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*XENOBIOTICS AFFECTING RENAL AND CARDIOVASCULAR FUNCTION*

Table of contents :

------------------------------------------------------------------------

* anti-arterial hypertension xenobiotics
<http://focosi.altervista.org/drugsrenal.html#Anti-hypertensive>
o diuretic xenobiotics
<http://focosi.altervista.org/drugsrenal.html#diuretics>
* anti-sexual dysfunction xenobiotics
<http://focosi.altervista.org/drugsrenal.html#Anti-sexual%20dysfunction%20xenobiotics>
* anti-arrhythmic xenobiotics
<http://focosi.altervista.org/drugsrenal.html#Antiarrhytmic%20drugs>
* anti-CHF xenobiotics
<http://focosi.altervista.org/drugsrenal.html#Anti-congestive%20heart%20failure%20%28CHF%29>
* vasoprotectants
<http://focosi.altervista.org/drugsrenal.html#Vasoprotectants>
* sclerosing solutions / sclerosants
<http://focosi.altervista.org/drugsrenal.html#Sclerosing%20solutions>

------------------------------------------------------------------------

*_Anti-systemic arterial hypertension
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#systemic%20arterial%20hypertension>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#systemic%20arterial%20hypertension>
xenobiotics_*
Side effects : orthostatic systemic arterial hypotension
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#orthostatic%20systemic%20arterial%20hypotension>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#orthostatic%20systemic%20arterial%20hypotension>.

* *_diuretic xenobiotics / diuretics_*
o _acting on proximal convoluted tubule_, where 66% of Na^+ is
re-absorbed
+ _type II (cytoplasmic) and type IV (mitochondrial)
carbonic anhydrases
<http://focosi.altervista.org/enzymes.html#carbonic%20anhydrase%20II>
<http://focosi.altervista.org/enzymes.html#carbonic%20anhydrase%20II>
inhibitors (CAI)_ inhibit NaHCO_3 reabsorption.

Side effects : block insulin
<http://focosi.altervista.org/stp.htm#insulin>
<http://focosi.altervista.org/stp.htm#insulin>
incretion (minoxidil
<http://focosi.altervista.org/stpion.html#minoxidil>
<http://focosi.altervista.org/stpion.html#minoxidil> :
hirsutism
<http://focosi.altervista.org/pathohomotissueskin.html#hirsutism>
<http://focosi.altervista.org/pathohomotissueskin.html#hirsutism>).
+ _D_1 <http://focosi.altervista.org/stpgspcrs.html#D1>_
<http://focosi.altervista.org/stpgspcrs.html#D1> agonists_
o _both arterial (including coronary) and venous vasodilators_
: veins are dilated > elastic arteries > arterioles
(including coronary arteries)
+ _spontaneous and bioreductive NO^. donors_ :
# _nitrites_
* _amyl or isoamyl nitrite_
* _isobutyl nitrite_
# _organic nitrates_
* _glyceryl trinitrate (TNT / GTN)_ (often
wrongly named _nitroglycerin_,
_trinitroglycerine_, _trinitrine_)
(Adesitrin^® , Deponit^® , Minitran^® ,
Nitroderm^® , Nitro-Bid^® , Nitrostat^® ,
Nitrol^® , Nitro-Dur^® , Nitrosylon^® ,
Perganit^® , Suscard^® , Topnitro^® ,
Triniplas^® , Trinitrina^® , Venitrin^® ,
...; Natispray^® spray)
* _erythrityl tetranitrate_ (Cardilate^® )
* _pentaerythritol tetranitrate (PETN)_
(Peritrate SA^® )
* _isosorbide 5-mononitrate_ (Imdur^® ,
Ismo^® , Leicester^® , Monoket^® , ....)
* _isosorbide dinitrate (ISDN)_ (Carvasin^®
, Isordil^® , Sorbitrate^® ,
Dilatrate-SR^® , ... ; Isocard^® spray)
o _hydralazine + isosorbide dinitrate
combination
<http://focosi.altervista.org/drugsrenal.html#hydralazine%20and%20isosorbide%20dinitrate%20combination>_
* _molsidomine_ (Corvasal^® , Corvaton^® ,
Molsidolat^® , Morial^® , Motazomin^® )
# _NONOates_
* _(Z)-1-[/N/-(2-aminoethyl)-/N/-(2-ammonioethyl)amino]diazen-1-ium-
1,2-diolate (DETA NONOate)_
* _spermine NONOate (spermine-NO)_
# _/S/-nitrosoglutathione (GSNO)_
# _sodium trioxodinitrate (NaN_2 O_3 , Angeli's
salt (AS))_ decomposes initially to HNO and
nitrite at physiologic pH
# _/S/-nitroso-/N/-acetyl-D,L-penicillamine (SNAP)_
# _sodium nitroprusside (SNP)_ (as it is unstable
to visible light, it has to be prepared at
need). Side effects : intoxication from
thiocyanates.
# _2,2-diethyl-1-nitroso-oxyhydrazine sodium salt
(DEA/NO)_
# _spermine/nitric oxide complex_
# _NOC-18_
# _NO-releasing aspirins (NO-ASA)_ are obtained by
adding a nitric oxide-releasing moiety to
acetylsalicilicic acid
<http://focosi.altervista.org/enzymes.html#acetylsalicylic%20acid>
<http://focosi.altervista.org/enzymes.html#acetylsalicylic%20acid>.
* _NCX-4016_ consists of the parent aspirin
linked to a 'spacer' via an ester linkage,
which is in turn connected to a nitric
oxide-releasing moiety. Both aspirin and
nitric oxide moieties of NCX-4016
contribute to its effectiveness, the
latter occurring via both cGMP-dependent
and -independent mechanisms. /In vitro/
studies have shown that NCX-4016 inhibits
platelet aggregation induced by
aspirin-sensitive (arachidonic acid) and
aspirin-insensitive (thrombin) agonist. In
contrast to aspirin, NCX-4016 exerts a
multilevel regulation of inflammatory
target, including caspase-1 and NF-kappaB.
This broad spectrum of activities
translates to an increased potency of this
drug in modulating cardiovascular
inflammation. Human studies have shown,
that while nitric oxide-aspirin maintains
its anti-thrombotic activity, it spares
the gastric mucosa.
* _NCX4040_
* _NCX4050_
* _NCX4060_
+ _NO^. scavengers_
# _2-phenyl-4,4,5,6-tetramethyl-imidazoline-1-oxyl
3-oxide (PTIO)_
+ _CO donors / carbon monoxide-releasing molecules
(CO-RMs)_. For therapeutic purposes these gases can be
delivered by :
# inhalation
# transition-metal carbonyls^ref
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14529551>

