites of pharm intervention on Noradrenergic system
- synth, storage, del of NE
- stim or block of postsyn a1, B1, B2
- stim or block of presyn a2 rec
- inhib of NE reuptake
- inhib of NE metab by MAO
direct acting muscarinic agonists
acetycholine (Miochol-E) carbachol (Isopto Carbachol) methacholine (Provocholine) bethanechol (Urecholine) pilocarpine (Salagen/Ocusert Pilo) cevimeline (Evoxac)
indirect acting drugs: cholinesterase inhibitors -reversible
edrophonium (Tensilon) physostigmine/eserine neostigmine (Prostigmin) pyridostigmine (Mestinon) rivastigmine (Exelon) donepezil (Aricept) carbamate insecticides (Carbaryl)
indirect acting drugs: cholinesterase inhibitors-irreversible
DFP/diisopropylfurophosphate/isoflurophate and echothiophate
organophasphate insecticides (Parathion, Malathion)
nerve gases in chem warfare (Sarin, soman, Tabun, Vx)
indirect acting drugs: cGMP phosphodiesterase (PDE-5) inhibitors
sildenafil (Viagra)
vardenafil (Levitra)
tadalafil (Cialis)
Cholinesterase Reactivator
pralidoxime/2-PAM (Protopam)
Toxins
botulinum toxin (BOTOX)
Muscarinic ANTAGONISTS (anticholinergics)
atropine (hyoscyamine) and homatropine scopolamine and methscopolamine dicyclomine (Bentyl) propantheline glycopyrrolate (Robinul) ipratropium (Atrovent) tiatropium (Spiriva) benztropine (Cogentin) trihexyphenidyl (Artane) tolterodine (Detrol) oxybutynin (Ditropan) solifenacin (VESIcare) tropicamide (Mydriacyl)
Botulinum toxin (BOTOX) acts by
inhib. syn/rel of ACh
M1 rec
in symp. gang and myenteric plexus, unclear function
possibly stomach: med gastric acid sec
M2 rec
located in heart, some smooth musc
M3 rec
glands, smooth musc, BVs
ACh stimulated muscarinic rec in what kind of manner
dose/conc. dependent, relatively nonselective
Nm vs Nn rec.
Nm rec. located on sk. music at NM junc, Nn rec. located in autonom ganglia and adrenal medulla
at low/mod doses ACh…
at high doses…
-stim both types nicotinic receptor
-desensitizes rec at high conc.–>gang. blockade, muscle paralysis
(in contrast to muscarinic: no desensitization, just plateau)
PS heart
atria, SA node, AV node, minor to ventricles
- dec. HR by slowing firing of SA nodal pacemaker cells and slowing AV conduction
- only min. effects on ventricular contractility and automaticity
PS BVs
not inn. by PS, but endothelial cells in most BVs do contain muscarinic rec., stim. by ACh or muscarinic agonists–>NO (cGMP) med vasodilation–>dec. in BP
-enhanced by cholinesterase inhibs like edrophonium, blocked by muscarinic antagonists such as atropine
BVs that receive more PS inn.
corpus cavernosum, some cerebral, coronary, skeletal musc. BVs
PS eye
pupillary constrictor muscles: miosis
ciliary muscle: accommodation
-lowered IOP (outflow of AH)
PS smooth muscle
bladder, stomach, sm. intestine, bowel, etc.
-typ. stim. contraction of sm. musc to increase motility
PS glands
salivary, lacrimal, mucosa of GI, airway, etc.
-stimulate secretions (muscarinic ANTAGONISTS have drying effect)
PS airways
bronchoconstriction and inc. respiratory secretions
-
Muscarinic ANTAGONISTS useful in asthma tx
ipratropium (Atrovent) tiatropium (Spiriva)
muscarinic agonist or cholinesterase inhibs. can aggravate asthma
PS GI
stimulate GI motility and secretion
also reg by “enteric NS”
PS NM junction
ACh released by motor neurons can act on nicotinic rec. at motor end plate to cause musc. contraction
- receptors are DESENSITIZED if excess ACh (i.e. high dose cholinesterase inhib.)–>musc. paralysis
- exogenously admin. ACh has little effect on skel. musc.
- nicotinic effects can be inhib by ganglionic and NM blockers
direct acting muscarinic agonist activity
inc. GI motility, secretion
dec. HR
dec. BP due to dec. CO and direct vasodilation
contraction of bladder, relax. of ur. sphincters
miosis and dec. IOP
stim of secretions
adverse effects of muscarinic stimulation
hypotension, bradycardia, chronchoconstriction, diarrhea, cramping, urinary incontinence, excessive sweating, salivation
major tx uses of muscarinic agonists
promote GI motility (bethanechol)
tx urinary retention (bethanechol)
tx of glaucoma (pilocarpine, acetylcholine, carbachol)
tx of sal. gland dysfunc (pilocarpine, cevimeline)
pulmonary function testing in asthma (methacholine)- dangerous dx test
when muscarinic agonists are contraindicated/used w/ caution
asthma, bradycardia, hypotension, vasomotor instability, CAD, peptic ulcer disease, hyperthyroidism, weakened smooth musc of bladder/GI, urinary/intestinal obstruction
DO NOT give choinesters..
