T3 Flashcards
phenylephrine
selective a1 rec
raises BP like NE–>more ref. brady
correct neurogenic shock, use during therap. spinal and other anesthesia
do not stimulate heart
phenyephrine local uses
hemorrhoids
nasal congestion
mydriatic agent
supraventricular tachycardias (IV)
midodrine
newer than phenyleprine
prodrug, “smoother absorbtion”
othostatic hypotension, urinary incontinence
–counterindicated for HTN pts.
oral absorption of phenylephrine is..
poor, midodrine is better
cocaine
inhibits reuptake of NE at symp. nerve terminals
- good LOCAL anesthetic, topical, local mucous membranes and for intubation of trachea through the nose
- constricts BVs at site, drug stays at site
- rarely for pain relief and redusing epistaxis while nose intubation
- CNS effects: abuse
psuedoephiedrine and ephedrine
stimulate rel. of NE from symp. nerve endings independent of nerve APs
–>stim. adrenergic rec. directly
psuedoephiedrine and ephedrine tx
nasal and bronchial congestion–>promotes nasal and sinus drainage
amphetamine, methamphetamine, methylphenidate
stim. rel. of catechols from symp. and central nerve endings
- concern is central effects
pharmkin considerations: selective a1, B2, B3 direct acting agonists and ind. acting drugs
readily absorb, tx effective after oral admin, action last for hours
pharmkin considerations: cocaine (and some other direct-acting agonists: NE, E, Isoproterenol, DA, Dobutamine))
must be given parenterally(IV, inhalation) to be effective tx and actions last only few min if given IV
*last longer if whole tissue injection: oral mucosa, skel. musc
tolerance in sympathomimetic drugs
recepters down regulate when exposed chronically
ex: DA or dobutamine for CHF pts., chronic nasal congestions w. pseudoephed., bronchoconstr in asthmatics w. sel B2 agonists (oral typ worse than inhaled)
rebound phenomena
symptoms you were attempting to tx return “with a vengeance”
side effects of symp. agonists
gen. extension of tx effects
lack of suff. rec. selectivity
CNS side effects
*worse when dose is higher
sympathomimetic side effects examples
tx dep. cardiac contractility after MI w. B agonist–>stim B rec.–>lead to more O2 deficite, tachy, arrhy
- attempt to prevent hypotension w/ NE–>HTN
- local dermal tiss. necr. when IV inf of a agonist for systemic tx ends up in surrounding tissue
- tx urine incontinence/ortho. hypotension w/ midodrine–>a-1 mediated piloerection and bladder urine retention
symp. drugs SE: lack of suff. rec selectivity
- attempt to prev. premature labor w/ terbutaline (B2 rec) ending up w/ tachy in both mother and fetus (all cardiac B rec)
- inha. albuterol for asthma–>B2s AND B1 stim–>arrhythmias
- DA to inc. renal blood flow–>went to high–>stim. a1 rec–>offset vasodilation
side effects: CNS
mainly seen w. indirect acting sympathomimetics (dir. less likely to enter brain, exc: nervousness from epinephrine (pt. “sensing” drug, not nec. CNS effect)
i.e. insomnia, anxiety, convulsions, agitation, hallucinations, etc)
B-Blockers
Acebutolol (Sectral)
Atenolol (Tenormin)
Exmolol (Brevibloc)
Metoprolol (Lopressor, Toprol-XL)
Nadolol* (Corgard)
Pindolol* Propranolol* (Inderal-LA) Timolol* (Timoptic) *B1 AND B2 rec selectivity ALL inhib B1
intrinsic sympathomimetic action (ISA) of B blockers
partial agonist effect
*can never deliver so much drug to completely shut down receptors
(in general: rev. competitive antagonists)
B blockers partial agonists
Acebutolol
Pindolol
B blockers membrane stability (“local anesthetic” action)
acebutolol
metoprolol?
pindolol?
propranolol
B blocker lipid solubility
L: others
M: metoprolol, pindolol
H: propanolol
-low: no liver inactivation but direct excretion thru kidney EXCEPT Esmolol: Low, but inactivated by circulating esterases (short duration)
-high: more likely to enter brain and be cleared by liver
B blockers: B1
by inhib. B1 rec: all B blockers can dec. most symp. supported cardiac fund (dec. HR, contract, automat, conduction velocity)
antiangina use of B blockers
–>by dec. HR and contract, can dec myocardial O2 deficit that causes angina inputs w/ poor coronary O2 deliver (atheroscl)
B blocker: anti-HTN
lower HTN by dec. rate and contractility, also dec renin sec (B1) in kidney JG cells
B blocker: prevent post-MI arrhythmias
dec. automaticity in potential cardiac pacemaker cells (in extraneous (non-SA) pacemaker cells)
- slow/inhibit automaticity (AV node, purkinje rec, wall of ventricles) can slow down conduction thru ventricles: prevent supraventricular arrythmias
B blockers: protect heart from
dangerous catecholamine-ind. tachys and arrhythmias during:
- surg. removal of pheochromocytomas (NE, E release)
- “thyroid storm” in hyperthyroidism: exc. catecholamine ACTION (not nec. presence) in heart
what about B2 blockers??