Indications : peripheral vasculopathies, systemic arterial
hypertension, pheochromocytoma, shock
Side effect : orthostatic systemic arterial hypotension
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#orthostatic%20systemic%20arterial%20hypotension>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#orthostatic%20systemic%20arterial%20hypotension>
within 90' from first dose ("_first-dose phenomenon_"),
compensatory tachycardia
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#tachycardia>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#tachycardia>,
sleepiness, headache, nasal congestion, xerostomia
<http://focosi.altervista.org/pathohomotissueheadneck.html#xerostomia>
<http://focosi.altervista.org/pathohomotissueheadneck.html#xerostomia>
o b_1 <http://focosi.altervista.org/stpgspcrs.html#b1>_
<http://focosi.altervista.org/stpgspcrs.html#b1> _-antagonists_
+ central inhibition of sympathetic tone
+ reduction of cardiac output via negative chronotropic,
inotropic and dromotropic effects (expecially during
physical exercise) => reduced oxygen request
+ inhibition of _renin
<http://focosi.altervista.org/enzymes.html#renin>
<http://focosi.altervista.org/enzymes.html#renin>_
incretion in juxtaglomerular cells
+ inhibition of presynaptic positive feedback on
norepinephrine release via b_2 -AR
<http://focosi.altervista.org/stpgspcrs.html#b2>
<http://focosi.altervista.org/stpgspcrs.html#b2>
A variation in adducin 2 (beta) (ADD2)
<http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=119> is
associated with lower than average SBP in hypertensive
people treated exclusively with b-blockers.
_Solubility_ :
+ lipophilic : massive first-pass effect (only 25%
reaches arterial circulation), accumulation in renal
or liver failure, short half-life (2-5 hrs), cross the
BBB => side effect : depression, nightmares, and
hallucinations; e.g. alprenolol, propanolol,
metoprolol, oxprenolol, labetalol, penbutolol
+ intermediate :
# timolol, betaxolol
# pindolol
# bisoprolol
# acebutolol
# sotalol
+ hydrophilic : poorly absorbed in gastrointestinal
tract, poorly metabolized by the liver, renal
clearance (unmodified or as catabolytes; recommended
in liver failure), long half-life (5-8 hrs); e.g.
practolol, nadolol, atenolol
_Selectivity_ :
+ cardioselective (b_1
<http://focosi.altervista.org/stpgspcrs.html#b1>_
<http://focosi.altervista.org/stpgspcrs.html#b1>
-antagonists only at low doses) are preferred in
patients with bronchial asthma
<http://focosi.altervista.org/pathohomotissuerespiratory.html#asthma>
<http://focosi.altervista.org/pathohomotissuerespiratory.html#asthma>,
COPD or peripheral vasculopathies; e.g. bisoprolol
(b_1 /b_2 ratio = 75), atenolol and metoprolol (b_1
/b_2 ratio = 35), acebutolol and esmolol
+ noncardioselective (b_1
<http://focosi.altervista.org/stpgspcrs.html#b1>_
<http://focosi.altervista.org/stpgspcrs.html#b1> and
b_2 <http://focosi.altervista.org/stpgspcrs.html#b2>_
<http://focosi.altervista.org/stpgspcrs.html#b2>
antagonists)
_Intrinsic sympatholytic activity (ISA)_ (i.e. acting also
as b_2 <http://focosi.altervista.org/stpgspcrs.html#b2>_
<http://focosi.altervista.org/stpgspcrs.html#b2> _-agonists_) :
+ with ISA : reduce less resting HR and CO preventing
excessive bradycardia and low CO at rest and during
bedtime, and the fall in arterial pressure is
correlated with a fall in PVR below pretreatment
levels. Neutral effect on metabolism (e.g.
acebutolol). Decreased risk of cardiodepression and
bronchospasm. They may cause sleep disorders and a
reduced anti-ischemic effect, reduced risk of rebound
effect after sudden withdrawal. They are recommended
in patients with low CO or mild alteration of AV
conduction. E.g. acebutolol, pindolol, alprenolol,
oxprenolol
+ without ISA : produce an initial reduction in CO and
HR, and a reflex-induced rise in PVR with no net
change in ABP. They reduce HDL-Ch and insulin
sensitivity (unfavorable metabolic effects). E.g.
atenolol, metoprolol, esmolol
_Membrane-stabilizing activity (MSA)_ is not very intense at
therapeutic doses so it not used :
+ with MSA : propanolol
+ without MSA : acebutolol, aprenolol, oxprenolol
_Third-generation b-blockers_ (with vasodilating activity) :
_combined a
<http://focosi.altervista.org/stpgqpcrs.html#a1A>_1
<http://focosi.altervista.org/stpgqpcrs.html#a1A>
<http://focosi.altervista.org/stpgqpcrs.html#a1A> - and _b_1
<http://focosi.altervista.org/stpgspcrs.html#b1>_
<http://focosi.altervista.org/stpgspcrs.html#b1>
_-antagonists_ (labetalol, carvedilol, celiprolol) : highly