IV or IM, but rather subQ, orally, topically(eye)
acetylcholine
limited, tx for glaucoma
–>rapidly hydrolyzed by pseudocholinesterase in plasma
carbachol
analog of ACh, resistant to hydrolysis
- stim both muscarinic and nicotinic
- topically for glaucoma
methacholine
ACh analog, stim muscarinic (little nicotinic effect)
used in asthma pulmonary function testing
bethanechol (Urecholine)
ACh analog, resis to hydrolysis, direct muscarinic agonist (little nicotinic effect)
stim. GI motility and tx for urinary retention
pilocarpine (Salagen, Ocusert Pilo)
muscarinic agonist, tx for glaucoma and xerostomia (dry mouth) due to poor salivary secretion
cevimeline (Evoxac)
muscarinic agonist, tx for salivary gland dysfunction
muscarine
natural in mushrooms (Inocybe and Clitocybe)
- salivation, lacrimation, nausea, extreme GI hypermotility, bronchospasm, bradycardia, hypotension, shock
- can be tx with high dose atropine (1-2 mg IM every 30 min)
cholinesterase inhibitors have similar effects as muscarinic agonists, plus
stimulation of skeletal muscle–>paralysis of skeletal muscles @ toxic doses
toxic effects of cholinesterase inhibitors (cholinergic crisis)
i. e. organophosphate insecticide/nerve gase poisoning
- SLUDGE (salivation, lacrimation, urination, defection, GI distress, emesis)
- skel musc fasciculations–>paralysis
- bradycardia, hypotension, shock
- severe miosis
- CNS stimulation and seizures–>coma
- chronic exposure to some–>demyelination of axons and various neuropathies
tx of acute cholinesterase inhibitor poisoning
- administer high doses atropine (2-4 mg IV initially) followed by 2 mg IM every 10 min until symptoms disappear to block muscarinic receptors
- admin pralidoxime to reactivate enzyme (effective w/ organophosphates only)
- provide additional symptomatic tx as needed (i.e. diazepam for seizures)
major tx uses of cholinesterase inhibitors: myasthenia gravis
dx: endrophonium test
tx: pyridostigmine, neostigmine
MG is AI against nicotinic rec. at motor end plate
Tensilon Test
admin 2-8 mmg edrophonium; improvement in musc. strength suppors myasthenia gravis dx
if musc. wkns worsens: indicative of musc. wkns from exc. doses other cholinesterase inhibitors (cholinergic crisis)
- 5 min duration of action
other (more commonly used) myasthenia gravis dx tests
electromyography (EMG)
serology
cholinesterase inhibitors: tx of glaucoma
cholinergic agonists (acetylcholine, carbachol, pilocarpine) cholinesterase inhibitors (echothiophate) again..these contract ciliary musc-->put tension on trabecular meshwork-->inc. outflow of AH through canal of Schlemm
cholinesterase inhibitors: tx of Alzheimer’s
loss of cholinergic neurons (Nucleus basal is of Meynert)–>raise ACh levels and reverse deficit
tetrahydroaminoacridine (Tacrine)* original, but causes liver damage
rivastigmine (Exelon)
donepezil (Aricept)
galantamine (Reminyl)
other uses of cholinesterase inhibitors
- tx of poisoning by atropine/other antimuscarinic drugs: physostigmine
- reversal of NM blockade by nondepol. NM blockers: neostigmine, pyridostigmine
- tx of atony of bladder or GI tract (i.e.: urine retention, paralytic ileus, etc)
- pyridostigmine used by military to protect against nerve gas: ““pre-exposure antidotal enhancement”
CI’s and precautions in cholinesterase inhibitor use
asthma
bradycardia, hypotension, CAD
peptic ulcer disease
urinary or intestinal obstruction
reversible cholinesterase inhibitors, quaternary ammonium compounds- cannot enter CNS
edrophonium (Tensilon), neostigmine (Prostigmin) pyridostigmine (Mestinon)
reversible cholinesterase inhibitor, nonquaternary-so able to enter CNS
physostigmine/eserine (Antilirium)
tx for atropine/other antimuscarinic agent poisoning
(fallen into disfavor, esp. with tricyclic antidep. OD)
Organophosphate insecticides
parathion, malathion
–>need to be oxidized to active metabolites (paroxone and malaoxone) happens faster in insects, cannot detoxify
(but can still cause toxicity in humans)
-can be absorbed thru skin
-S&S typical of cholinesterase inhibs.
-tx poisoning w. atropine, pralidoxime (& other sympt. support)
Carbamate insecticides
carbaryl
- absorbed less thru skin
- tx poisoning w/ atropine, pralidoxime is NOT useful in tx of carbamate insecticides!
DFP/Isoflurophate and Nerve Gases
Sarin
potent, toxic, irreversible cholinesterase inhibitors
-S&S typ. for cholinesterase inhibs.
-tx poisoning w/ atropine and pralidoxime
-DFP/Isoflurophate: glaucoma tx
Pralidoxime/2-PAM (Protopam)
cholinesterase reactivator! binds phosphate grp that inhib. enzyme thereby regenerating enzyme
- antidote for orgphos poisoning w/in 2 hours of exposure
- does not work with carbamate insecticides
ED drugs
Sildenafil (Viagra)
Vardenafil (Levitra)
Tadalafil (Cialis)
-NO activates guanylcyclase in vasc. sm musc to produce cGMP–>vasodilation–>erection
-drug inhibits cGMP phosphodiesterase type 5 (PDE-5) which breaks down cGMP
ED drug side effects/toxicities
- general vasodilation–>hypotension–>reflex inc. in HR (problem for men w/ CV disease)
- visual distrubances: blue/green discrim. probs
- auditory disturbances
ED pharmacokinetics
oral admin, sildenafil and vardenafil onset: 30 min, pk plasma levels about 1 hr, duration 4 hrs
tadalafil longer 1/2 life, onset 45 min, and duration about 36 hrs
-metabolized by CYP3A4: potential for drug interactions
-dosage adj. for renal/hepatic disease pts
ED drug interactions
erythromycin, ketaconazole, cimetidine, others metabolized by CYP3A4
vasodilators (nitrates, Ca2+ channel blockers, a1 blockers)
sympathomimetics
botulinium toxin
produced by Clostridium botulinium
- rel. of ACh from nerve endings–>affects both autonomic nerve endings (antichol. effects) and NM junction (paralysis)
- death from diaphragmatic paralysis, 0.5-1.0 ug dose may be fatal
tx: sympt. support (resp) + abx to toxin - med uses: optham. disorders, wrinkles (BOTOX), dystonia, exc. sweating, over-active bladder
anticholinergic pharm effects
competitive antagonists at muscarinic receptors
- drying of secretions
- dec. tone and motil. of GI tract
- relax. of bladder and urine retention
- bronchodilation
- mydriasis w/ cycloplegia (loss of accomm.) and inc. in IOP
- inc. HR (*atropine may cause initial slight bradycardia)
- CNS: sedation and amnesia at low doses; excitation and seizures at toxic doses
- quaternary salts do NOT produce CNS effects
therapeutic uses of anticholinergics part 1
- GI disorders
- urine incontinence
- opth: mydriatic agents (*do NOT use in pts w/ glaucoma!)