do not want to inhibit vasodilation, alpha rec. would then be uninhibited–>vasoconstrictor
B2 blockers
- tx for glaucoma: dec. AH production in ciliary epithelium to lower IOP
- timolol (Timoptic): no membrane stabilizing, unless v. high dose (“local anesthetic action”, good!) if - undesirable in eye–>could lead to eye damage
what about Nadalol? (non mem stab, B2) -low lipid solubility, would need systemic dose
unlike nonsel. B blockers w.out ISA (partial agonist activity), those WITH ISA (pindolol) do not interfere w.
B2-mediated relaxation of vessels in skeletal muscles
–>can actually enhance such relaxation enough to dec. TPR–>overall antiHTN mech (“vasodilator” B-blockers), further enhancement of lowering BP
membrane stabilization may have..
antiarrhythmic props. but at such high doses, not commonly used (propranolol)
high Lipid solubility
may enter brain: potentially beneficial CNS-rel. CV actions (lowering BP)
-inactivated by liver, req. good liver fund.
low lipid solubility
req. good RENAL function–>inactivated by renal excr.
* lipid sol. det. drug choice for certain pts.
this drug has shortest duration due to rapid inactivation by circ. esterases (10 min)
Esmolol: used only IV to control critical, acute CV conditions (HTN, MI, SV arrhythmia post-surg) want only temporarily
longer acting B blocker (24 hr duration)
Nadolol: for chronic conditions where pt. compliance is important
other nonspecific actions of B blockers
- migraine and “stage fright”
- heart failure?? (CI!: not well understood but true)
B1 blocker side effects: excess depression of cardiac B1 rec
sinus brady, AV blockade, depressed CO–>Raynaud’s and intermittent claudication, exercise intolerance (phys. active pts)
B2 blocker side effects
- bronchoconstriction (or spasm) in asthmatics due to inhib. of B2 med. relax. of airways
- intermittent claudication and exer. intolerance (no B2 vasodilation)
- delayed recovery from insulin-induced hypoglycemic episodes (dec. B2 med hep. glucose output)
partial agonist activity B blockers
potentially same side effects but less severe (understandably w/ agonist activity)
lipid solubility side effects
inc. CNS effects: i.e. somnolence, depression
other non-sp. B blocker side effects
- aggravation of insulin resistant states in HTN and T2 DM pts
- induction/aggr of abnormal blood lipid profiles
- less sever w/ use of B1 blockers and B blockers w/ ISA (partial agonist activity)
combination agent: nonselective B blocker and selective a1-blocker
Labetalol (Trandate)
non-sel a blockers (a1&a2)
Phenoxybenzamine (Dibenzyline)
Phentolamine (gen. OraVerse)
selective a1 blockers
prazosin (minipress) terazosin (hytrin) doxazosin (cardura) tamsulosin (flomax) alfuzosin (uroxatral) silodosin (rapaflo)
a blocker mechanisms
-inhibition of vascular and other PERIPHERAL a-adrenergic recmost important
B blockers are rev. competitive inhibitors and most a blockers are as well except
phenoxybenzamine: non comp. inhibition: TOXIC, irreversible, long acting
only syn. of new rec. can restore a adr. function
a blockers inhibit
competitively, rel. fast, reversibly
a1 blockers dec. BP primarily by dec..
peripheral vasc. resistance dued to inhibition of a1-med. arterial vasoconstriction
common a-blocker side effects
-rel. to too much loss of a rec func.: nasal congestion, ejac. difficulties, reflex tachy, syst. EC fluid retention(over perfused capillaries), and othostatic hypotension
Phenoxybenzamine
long-acting irrev. inhib of both a1 and a2 rec.
- prev. sev. caechol. ind. HTN episodes occure in pheochromocytoma pt. during reop period prior to surgery, also to tx HTN in pts w/ pehochrom.
- better than other a blockers bc irreversible,(others not going to overcome pheochrom.) (extrasyn. a2 more NE,E exposure)
Phentolamin
rev. inhibs both a1, a2, short acting
dx. of pheochrom. “Phentolamine Test”
-during surge. rem of pheo.