lipophilic, no ISA, low MSA. Gastrointestinal absorption =
80%, plasma concentration peak after 1-2 hrs,
bioavailability = 23% after liver first-pass effect, 95%
bound to plasma proteins, half-life = 2-3 hrs, liver
clearance (recommended in renal failure). No effects on HR,
smaller reduction of CO, reduced PVR without activation of
RAAS thanks to b_1 antagonist activity. No effects on lipid
profile and glucose tolerance, antioxidant properties
Indications : angina pectoris
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#angina%20pectoris>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#angina%20pectoris>
(reduction of oxygen consumption and contractility),
secondary prevention of AMI
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#acute%20myocardial%20infarction%20%28IMA%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#acute%20myocardial%20infarction%20%28IMA%29>,
_systemic arterial hypertension
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#systemic%20arterial%20hypertension>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#systemic%20arterial%20hypertension>_
(reduced CO, renin incretion and NE release), arrhythmias
(expecially those caused by hypercatecholaminemia :
pheochromocytoma, anxiety), thyrotoxicosis, somatic anxiety
disorders, open-angle glaucoma, prevention of migraine
<http://focosi.altervista.org/pain.html#migraine>
<http://focosi.altervista.org/pain.html#migraine>,
tachycardia
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#tachycardia>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#tachycardia>,
tremor (dopants in precision exercises)
Contraindications : pregnancy, diabetes mellitus
<http://focosi.altervista.org/pathohomotissueendocrine.html#Diabetes>
<http://focosi.altervista.org/pathohomotissueendocrine.html#Diabetes>
(reduce symptoms from mechanisms that compesate iatrogenic
insulin-induced hypoglycemia), bronchial asthma
<http://focosi.altervista.org/pathohomotissuerespiratory.html#asthma>
<http://focosi.altervista.org/pathohomotissuerespiratory.html#asthma>,
SA and/or AV node dysfunctions
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#arrhythmias>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#arrhythmias>,
CHF
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>
(even if they are useful if monitorated !), Raynaud
phenomenon
<http://focosi.altervista.org/pathohomotissueimmunity.html#Raynaud%27s%20disease>
<http://focosi.altervista.org/pathohomotissueimmunity.html#Raynaud%27s%20disease>,
or treated with NSAIDs (effect depends on PC synthesis),
systemic arterial hypotension, bradycardia (HR < 60 bpm for
drugs without ISA), COPD, obliterating lower limb disease,
spontaneous angina pectoris (unmasking of a-tone worsens
vasospasm)
Side effects
+ due to b-blockage :
# cardiovascular :
# metabolic : delayed recovery from
insulin-induced hypoglycemia (b_1 -antagonists
should be preferred), masking of hypoglycemic
symptoms (sweating, palpitations), alterations
of lipid profile (reduced HDL-Ch, increased TG)
# respiratory : bronchospasm (blockage of b_2 -AR
on bronchial smooth muscle cells)
# other : worsening of claudicatio intermittens,
cold extremities
+ not due to b-blockage :
# CNS (due to lipophilia) : fatigue, sleep
disorders (insomnia, nightmares), depression
# gastrointestinal : nausea, vomiting,
constipation
<http://focosi.altervista.org/pathohomotissuegastro.html#Constipation>
<http://focosi.altervista.org/pathohomotissuegastro.html#Constipation>
# others : impotentia coeundi, reduced libido
+ atenolol is not a suitable drug for hypertensive
patients and should not be used as a reference drug in
outcome trials in hypertension. Despite major
differences in blood pressure lowering, there are no
outcome differences between atenolol and placebo in
all-cause mortality, cardiovascular mortality, or
myocardial infarction at 4-6 yrs. The risk of stroke,
however, tends to be lower in the atenolol than in the
placebo group. When atenolol is compared with other
antihypertensives, there are no major differences in
blood pressure lowering between the treatment arms.
There is a significantly higher mortality with
atenolol treatment than with other active treatment.
Moreover, cardiovascular mortality also tends to be
higher with atenolol treatment than with other
antihypertensive treatment. Stroke is also more
frequent with atenolol treatment^ref
<http://www.thelancet.com/journal/vol364/iss9446/full/llan.364.9446.primary_research.31148.1>