- anesthesiology to reduce vagal tone on heart and dry secretions; also to prevent muscarinic side effects when cholinesterase inhibs used to reverse effects of NM blockers
- antidote for poisoning with cholinesterase inhibs. or muscarinic agonists (some mushroom poisoning)
therapeutic uses of anticholinergics part 2
- prevent motion sickness (Scopolamine)
- Parkinson’s (benztropine, trihexyphenidyle, diphenhydramine)
- dental proc. to inhib salivation (atropine, glycopyrrolate)
- cardiac stim in emergencies (atropine)
- asthma and COPD (ipratropium, tiatropium)
- pulmonary med to dry resp secretions
anticholinergic side effects/toxicities
dry mouth
dry, hot skin
constipation, urine ret.
visual disturbances, blurred vision, photophobia
CNS effects: sedation, confusion, amnesia (elderly)
anticholinergics/muscarinic antagonist
CIs/precautions
glaucoma (esp. narrow angle)
prostatic hypertrophy
CV instability
severe ulcerative colitis
acute antichol. poisoning
dry, hot skin/ hyperthermia
severe mydriasis, blurring, photophobia
CNS stim: agitation, halluc, seizure–>coma–>death
cessation of GI motility (no bowel sounds)
weak rapid pusle, tachy, arrhyths.
tx of acute antichol. poisoning
admin of physostigmine or other cholinesterase inhibitors
benzos for seizure tx
ice baths to cool down, keep pt in dark, quiet area
other drugs with anticholinergic side effects
antihistamines, antipsychotics, antidepressants, etc.
atropine (Hyoscyamine) and Homatropine
-belladonna alkaloid found in nightshade (Atropa belladonna) and jimsonweed, mixture of d, l* -hyoscyamine
(semi-syn. analog), methylbromide salt does NOT penetrate CNS
prototype antimuscarinic
atropine effects: heart
tachycardia w/ slight inc. CO (may have transient bradycardia)
tx for MI w/ inc. vagal tone: low CO and dec. BP
atropine effects: BVs
can reverse hypotensive actions of acetylcholine/other muscarinic agonists
cutaneous vasodil and flushing of skin
atropine effects: eye
- mydriasis
- cycloplegia (paralysis of accomm.)
- inc. IOP
atropine effects: GI tract
inhib. motility and tone (antispasmodic action for IBS)
need high dose to dec. acid sec, so H2-histamine blockers (cimetidine, ranitidine, nizatidine, famotidine, or PPIs) used for peptic ulcers instead
atropine effects: urinary tract
relaxes bladder body and contracts sphincter–>retention
tx incontinence, CI in prostatic hypertrophy
atropine effects: sweat glands
blocks muscarinic rec.–>inhib sweating–>rise in body temp
*children extra sensitive
atropine effects: salivary glands
inhib. saliva sec. “dry mouth”
atropine effects: respiratory tract
dries secretions, bronchodilation
atropine effects: CNS
depressant (low doses) and stimulation (hight doses): agitation and seizures
mod-high: hallucinogenic
atropine tx uses
- preop to red sec (old) and block vagal ref on heart (new)
- cardiac stim post-MI
- antidote for poisoning with cholinesterase inhib/musc. agonists
- to dry resp. sec
- mydriatic and cycloplegic
- antispasmodic for GI: IBS, biliary colic
at 0.5 mg atropine
some cardiac slowing, mouth dryness, sweating inhib
1.0 mg atropine
def dry mouth, thirst, heart accel. (slowing 1st), mild pupil dilation
2.0 mg atropine
rapid HR, marked dry mouth, dil. pupils, blurred near vision
5.0 mg atropine
all above + diff speaking/swallowing, restless, fatigue, HA, dry, hot skin, diff mictur., red intestinal peristalsis
10.0+ mg atropine
all above + more marked, pulse rapid/wk, iris almost obliterated, vision v. blurred, skin flushed, hot dry, scarlet, ataxia, restless, excitement, hallucinations, delirium, coma
Scopolamine (hyoscine) and Methscopolamine
-plant Hyoscyamus niger (henbane), chem sim to atropine
quarternary analog, does NOT cross BBB
-sim to atropine but more of CNS depressant (sed/amn) than atropine
-oral and patch form (Transderm Scop) for pref of motion-sickness, vertigo
Dicyclomine (Bentyl)
nonquart. antimuscarinic
- used as intestinal antispasmodic for IBS tx
Propantheline (Pro-Banthine)
antimuscarinic
-antispasmodid, IBS tx
quaternary comp. w/ few CNS effects
Glycopyrrolate (Robinul)
quart. antimuscarinic (no CNS effects)
- used in anesthesiology as prep med to dry resp. sec and inhib vagal reflexes
- also used as gen purpose antimuscarinic
Ipratropium (Atrovent)
Tiatropium (Spiriva)
aclidinium (Tudorza)
antimuscarinics
quat. salts admin. by inhalation for asthma and COPD tx