-prev. rise in BP from cate. might be rel. from tumor DURING surgery
-to reverse acute syst. HTN from IV a agonist overdose (NE)
-prev. a agonist rel. local dermal tissue necrosis (NE spill)
-OraVerse (new) to rev. oral soft-tiss. anesthesia in dentistry
after vasoconstr. inj. (EPI)
Prazosin
sel. a1 blocker
- long-term tx of mild-mod prim. HTN (esp. + diuretic)
- relax smooth musc. (sphincter) in bladder neck and prostatic urethra–>relieving obstructive urin. symps of BPH
- Raynaud’s syndrome (exc. response to cold stress)
- tx for nightmares rel. to PTSD (inh. of central a1 rec)
Prazosin SEs
otho hypotension w. syncope (“first dose phenom”), Na/H2O retention (offset by diuretic), refl. tachy, (not as much w.non-sel: no inhib. of presyn. a2 med. neg fdbk control of NE rel from symp. nerve endings in SA node of heart) i.e. still get a2 med. neg fdback–>less NE rel. from SNS in SA node
Doxazosin and Terazosin
newer a1 rec blockers
mechanism, SE and peripheral uses as prazoson longer 1/2 life better for chronic HTN and BPH, fewer doses (better compliance)
*not into CNS (can’t be used for PTSD)
Tamsulosin and Silodosin
block subtype a1A receptors (subtype A) main type in sm. muscle of bladder nk and prostate vs. other a1 in BVs
- tx BPH, more sp. w/ less syt. vasc actions and SEs (less dec. BP, syncope than other a1 blockers)
- can still cause abn. ejaculation due to local inhib. of a1A rec in vas deferens
Alfuzosin
block a1 rec for BPH but not rec subtype-sel, but shows “uroselectivity” for BPH but not sig. influencing vasc a1 rec (no BP, venous pooling effects)
-accumulation of alfuzosin in prostatic tissue (over 2x circulating plasma levels)
Labetalol
combo nonsel B blocker and sel. a1 blocker
tx for mod-sev prim. HTN (oral) and emergency tx of HTN crisis (IV)
SE: bronchoconstriction, othostatic hypotention, less Raynaud’s (a blocked) and less reflex tachy (B blocked)
sympathetic (adr) neuronal blockers: peripherally acting (inc. NE)
Reserpine*
Guanethidine
centrally acting symp. neuronal blockers mechanism
stim. CNS a2 adr rec thus ind. reduce sympathetic neuronal traffic from central symp. vasomotor centers to peripheral CV organs
centrally acting symp. neuronal blockers
methyldopa*
clonidine* (catapres)
guanfacine* (tenex, intuniv)
guanabenz (wytensin)
Reserpine
dec. uptake of DA and NE into storage vesicle, deplete stored levels–>dec. amount rel–>reduced CO AND peri. art resistance–>reduces BP
Tx HTN
(will not get rebound)
(replaced by newer drugs, but less expensive)
reserpine SE
sedation, mental depressiont (depl. action on CNS)
postural hypotension, brady, fluid retention (depleted peripheral sympathetics)
sev. diarrhea and ulcers (unopp. PSA)
reserpine inactivation
unknown mech.
cleared fast, depletes NE irreversibly so long-acting
Guanethidine
like reserpine: blocks uptake of DA and NE into storage vessels; but also DIRECTLY blocks NE release from nerve endings
-same peripheral BP effects as reserpine, not used to tx HTN in US anymore
must be taken up by reuptake pump of symp. NT, prevented by tricyclic antidepressants (imipramine, desipramine) these will interfere with/antagonize guanethidine effects
Central acting adr. neuronal inhibitors
a2 rec agonist at various CNS sites: vasomotor centers in brain, red. symp. neuronal outflow–>dec to heart, vessels, kidney
-prevent rel. of NE (involves pre-syn. a2 rec)
-do not do much in periphery?? (mech of a2 rec) also conc. in CNS
tx for HTN
*do not interfere w/ normal reflex med. changes in symp nerve activity, fewer othostatic hypotensive symptoms, do not help for Raynaud’s
-little/no decrease in exercise capacity
alpha-methyldopa
(prodrug, req. metab. to active form, some unique AI SEs)
DOPA–>DA–>NE enzymes also converted this prodrug to alpha-methylnorepinephrine–>a2 adr agonist in central vasomotor centers, dec. symp. outflow, art periph. resistance falls
–>dec. renal renin, dec HR, dec CO
tx: HTN second. to pregnancy
(no rebound HTN)
alpha-methyldopa SE
fluid retention, dry-mouth, sedation (all a2 agonists)
induces “AI” disorders:
positive Coombs test: hemolytic anemia (easily rev.)