* _L-type voltage-dependent Ca^2+ channels blockers (CCB)
<http://focosi.altervista.org/stpion.html#Ca2+%20channel>
<http://focosi.altervista.org/stpion.html#Ca2+%20channel>_ reduce
contractility in both arterial smooth muscle cells and
cardiomyocytes. Complete absorption after oral administration,
massive hepatic first-pass effect => reduced bioavailability,
70-98% is bound to plasma proteins, hepatic catabolism (reduced
doses in liver failure), very variable half-lifes, poorly active
catabolytes. Proportional dose-response curve : increased dose
increases the therapeutic effect (on the contrary of the flat
curve of ACEis) ! They can be used in pregnancy
o _dihydropyridine CCBs_ (e.g. nifedipine and amlodipine) :
more effective on arteries (peripheral and coronary
vasodilators), mild increase in CO, reduced PVR, activation
of SNS (increased HR, CI, catecholaminemia) and RAAS. Used
in hypertensive emergencies (administer PO as SL induces
excessive hypotension and could lead to CNS damage !).
Amlodipine induces a lesser reflex tachycardia due to long
half-life (35-50 hrs)

Side effects : headache
<http://focosi.altervista.org/senseorgans.html#Headache>
<http://focosi.altervista.org/senseorgans.html#Headache>,
facial flushing
<http://focosi.altervista.org/pathohomotissueskin.html#flushing>
<http://focosi.altervista.org/pathohomotissueskin.html#flushing>,
malleolar angioedema (dose-dependent), palpitations
(reflexed tachycardia
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#tachycardia>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#tachycardia>),
gastrointestinal disturbances (vomiting, constipation
<http://focosi.altervista.org/pathohomotissuegastro.html#Constipation>
<http://focosi.altervista.org/pathohomotissuegastro.html#Constipation>),
o gingival hypertrophy (rare) _benzothiazepine CCBs_ (e.g.
diltiazem) : equally effective on heart (negative
dromotropic, chronotropic and inotropic effects lesser than
phenylalkylamines) and arteries, reduction of PVR without
reflex tachycardia