few systemic effects
tiatropium longer duration than ipratropium
aclidium: new drug approved for COPD (long acting in lungs, broken down by esterases in plasma: few systemic effects)
Benztropine (Cogentin)
Trihexyphenidyl (Artane)
centrally acting antimuscarinics used in Parkinson’s/drug-ind. Parkinsonism tx
Tolterodine (Detrol)
Oxbutynin (Ditropan)
Solifenacin (VESIcare)
antimuscarinics, tx of urinary incontinence due to overactive bladder
Tropicamide (Midriacyl)
antimuscarinic used to dilate pupil for examination
first gen H1 antagonists: v. sedating antihistamines
Promethazine hydrochloride (Phenergan) Hydroxyzine (Vistaril)
first gen H1 antagonists: sedating antihistamines
Diphenhydramine (Benadryl) Dimenhydrinate (Dramamine) Doxylamine (Unisom) Chorpheniramine maleate (Chlor-Trimeton) Meclizine (Bonine, Antivert)
second gen H1 antagonists: non-sedating antihistamines
Loratadine (Claritin, Alavert)/Desloratidine (Clarinex)
Certirizine (Zyrtec) and Levocetirizine (Xyzal)
Fexofenadine (Allegra)
H2 antagonists
Cimetidine (Tagamet)
Ranitidine (Zantac)
Famotidine (Pepcid)
Nizatidine (Axid)
histamine functions
mediates phys. resp to tissue/cell injury
mediates inflamm. resp/allergic reactions
reg. cell growth/repair
reg. gastric acid sec
NT in CNS
pos. reg. of cardiac functions
histamine syn
syn from histidine by histidine decarboxylase
histamine metab
involved N-methylation–>oxidation to N-methylimidazole acetic acid
histamine storage
mast cells and basophils
skin and mucosa of GI and resp tracts
IC histamine stored in granules, loosely bound to proteoglycans like heparin sulfate or chondroitin sulfate
histamine release: drug/chem induced
- displaced by amine drugs (morphine, tubocurarine, B-blockers)
- compound 48/80
- toxins and venoms
histamine release may released in response to
cell/tissue damage
histamine release: immunologic stimulation
mast cells sensitized w/ IgE Abs–>rel. histamine when exposed to approp. allergen
-other autocoids syn or del: PGs, LKTs, kinins (bradykinin)
histamine release: neuronal and endocrine stimulation
gastric mucosa: rel in resp to neuronal (vagal)/endocrine stim (gastrin)
-neuronal med. by ACh
-the histamine binds to H2 rec on parietal cells–>HCl sec–>permissive effect, allows gastrin and acetyl choline to directly stim. acid secretion
(H2 rec ANTAGONISTS are effective in red. sec of gastric acid in response to histamine, vagal stim, ACh, or gastrin)
physio effects of histamine
- dil of small BVs–>flushing, lowered peripheral resistance, drop in BP
- inc. in cap perm–>leakage of fluid and prot. into extravascular space
- stimulation of peripheral nerve endings–>pain, burning, itching
physio effects of histamine: triple response
- red spot (dil. of minute BVs)
- flare (dil. of neighboring arterioles)
- wheal (inc. cap permeability)
physio effects of histamine: histamine shock
vasodilation and fluid leakage into EV space–>sig. drop of BP (resembles traumatic, septic, or hemorrhagic shock)
physio effects of histamine: bronchial constriction
asthmatic and anaphylactic bronchospasm
-not completely dep. on histamine, so not effectively antag. by antihistamines alone (use sympathomimetic drugs, methylaxanthines)
physio effects of histamine: stimulation of gastric acid secretion
in response to stress, vagal stim, gastrin and cholinergic agonists
-mediated by H2 rec. (blocking these red. stomach acid sec.)
physio effects of histamine: cerebral vessels and histamine
-v. sens to histamine!–>intense diation–>pulsatory HA (stretching of sensory nerve endings-histamine cephalgia)
(attempt to antag H1 and H2 rec, little success)
physio effects of histamine: direct effects on heart
inc. force of contraction
slowing of AV conduction
H1 receptor
- skin, BVs, heart, airway, CNS
- mediate rapid vasodil., inc. cap perm, irritation of peripheral nerve endings, bronchoconstriction
H1 receptor blockers/histamine antagonists
“antihistamines”, tx allergies, rhinitis
actually inverse agonists: red. activity of constitutively act. H1 rec.
H2 receptor
- GI, heart, brain, various BVs
- mediated gastric acid secretion
H2 receptor blockers
- reduce gastric acid sec. (peptic ulcer disease)
- may be used to tx histamine-induced symps of Type 1 immediate hypersensitivity rxns (urticaria)
H3 receptors
- CNS
- presyn. autoreceptors to reg rel of histamine as NT (like alpha adrenergic rec?)