abnormal LFTs–>sev. necrosis
Clonidine
direct a2 adr agonist, dec. symp outflow from CNS vasomotor centers
tx HTN
oral but dermal patch for smoother BP control, less SE except skin rxn
*SE: rebound HTN w/ abrupt cessation (like B blockers)
other Clonidine uses
tx for w/drawal of addictive drugs (etOH, nicotine, morphine), ADHD, PTSD, hot flashes, migraine (rare)
-direct inj into spinal cord may have analgesic action: inhib rel of transmitters from terminals of aff. pain fibers (presyn. a2 agonist action in SC)
apraclonidine (iopidine)
- to lower postsurg IOP inc. by a2 agonist action in eye (brinonidine lowers IOP in glaucoma)
(struct. rel to clonidine)
Guanfacine
a2 anti HTN use (Tenex) like clonidine, but slightly less sedation and less tendency towards rebound
-ADHD tx (intuniv)
Guanabenz
sim. to clonidine, tx for HTN
also: lowers tot. serum cholesterol, causes less reactive fluid retention (may not need diuretic)
Nicotine
stimulant at low doses (nicotinic agonist) but depressant at v. high doses in all organs where ACh is NT and rec is nicotinic
stim: normal depot of cell men around mic rec
depress: persistent depol–>desensitation
ganglionic stimulants
nicotine:
Nicorette, NicoDerm, Nicotrol
ganglionic blockers
Mecamylamine (Inversine)
others: trimethaphan, hexamethonium
sites of nicotine action
CNS CV GI Skel muscels *affects all nicotinic rec. subtypes, will stimulate/block(if high dose) dominant receptor
CNS nicotine effects
-addiction tx
initially stimulation: inc. respiration
-can cause vomiting (CRTZ)
at higher doses, CNS stim–>depression
CV nicotine effects
complex, at low dose: stim ANS–>adrenergic(symp) predom: inc. periph vasoconstriction w/ acute HTN
at higher doses: drop in BP
GI nicotine effects
(ANS)
increase GI motility at low doses, opp. @ high doses
nicotinic toxicity
as levels rise, symptoms may change to other types
tx largely symptom-directed; may need support of adrenergic agonists if NT blocked by high nicotinic levels
-if skel. musc blockade occurs, may need to support respiration
-
nicotine absorption, excretion
rapid acting, absorbed from all routes
metab. in liver, excr. by kidney as cotinine
passes placental barrier and BBB
nicotine therapy
smoking cessation (may inc. BP)
start high–>taper to wean off addiction
-warns against concurrent tobacco use
risks of nicotine tx
- accidental nicotine ingestion from E-cig (not FDA approved) refill solutions, insecticides, and tobacco products
- field workers: dermal nicotine absorb from wet tobacco leaves: Green tobacco sickness
Mecamylamine
ganglionic blocker, discontinued
tx: v. severe/malignant HTN (high doses), Tourette’s, suppress nicotine addiction (low doses)
B1 blocker SE: removal of warning sign of tachycardia
going into hypoglycemia (for insulin-taking pts)
-pay attention to sweating! not affected by B-blockers
B1 blocker SE: when suddenly removed
rebound HTN and/or angina
due to rec. up-regulation while blocking (potential for MI!)
Labetalol tx
mod-sev. prim. HTN and emerg. tx of HTN crisis (IV)
-dec. art resist: a-block, partial B2 agonist, renin-reducing, dec. CO
Labetalol SE
orthostatic hypotension (a-block) bronchoconstriction (B-block) less Raynaud's (B-block) and tachy (a-block) seen with others
phenoxybenzamine SE
inhib. some non-adr. rec (hist, ser, Ach)
miosis, sedation, drowsiness, vom, leth (CNS)
shock, circ. failure
phentolamine SE
N/V/D
inc. GI motility (bad for ulcers)
may stim. or block non-adr. rec.
mechanism of peripherally acting adr. neuronal inhibitors
dec. NE available to adr. rec of peripheral postgang SN endings
guanethidine SE
postural hypotension, bradycardia, fluid retention
diarrhea, aggrav. of peptic ulcers, etc (like reserpine)
no CNS effects (unlike reserpine)
Raynaud’s
abnormally exaggerated THERMAL reflex-mediated increase in SNA to blooc vessels in response to cold or emotional stress
nicotine toxicity is usually not fatal bc
nicotine is inactivated quickly: 1/2 life of 2 hours
mecamylamine: mechanism of gang. blockade
block neuronal nicotinic rec. (blocks pre–>post gang. transmission)
- does NOT affect post-gang autonom. nerve terminals or rec. sites (can still respond to autonomic agonists like musc. and adr. rec stimulants)
- does not affect muscular subtype nicotinic receptors (only neural) of NMJ in skel musc (can still move)
mecamylamine adverse reactions
postural hypotension (interfere with compensatory baroreflexes)
dry mouth, diff swallowing
dec. GI, GU motility
mydriasis, cycloplegia (intol. to light, blurred vision)
sedation and other CNS side effects
antidotes for too much gang. blockade
i.e. NE for CV support if neurogenic shock
absorption, fate, excretion of mecamylamine
good GI absorb. (oral), crosses BBB and placenta, elimited mostly via renal excretion, 10 hr duration