Side effects : hypokinetric arrhythmias, skin alterations,
fatigue, constipation
<http://focosi.altervista.org/pathohomotissuegastro.html#Constipation>
<http://focosi.altervista.org/pathohomotissuegastro.html#Constipation>,
o gingival hypertrophy (rare) _phenylalkylamine CCBs_ (e.g.
verapamil) : more effective on heart (negative dromotropic,
chronotropic and inotropic effects higher than
benzothiazepines) => used as class IV antiarrhythmic drugs
<http://focosi.altervista.org/drugsrenal.html#class%20IV>,
reduction of PVR without reflex tachycardia

Side effects : bradycardia
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#sinusal%20bradicardia%20or%20sinoatrial%20%28SA%29%20block>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#sinusal%20bradicardia%20or%20sinoatrial%20%28SA%29%20block>,
CHF
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>,
atrioventricular blocks
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#atrioventricular%20%28AV%29%20block>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#atrioventricular%20%28AV%29%20block>,
headache
<http://focosi.altervista.org/senseorgans.html#Headache>
<http://focosi.altervista.org/senseorgans.html#Headache>,
constipation
<http://focosi.altervista.org/pathohomotissuegastro.html#Constipation>
<http://focosi.altervista.org/pathohomotissuegastro.html#Constipation>
(reduced muscle tone), gingival hypertrophy (rare) Effects :
o distrectual effects :
+ renal circulation : reduction of RVR, natriuresis
+ coronary circulation : reduction of coronary
resistances, but only DHP increase coronary blood flow
+ cerebral circulation : some DHP CCBs (nimodipine and
isradipine) cross the BBB and induce direct
vasodilatation of cerebral blood vessels
o cardiovascular effects : reduction of arterial pressure,
regression of cardiac hypertrophy, reduction of mortality
and major cardiovascular events in patients with AMI without
SC, prevention (but not therapy) of atherosclerotic plaques,
o metabolic effects : do not modify carbohydrate and lipid
profile, nor potassemia
Therapeutic indications :
o _systemic arterial hypertension
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#systemic%20arterial%20hypertension>_
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#systemic%20arterial%20hypertension>
o non-DHP CCBs :
+ AMI
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#acute%20myocardial%20infarction%20%28IMA%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#acute%20myocardial%20infarction%20%28IMA%29>
(verapamil, diltiazem)
+ angina pectoris
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#angina%20pectoris>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#angina%20pectoris>
(verapamil, diltiazem, but also amlodipine)
+ migraine
<http://focosi.altervista.org/pain.html#migraine>
<http://focosi.altervista.org/pain.html#migraine>
(inhibit the initial vasoconstriction followed by
vasodilation) (verapamil)
+ supraventricular tachyarrhythmias (verapamil, diltiazem)
o peripheral vasculopathies and Raynaud's phenomenon (nifedipine)
* _RAAS inhibitors_
o _renin <http://focosi.altervista.org/enzymes.html#renin>
<http://focosi.altervista.org/enzymes.html#renin> inhibitors_
o _vasopeptide inhibitors_
+ _ACE
<http://focosi.altervista.org/enzymes.html#angiotensin%20I-converting%20enzyme%20%28ACE%29>
<http://focosi.altervista.org/enzymes.html#angiotensin%20I-converting%20enzyme%20%28ACE%29>
inhibitors (ACEI)_ : angiotensin II rapidly modulates
PVRs and slowly modulates renal sodium excretion and
heart remodelling. Unfortunately alternative pathways
exist for activation angiotensinogen (e.g. cathepsin
G, chymase, t-PA, ...) and at level of myocardium >
90% of angiotensin II is generated by chymase. They
prevent the positive effects of angiotensin II via
AT_2
<http://focosi.altervista.org/stpgipcrs.html#AT2>_
<http://focosi.altervista.org/stpgipcrs.html#AT2>
receptors.
# _short-acting_ (2-3 doses/day) : captopril,
delapril, quinapril, spirapril
# _long-acting_ (1 dose/day) : cilazapril,
enalapril, fosinopril, lisinopril, perindopril,
ramipril, trandolapril, zofenopril, moexipril,
alacepril
The esterified prodrug is hydrolyzed in mouth to
active diacid and biotrasformed in liver, plasma and
tissues. Renal clearance for most : hepatic clearance
for spirapril, mixed clearance for zofenopril and
fosinopril. While acute effect relates to renin
concentration, chronic effects are independent. Flat
dose-response curve : increased dose increases only
duration of action and side effects but not the
therapeutic effect (on the contrary of the
proportional curve of CCBs) !
Effects :
# mixed venous and arterial vasodilators,
reduction of PVRs without modifications of HR