- no sp. drugs for clinic use (potentials: sleep/mood disorders, Alzheimer’s disease)
H4 receptors
- hematopoetic cells
- unclear, inflammation
therapeutic uses of histamine
few
dx tests for allergies, asthma, and sensory nerve function
structure of antihistaminic drugs: H1
lipophilic ring structure + charged side chain amino group
structure of antihistaminic drugs: H2
hydrophilic ring structure + uncharged side chain
1st gen H1 antagonists: v. sedating
Promethazine hydrochloride (Phenergan) Hydroxyzine (Vistaril)
1st gen H1 antagonists: sedating
Diphenhydramine (Benadryl) Dimenhydrinate (Dramamine) Doxylamine (Unisom) Chlorpheniramine maleate (Chlor-Trimeton) Meclizine (Bonine, Antivert)
2nd gen H1 antagonists: non-sedating
Loratadine (Claritin, Alavert)/Desloratidine (Clarinex)
Certirizine (Zyrtec)/ Levocetirizine (Xyzal)
Fexofenadine (Allegra)
H1 antagonist pharm effects
occupy H1 rec w/out prod/initiating active response (competitive antagonism) OR inverse agonism
- reduce pain, itch, flare, vasodilation, inc. vasc. perm (red), congestion
- DO NOT prevent release of histamine/other inflamm/allerg mediators
- DO NOT reverse anaphylactic bronchospasm
uses of H1 antihistamine: allergy tx
hay fever (seasonal) rhinitis
relief of sneezing, wheezing, eye/nose/throat itch, rhinorrhea
certain allergic dermatitis (urticaria) (i.e. diphenhydramine in “anti-itch” topical meds)
alone, H1 antihistamines are NOT effective in..
anaphylaxix, angioedema, asthma
*bronchospasm may be life threatening, should be tx w/ epinephrine or other B-agonists, H1 antihist can be adjunct
uses of H1 antihistamine: common cold tx
alleviate nasal irritation (burning, itching, “runny nose”)
DO NOT alter course of cold
uses of H1 antihistamine: antiemetics
(dimenhydrinate, meclinzine): prevent and tx motion sickness/vertigo
(doxylamine) : sometimes to tx N/V during pregnancy
- may be more general anti emetics (3 above + hydroxyzine)
uses of H1 antihistamines: sedative and sleep aids
- night time cold remedies (Nyquil) and sleep aids
- Hydroxyzine (Atarax: Vistaril): sedatives
- Diphenhydramine, doxylamine: OTC sleep aids
uses of H1 antihistamines: antisecretory agents
(diphenhydramine) used in pulmonary medicine (tracheostomy care, etc)
uses of H1 antihistamines: Parkinsonism tx
anticholinergic activity (diphenhydramine)
side effects/toxicities of H1 antihistamines
anticholinergic: dry mouth, dry/hot skin, constipation, urine retention, loss of visual accomm. etc.
sedation drowsiness, confusion, amnesia, behavioral disturbances occur at common therapeutic doses
*may be more pronounced in elderly
*2nd gen (loratidine, fexofenadine, ceirizine) less CNS effects and sedation
more side effects/toxicities of H1 antihistamines
- paradox. CNS stim in some (esp. kids)
- reported teratogenic effects (doxylamine story)
- allergic rxns (topical use)
- lowers seizure threshold
- serious arrhythmias (Astemizole, terfenadine -w/drawn)
even more side effects/toxicities of H1 antihistamines
-acute poisoning/OD (kids esp):
symptoms like atropine poisoning: excitation, halluc., ataxia, uncoordination, convulsion, musc tremors, uncontrollagle clonic/tonic jerky motions, fixed dil. pupils, flushed face, fever, coma, cardio-resp collapse and death
tx: symptomatic: cholinesterase inhibitors (physostigmine), anti-seizure, CV meds as needed
antihistamine pharmacokinetics: admin
oral*, parenteral, topical
oral:
onset: 15-30 min, pk: 1 hour, duration 3-6 hours
degraded in body, excr. w/in 24 hours
*no cumulative effect if liver/kidneys are functional
2nd gen antihistamine pharmkin.
DO NOT cross BBB, do not cause sedation
longer durations of action (about 24 hrs), long 1/2 lives: wk+ to reach steady state
antihistamine drug interactions
- potentiates CNS depressants, etOH, barbs, opioids, benzos
- arrhythmias (torsades de pointes) in pts taking terfenadine or astemizole (metab by P450: CYP3A4 to active drug) w/ erythromycin, ketoconazole, or itraconazole
- the antihist. prodrug can block K+ channels in heart, not all prodrug broken down when taken w/ other drugs metabolized by CYP3A4
- both terfenadine (Seldane) and astemizole (Hismanal) w/drawn (Allegra, flexofenadine) is active metab of terfenadine
antihistamines can interfere w.
allergy testing, must stop antihistamine 5-7 days before testing
antihistamine combo preps
in cold, cough, allergy remedies
-decongestants, analgesics, antitussives, etOH, w/ the antihistamine
H2 histamine antagonists summary
comp. antags at H2 rec
tx for peptic ulcer disease
H2 histamine antagonists
Cimetidine (Tagamet)* cytP450 metab., anti-androgen
Ranitidine (Zantac)
Famotidine (Pepcid)
Nizatidine (Axid)
H2 histamine antagonist pharm effects
- inhib gastric acid secretion (stim. by histamine) in response to:
- vagal stimulation (ACh)
- gastrin secretion (ZES: tumor)
- stress
H2 histamine antagonists tx
- duodenal/gastric ulcers
- gastroesophageal reflux
- ZES
- pre-op to lessen aspiration damage
- prevent stress ulcers
H2 histamine antagonist adverse rxns
(low: highly selective @ H2 rec)
- HA, dizzy, nausea, myalgia, skin rashes/itching (elderly, renal dysfunction)
- loss of libido, impotence, gynecomastia (chronic high does of Cimetidine–>can tx hirsutism)
- Cimetidine also can cause hematological rxns (cytopenias) and competes w. creatinine for renal secretion (inc. plasma conc. creatinine)
H2 antagonist pharmkin
- oral admin–>well absorbed
- 1/2 lives about 2-4 hrs
- also injectable: cimetidine, ranitidine, famotidine
- metab by liver (cimetidine can inhib cytP450 and interfere w. metab of other drugs)
- sig. amounts excr unchanged in urine (adj. dose in renal disease pts.)
