smooth muscle

Question 1

mechanisms of smooth muscle contraction

Answer 1

Calcium- cell membrane and intracellular signaling mechanism
Intracellular signaling- myosin light chain kinase, rho kinase
Hormonal and paracrine factors- norepinephrine, angiotensin 2 and endothelin 1

Question 2

mechanism of smooth muscle relaxation and therapeutic applications

Answer 2

signaling pathways that inhiibit contractile mechanisms
Paracrine factors- NO, dopamine, prostacyclin
for CV, Uterine, Gastrointestinal, pulmonary

Question 3

Nitric oxide donors MOA

Answer 3

intracellular signaling: Cyclic GMP/protein kinase G

NO combines with the heme group of soluble guanylyl cyclase–> increase in cGMP –> activates K channels–> enhanced mmyosin light chain dephosphorylation–> relaxation

arterial and venous circulation both affected

Nitroglycerin- venous dominant dilator
Nitroprusside- arteriole and venule dilator

Question 4

nitroglycerin

Answer 4

Relaxation of venous smooth muscle and coronary arteries

metabolized to NO via mtALDH (mito aldehyde reductase), which is high in venous smooth muscle.

Venous dilation–> decreased cardiac preload (and coronary artery dilation)–> anti-anginal actions

treatment for angina and coronary artery disease

Sublingual admin (liver inactivates NO), F for nitroglycerin is low, sub lingual gives therapy in a few minutes with a small dose

Contraindicated- elevated intracranial pressure

can develop tolerance

Toxicity- orthostatic hypotension, tachycardia, syncope, and throbbing headache

Question 5

nitroprusside

Answer 5

Relaxes arterial and venous circulation

has iron, cyanide, and nitroso, rapidly metabolized by uptake into RBC w/ release of NO and cyanide (cyanide is metabolized to less toxic compund)

Rapid arterial pressure reduction

Nitroprusside is given IV infusion, effects gone within a few minutes, make fresh and cover with foil

No tolerance

Toxicity- hypotension, cyanide accumulation, metabolic acidosis, arrythmias

Question 6

hydralazine

Answer 6

relaxation of arterial circulation for heart failure and hyper tension

effective in severe HTN, used in combination with nitrates

toxicity- headache, nausea, anorexia, palpitations, sweating, and flushing

Question 7

minoxidil

Answer 7

Arterial circulation

Minoxidil sulfate- active metabolite

activates potassium channels–> hyperpolarization

used for HTN and heart failure

Toxicity- fluid and salt retention, CV effect and hypertrichosis

Question 8

diazoxide

Answer 8

arterial circulation

activates K channels–> hyperpolarization

long acting, paternally administered

trt for: hypertensive emergencies and hypoglycemia secondary to insulinoma

Toxicity: hypotension and hyper glycemia

Question 9

Ca channel blockers

toxicity

Answer 9

all have arterial dilatory effects but differ a little

Dihydropyridines- nifedipine, nicardipine, amlodipine

Phenylalkylamine- verapamil

Benzothiazepine- diltiazem

toxicity: Cardiac- bradycardia, AV block, cardiac arrest, and heart failure
Flushin, dizziness, nausea, constipation (verapamil) and peripheral edema

Question 10

Ca channel blockers and vascular smooth muscle slecetivity

Answer 10

Dihydropyridines- stronger vascular effects than Cardiac effects than verapamil and diltiazem

Nicardipine- cerebral vasospasm and infarct during stroke, IV admin

Verapamil- intra-arterially administered for stroke (no cerebral affinity like nicardipine)

Question 11

phosphodiesterase 3 inhibitors

Answer 11

milrinone and inamrinone

PDE3 inhibtion -> increase in intracellular cAMP–> PKA phosphorylation–> activates cardiac Ca channel and vascular smooth muscle K channels

positive cardiac ionotropic and vasodilator effects

used for short term heart failure IV admin

Toxicity- arrhythmias, headache, thrombocytopenia

Question 12

phosphodiesterase 5 inhibitors

Answer 12

sildenafil, tadalafil (TADA! viagra and cialis)
PDE5 inhibition–> increase intracellular cGMP–> PKG phosphorylation

Used for erectile dysfunction and pulm HTN-> relax non vascular smooth muscle of corpora cavernosa–> inflow of blood

Toxicity- adverse effects w/ nitrates, color vision for sildenafil

Question 13

fenoldopam

Answer 13

Dopamine D agonist

dilation of peripheral arteries and natriuresis

HTN emergencies and postop HTN-iv

Toxicity- reflex tachycardia, headach, flushing, increase intraocular pressure (cont indicated in pt w/ glaucoma)

Question 14

prazosin

Answer 14

a-adrenergic blocker

Arterial and venous dilatior

HTN

Toxicity- reflex tachycardia, dizziness, headache

first dose orthostatic hypotension

Question 15

atosiban

Answer 15

Oxytocin receptor antagonist- prevents preterm labor

Question 16

misoprostol and alprostidl

Answer 16

PGE1 analog

misoprostol: stimulates uterine contractions and prevents postpartum hemmorage

Alprosidil: smooth muscle relaxant, keeps PDA open, injectable erectile dysfunction

Question 17

oxytocin

Answer 17

uterine contraction

Question 18

Ergonovine

Answer 18

uterine contraction

dose dependent contractions, more sensitive in late term pregnancy

Question 19

metoclopramide

Answer 19

dopamine D2 antagonist, increases smooth muscle stimulation of upper GIT, and opens sphincter

no effects on small intestine and down

Inhibits D2 receptors in medulla–> anitemetic

used for GERD, gastric emptying, emesis

Toxicity- restlessness, drowsiness, insomina, anxiety, agitation

Question 20

bethanechol

Answer 20

muscarinic agonist

long duration use for xerostomia, UT retention, expulsion of urine

Question 21

erythromycin

Answer 21

stimulate motilin receptors on GIT, promote onset of migrating motor complex

IV injection for gastroperisis, (can develop tolerance)

Upper GIT hemorrage treatment

Question 22

albuterol, pirbuterol, terbutaline, salmeterol, formoterol

Answer 22

B2 receptor antagonist for bronchodilation

Question 23

Ipratropium, tiotropium

Answer 23

Anti cholinergic for bronchodilation

Question 24

theophylline and aminophylline

Answer 24

bronchodilators, asthma and COPD

Theophylline- nonselective PDE inhibitor, adenosine antagonist, increases release of IL10 (antiinflammatory)
narrow therapeutc index

Question 25

epoprostenol, iloprost

Answer 25

PGI2 analog- treatment for HTN in lung

IV and inhalation

Epo has a short half life- continuous half life

Ilo has a little longer frequent inhalations

Toxicity- flushing, headache, hypotension, nausea and diarrhea

Question 26

bosentan

Answer 26

ETa receptor antagonist

reduces primary pulmonary HTN, IV and inhaled
Ambrisentan- orally active only ETa (ETb- dialates)

toxicity- liver toxicity, anemia, headaches, peripheral edema