and CI (thanks to inhibition of SNS), mild
natriuresis
# renal circulation : increased PRF and GFR
(vasodilation of efferent arteriole and reduced
contractility of mesangial cells) in patients
with normal renal function. In patients with
renal failure they increase PRF without
increasing GFR, so FF is not modified
# coronary circulation : increased coronary flow
thanks to reduction of coronary resistances
# cerebral circulation : vasodilation of
resistance arteries with left displacement of
autoregulation curve
# metabolic effects : do not modify lipid and
carbohydrate metabolism
Therapeutic indications :
# _systemic arterial hypertension
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#systemic%20arterial%20hypertension>_
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#systemic%20arterial%20hypertension>
# prevention of diabetic nephropathy (+/- renal
failure) also in patients with normal ABP,
glomerulonephritis, decrease of proteinuria.
Acutely ACEIs reduce GFR due to sudden drop of
intraglomerular pressure, but chronicly the
patient maintains for a longer time a good
filtration pressure as ACEIs avoid mesangial
hypetrophy and chronic glomerular stress
# increase efficacy of diuretics due to decreased
aldosterone incretion
# reduction of preload and afterload and systolic
wall stress => improves left ventricle
hypertrophy and hence CHF
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>.
Side effects : orthostatic systemic arterial
hypotension
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#orthostatic%20systemic%20arterial%20hypotension>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#orthostatic%20systemic%20arterial%20hypotension>
and bilateral renal artery stenosis (RAS)
<http://focosi.altervista.org/pathohomotissueurinary.html#renal%20artery%20stenosis%20%28RAS%29%20/%20ischemic%20nephropathy>
<http://focosi.altervista.org/pathohomotissueurinary.html#renal%20artery%20stenosis%20%28RAS%29%20/%20ischemic%20nephropathy>
=> acute renal failure
<http://focosi.altervista.org/pathohomotissueurinary.html#acute%20renal%20failure>
<http://focosi.altervista.org/pathohomotissueurinary.html#acute%20renal%20failure>
(the high ABP aimed to maintain an adequate GFR) in
patients with CHF, hyperkalemia
<http://focosi.altervista.org/chemicalcauses.htm#hyperkalemia>
<http://focosi.altervista.org/chemicalcauses.htm#hyperkalemia>
(in patients with CRF and assuming potassium-sparing
diuretics; not when associated with thiazide
diuretics), foetopathies, angioedema
<http://focosi.altervista.org/pathohomotissueimmunity_hypersensitivity.html#angioedema>
<http://focosi.altervista.org/pathohomotissueimmunity_hypersensitivity.html#angioedema>
(of the arytenoids^ref
<http://content.nejm.org/cgi/content/full/353/17/e15>
), dry cough
<http://focosi.altervista.org/pathohomotissuerespiratory.html#dry%20/%20non-productive%20cough>
<http://focosi.altervista.org/pathohomotissuerespiratory.html#dry%20/%20non-productive%20cough>
(10-20% due to decreased cleavage of bradykinin and
substance P; dose-independent), neutropenia
<http://focosi.altervista.org/pathohomotissueblood_WBCquantitative.html#neutropenia>
<http://focosi.altervista.org/pathohomotissueblood_WBCquantitative.html#neutropenia>,
hepatotoxicity, rarely parageusias
<http://focosi.altervista.org/senseorgans.html#parageusia>
<http://focosi.altervista.org/senseorgans.html#parageusia>,
bullous pemphigus
<http://focosi.altervista.org/pathohomotissueskin.html#pemphigus>
<http://focosi.altervista.org/pathohomotissueskin.html#pemphigus>,
fatigue, vertigo, dysphonia. Shift to _AT_1a
<http://focosi.altervista.org/stpgqpcrs.html#AT1a>_
<http://focosi.altervista.org/stpgqpcrs.html#AT1a> _
receptor blockers. Infants exposed to ACEIs during any
of the 3 trimesters of pregnancy are at increased risk
for malformations of the cardiovascular system (risk
ratio = 3.72) and the CNS (RR = 4.39)^ref
<http://content.nejm.org/cgi/content/abstract/354/23/2443>
+ _NEP
<http://focosi.altervista.org/enzymes.html#dipeptidyl-dipeptidase>
<http://focosi.altervista.org/enzymes.html#dipeptidyl-dipeptidase>
inhibitors_
o _AT_1a <http://focosi.altervista.org/stpgqpcrs.html#AT1a>_
<http://focosi.altervista.org/stpgqpcrs.html#AT1a> receptor
blockers (ARB) / antagonists (ATRA)_ (-sartans) : effective
after 4-6 weeks. They can be associated to ACEI and
diuretics (less effective than ACEIs against hypertension).
Only candesartan is a prodrug. Half-life varying from 2 hrs
(losartan) to 15-17 hrs (irbesartan). Losartan is
transformed into a metabolite (E3174) with longer half-life
(6-9 hrs) and more active. Hepatic clearance, very low
bioavailability