H2 antagonist drug interactions
Cimetidine: inhib hep microsomal drug metab enzymes:
warfarin, phenytoin, theophylline, phenobarbital, benzos, propranolol, nifedepine, digoxin, quinidine, tricyclic antidepressants
(Famotidine and nizatidine do not inhib P450 system, ranitidine has slight effect, not sig.)
-H2 blockers alter gastric pH: alter bioavailability of certain drugs
H2 antagonist therapeutic uses
gastric/duodenal ulcers, ZES, stress ulcers, reflux esophagitis, short bowel syndderom, hypersec. states (ZES), preanesthetic meds
- typ. not frontline drugs, PPIs used more commonly
- *cimetidine is most widely used, but potential for most side effects/drug interactions
CRTZ
-floor of 4th ventricle, area postrema
-vomiting assoc. w. exposure to drugs, metabolic toxins, chemotherapy, radiation, changes in blood chemistry
NTs: DA, 5HT (serotonin) so tx w/ DA/serotonin antagonists
Dopamine antagonists: tx CRTZ induced N/V, NOT motion sickness/vertigo
serotonin also
NT action: is released by enterochromafin cells of GI tracts when GI distress (5-HT3 rec blockers prevent N/V)
vestibular apparatus and cerebellum
respond to motion (or “perceived” motion)
NTs: ACh and possibly histamine (inhibitors tx)
anticholinergics/antihistamines: tx motion sickness, vertigo NOT other causes of N/V (antihist. have some effect on CRTZ and vomiting center, but less eff. than DA antags)
cerebral cortex and limbic system:
vomiting ref. activated by emotional state (can be consciously suppressed): anxiolytic agents
efferent component of reflex
output from vomiting center–>salivary glands, stomach, sm. intestine, diaphragm, abd. mm
anticholinergic agents for nausea
Scopolamine
- acts on vestibular system, tx/prevents vertigo/motion sickness
- gen. effects on CRTZ, not as effective as DA, 5-HT untags
- Transderm Scop preperation
Scopolamine side effects/toxicity
- antichol. effects: dry mouth, constip, urinary retention, loss of accomm.
- sedation, confusion, amnesia
antihistamine for N/V effects
- primarily on vestibular, some have weak effects on CRTZ or vomiting center (cyclizine, doxylamine, meclizine, promethazine, hydroxyzine) (b/c of antichol. activity?)
- tx for motion sickness/vertigo
- some for gen. antiemetic (cyclizine, meclizine, promethazine, hydroxyzine)
antihistamine side effects/toxicity
antichol. effects, sedation, teratogen effects?
antihistamines for N/V
dimenhydrinate (Dramamine) meclizine (Bonine, Antivert) promethazine (Phenergan) diphenhydramine (Benadryl) doxylamine (Bendectine: teratogen? no-->now Diclegis)
Dopamine (D2) antagonists action
acts on CRTZ, tx:
postop nausea, cytotoxic drugs, radiation sickness, toxins
DA (D2) antagonist side effects/toxicity
parkinsonism (blocks striatum), post. hypotension, anticholinergic effects, sedation, lethargy, psychomotor slowing (antipsychotics), possible teratogen
D2 antagonists for N/V
prochlorperazine (Compazine) -phenothiazine
metoclopramide (Reglan)
metoclopramide (Reglan) for N/V
DA antag in CRTZ but also acts on enteric nerves to inc. GI/lower eso. sphincter tone and motility
tx: N/V from chemo, postop, toxin-induced, radiation
tx: gastric stasis, GERD, possible aspiration of vomitus
metoclopramide (Reglan) side effects
sedation, extrapyramidal motor problems: parkinsonism and acute dystonia
5-HT3 antagonists (serotonin) for N/V
ondansetron (Zofran)
granisetron (Kytril)
dolasetron (Anzmet)
5-HT3 antagonist actions
tx: N/V from chemo, postop; effective in about 80% pts
- depress CRTZ and inhib serotonin mediated afferent input from GI tract
- may be given orally/IV, metab by hepatic microsomal enzymes (drug interactions)
- adverse effects: HA, constipation
cannabinoids for N/V
dronabinol (Marinol): d-9-THC (marijuana)
-oral oil capsule
tx for N/V in chemo (back-up drug), prevent wasting “kekexia” in AIDS pts.
*smoking may be more effective than oral, bypass liver and produces combustion products
cannabinoid side effects
sedation, confusion, disorientation, loss of control, alt. sensations, paranoia, psychotic rxns (not tol. well in some esp. elderly)
corticosteroids for N/V
dexamethasone, prednisone, methylprednisolone
-adj. antiemetics in chemo regimens
P/neurokinin rec (NK1) antagonist for N/V
aprepitant (Emend)
tx: N/V from chemo, v. expensive, not 1st line
pyridoxine (vit B6) and doxylamine
Bendectine: terotogen scare in 80’s–>unfounded–>now Diclegis (2013) for N/V during pregnancy
amphetamine
- some benefits in preventing motion sickness, can counteract sedative effects of other drugs
- not typ. used: CNS effects, abuse potential
other antiemetics
- phosphorylated carb. solutions (Emetrol), cola syrups
- antimicrobial agents
- antianxiety drugs: benzos for N/V from fear, anxiety
- ginger
antiemetics for motion sickness/vertigo
antihistamines, anticholinergics
antiemetics for postop
DA or 5-HT3 antagonists
antiemetics for radiation sickness
DA antagonists
antiemetics for drug-induced vomiting
DA / 5-HT3 antagonists, cannabinoids
antiemetics for pregnancy
try to avoid drugs, diet modification
pyridoxine +/- doxylamine–>antihistamine–>DA antagonist (avoid 5-HT3 antagonists)
cough reflex controlled by….
receives input from..
responds to..
cough control center
input from pharynx, larynx, airway, lungs
stretch (distension), presence of particulate matter, chem. irritation
afferent impulses from receptors sent to cough control center via
glossopharyngeal and vagus nn.
efferent component of cough reflex
epiglottis, pharynx, larynx, lungs, diaphragm, mm. of thorax/abdomen
-cough mech can be activated and suppressed (to some extent) consciously
rationale for antitussive therapy
- remove cause of irritant
- inc. airway sec. to mobilize irritants (expectorant)
- desens. peripheral rec.
- act on CNS component
antitussives that act on cough control center: opioids
codeine, hydrocodone, etc.
- prob. most effective, given at lower doses than for pain
- side effects: sedation, lightheaded, confusion, nausea, dizzy, constipation, abuse, physical dependence
antitussives that act on cough control center: non-opioids
dextromethorphan (syn. analog of levorphanol)
-effective as codeine for mild-mod cough, not as eff. for severe cough
-block NMDA rec
side effects: mild; sedation, dizzy confusion
-no analgesic effects, lower abuse potential
non-opioid antitussives
dextromethorphan:
Benylin DM, Pertussin, Vicks Formula 44, etc. OTC
*may be abused in higher doses (kids, i.e. cough syrup)
agents that act on airway receptors
benzonatate (Tessalon):
-local anesthetic, desens. airway receptors
-some effect on CCC, capsule for oral use
-side effects: mild: constipation, nasal cong., nausea, drowsiness, rashes
menthol (in many preps)
antitussives: expectorants
guaifenesin: questionable efficacy
mild irritants in GI tract–>activates reflex–>inc. mucus production in airway
antitussives: mucolytic agents
acetylcysteine (Mucomyst) (nebulization)
disrupts disulfide linkages–>inc. mucus viscosity, breaks mucus plugs–>easier to mobilize, humidifies air
antitussives: mucolytic agents tx
postop, tracheotomy care, sever bronchitis, emphysema
*antidote in Tylenol (acetaminophen) poisoning (Acetadote)
antitussives: antihistamines
diphenhydramine, promethazine, etc (in many cough/cold remedies)
-antag effects of histamine–>dec. irritation/constriction of airway–>also sedation and weak effects on CCC
antitussives: bronchodilators
dec. airway resistance (asthma)
antitussives: demulcents
“syrupy” materials that exert coating and soothing action (cough preps)
should cough be tx?
- cough is useful if productive
- tx in pts w/ hernias, CV probs, postop/trauma
mild-mod cough tx
dextromethorphan
severe cough tx
codeine (or other opioid)
if overly productive cough, consider a prep with
antihistamine
antitussives may be combo of
antihistamines, expectorants, decongestants, acetaminophen, etOH
direct acting sympathomimetics (adr. rec agonists): mixed, nonselective agonists
epinephrine (adrenalin, EpiPen, Auvi-Q)
NE (Levophed)
Isoproterenol (Isuprel)
DA (Intropin)
selective B1 agonists
dobutamine (Dobutrex)
selective B2 agonists
albuterol (Proventil) Metaproterenol Pirbuterol (Maxair) Salmeterol (Serevent) Terbutaline
selective B3 agonists
Mirabegron (Myrbetriq)
Solabegron
selective a1 agonists
phenylephrine midodrine (ProAmantine)
indirect-acting sympathomimetics (next exam?)
cocaine
pseudoephedrine (Sudafed) ephedrine
amphetamine and methamphetamine
methylphenidate (Ritalin)
NE and E released from
adrenal medulla (E>NE) pheochromocytoma cells (NE>=E)
pheochromocytomas tx w.
metyrosine: sp. tyrosine hydroxylase inhibitor
extrasynaptic receptors
a2, B2
activated pref. by circulating NE > NE from nerve endings
intrasynaptic receptors
a1, B1
activated by NE from nerve endings, would need ^^^ conc. circ. NE to be stimulated
more intra>extrasynptic receptors
(narrow syn. space, reuptake pump)
inactivation of NE or E
MAO–>deaminated metabolites
COMT–>O-methylated metabolites
Vanillylmandelic acid (VMA) is a deaminated AND o-methylated metabolite
high urine levels of these are dx for pheochromocytoma
metanephrines and/or VMA
pts on these meds will experience more intense effects of symp. drugs
MAO inhibitors
these vessels typ. do not become highly constricted during sympathetic activity (a rec. agonist admin)
coronary and cerebral vasc. smooth muscle
fewer in #, receive less symp. neural traffic, powerful authoreg. capabilities
dopamine receptors are present here to mediate vasodilation
renal and other splanchnic (gut) beds
normal resting symp. nerve activity is
10-20% of max
-maintains BP, body temp
(i.e. spinal anesthesia–>drop in art. pressure–>restored w/ NE
can be altered by brain centers receiving info from sens. afferent neurons from baroreceptors and thermoreceptors
baroreceptors
in carotid arteries and aortic arch
sense small changes in mean BP–>changes ANS outflow from CNS vasomotor centers to the vessels (symp) and heart (symp + PS) to correct BP changes
inc in SNA to lower body vv imp. to..
prevent venous pooling during orthostasis, helps maintain art. perfusion pressure
thermoreceptors
brain, skin, etc.
- redistrib. SNA to surface + core vessels in response to temp changes
- also: brain tells adrenomedulla–>rel. more E to inc. glucose output (hep. cells) and FFA output for thermogenesis (also triggered by exercise and hypoglycemia)–>HR will inc.
abnormally excessive symp. NE response to cold stress can lead to
Raynaud’s disease
epinephrine stimulates
ALL receptors nearly alike: a1, a2, B1, B2
low IV rates of E stimulate
extrasynaptic rec (a2, B2): dec. in diastolic and increase systolic, PP, and HR (MAP unchanged)
higher IV rates of E stimulate
intrasynp. rec as well (a1, B1 as well as a2, B2): inc. PP, inc. diastolic and systolic, inc. MAP
E used in circulatory shock
tx bronchospasm and circ. collapse from anaphylactic shock
-high systemic dose, multi. rec stim: bronchial B2, vascular a, cardiac ventricular B
low, local E used to tx
asthma: bronchial B2
cardiac arrest: high systemic (cardiac B, vascular a) accomp. CPR, e-stim
high, systemic E used to tx
cardiac arrest: (cardiac B, vascular a) accomp. CPR, e-stim
E also tx bradycardia
high doses for A-V block (AV node B and/or purkinje fiber B) until pacemaker insertion
low doses for non-A-V block bradycardias, so MAP is not increased (SA node B2)
E can also be mixed w.
local anesthetics; prolongs action at local inj. sites, min. syst. toxicity and local bleeding
*high local conc. to stim. all vascular a rec.
NE stimulates these rec
a1, a2, B1 (not B2)
both low and high doses of NE..
increase all pressures
NE reflexively
DECREASES HR
most uses of NE due to effects on
vascular a rec.
NE used in
shock: i.e. cardiogenic and neurogenic: stim cardiac B1 and/or vascular a rec
and early septic shock: esp. when shock persist after fluid replacement (vasc. a)
NE supports BP during
spinal anethesia
NE could be used w.
anesthetics (like E) (this use discontinued)
Isoproterenol stimulates these rec
B1, B2 (NOT a)
both low and high doses Iso..
dec. diastolic and MAP
inc. PP and HR
Iso was rec. removed from use as
a bronchodilator, but longer action than epi
Iso tx this when other tx fail
bradyarrhythmias (cardiac B)
Iso used as
“pharmacologic provocation” med. alternative to tilt-table test to dx unexplained syncope (vasovagal) (cardiac ventricular B)
diastolic pressure reflects
total peripheral resistance
mean pressure is
a rough average of sys and dias pressure
control of HR may be affected by barorec. as well as
direct stimulation of rec in SA node
pulse pressure reflects
left ventricular cardiac contractility
systolic pressure =
diastolic + pulse pressure
Dopamine (DA) stimulates
DA receptors>B1>a1
low doses DA stimulates
DA rec in splanchnic regions like GI and renal art. smooth muscle: inc. blood flow here
intermediate doses DA stim
B1 rec: cardiac contractility and rate (as well as DA)
high doses DA stim
a1 rec: may blunt effects of DA on splanchnic/kidney art. sm musc. (constricts)–>stim of all other vasc. a1–>rise in MAP due to increase in TPR
DA used in shock
cardiogenic and neurogenic (B1 +/- a1)
early or late septic shock
DA also used in..
CHF (w/ other tx failure) (cardiac B1 +/- renal D)
-controversial
DA for bradycardia
in pts. unrespon. to other tx
-desirable to stim. B1 not a1 so inc. HR w/out inc. MAP(would cause reflex bradycardia)
selective B1 agonist
Dobutamine (+a1 agonist or a1 antag + B1 agonist)
-inc. cardiac contractility, rate–>inc. CO, PP
(not much inc. in diastolic and MAP)
Doputamine used for
CHF
shock (cardiogen, late phase septic) (only B1)
IMPORTANT use of Doputamine
stimulate the heart during emergence from heart surgery
selective B2 agonists used as
bronchodilators (“rescue” inhalers) for COPD, asthma
post-exercise-induced bronchospasms
(oral, IV, inhaled)
terbutaline (B2 agonist) used to manage
premature labor: B2-mediated uterine relaxation (not. rec. for prolonged use, risk of CV effects)
selective B3 agonists
Mirabegron and Solabegron
tx for over-active bladder, relaxes detrusor sm. musc (relax to keep urine in)
tx anaphylactic shock w/
epinephrine 1st: high systemic dose
cardiogenic shock usually caused by
sig. loss of left ventricular musc. contractile function (post-acute MI)
- ->dec. CO, resistance may inc., pressures still fall
tx cardiogenic shock w/
NE, DA, and/or dobutamine (support circulation)
-B just for heart or a to support diastolic pressure btw contractions
tx neurogenic shock w/
NE, DA, phenylephrine
heart, BVs, or both?
septic shock typ. involves
G- bacteria, endotoxins
2 phases of septic shock
warm phase, cold phase
warm phase of septic shock
dec. syst. resistance–>massive systemic dilation–>art. pressure falls
tx: NE and/or vasoconstrictor (a1-stim) dose of DA (or phenylephrine)
cold phase of septic shock
1-2 days later
myocardial depression–>low CO–>low art pressure
vasc. resistance may go up (high SNA)
tx: DA (not high vasc. a1-stim level), dobutamine to reverse low CO
late phase septic shock
involves inadeq. perf. of vital vasc. beds
mesenteric/renal circ. compromise
tx: low dose DA (acts on D rec) can improve flow to those regions (vasodil)
effects of HIGH IV epinephrine infusion
all pressures go up, enough a1, a2 constriction to overcome B2 vasodilation (in contrast to low epi dose, diastolic goes down due to vasc B2 rec not opposed enough by a rec-vasoconstriction)
-inc. in pulse pressure: left ventr. B1 rec. are stim. along w/ B2 rec.