Effects :
+ prevention of fast pressure responses (direct
vasoconstriction, peripheral SNS stimulation to
increased norepinephrine release, central SNS
hypertone, reduced norepinephrine reuptake, adrenal
catecholamine release)
+ prevention of slow pressure responses (renal sodium
resorption, aldosterone incretion, renal hemodynamics)
+ mitogen activities
+ uricosuria
+ neutral effect on lipid metabolism
+ improve insulin resistance
Indications : hyperuricemia (gout)
<http://focosi.altervista.org/pathohomotissueskeletal.html#gout>
<http://focosi.altervista.org/pathohomotissueskeletal.html#gout>
as they increase uricuria
+ patients who took their pills every day halved their
risk of dying by the end of the study, compared with
those who skipped pills, regardless of whether they
took candesartan cilexetil or a placebo. Those who
stuck to their pills were also less likely to spend
time in hospital. Experts suspect that those who stick
to their medicine are also more likely to stick to
other heart-healthy activities such as regular
exercise, good diet and not smoking or drinking. These
behaviours alone probably outweigh the physiological
effect of the drug. If doctors could identify those
patients who are unlikely to take their drugs
regularly, Granger believes that they could be
targeted with education or social support that would
encourage them to follow a healthier lifestyle. Some
researchers, for example, are examining whether there
are biochemical tests that would reliably show whether
people are taking their drugs regularly. 2 other
earlier investigations have also shown that patients
with heart disease get benefits from taking a regular
placebo that almost match those provided by b-blockers
or lipid-lowering drugs. But researchers have
struggled to explain exactly what is different about
those who follow their doctor's instructions compared
with those who flout them. Another, more
controversial, implication of the new results is that
those people who are diligent about taking their drugs
and following a healthy lifestyle might reap the same
benefit if they cut their dose or switched from active
drugs to a cheaper placebo
Contraindications : pregnancy
Side effects : they don't cause severe orthostatic systemic
arterial hypotension
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#orthostatic%20systemic%20arterial%20hypotension>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#orthostatic%20systemic%20arterial%20hypotension>,
dry cough
<http://focosi.altervista.org/pathohomotissuerespiratory.html#dry%20/%20non-productive%20cough>
<http://focosi.altervista.org/pathohomotissuerespiratory.html#dry%20/%20non-productive%20cough>,
angioedema
<http://focosi.altervista.org/pathohomotissueimmunity_hypersensitivity.html#angioedema>
<http://focosi.altervista.org/pathohomotissueimmunity_hypersensitivity.html#angioedema>
o _AT_2 <http://focosi.altervista.org/stpgipcrs.html#AT2>_
<http://focosi.altervista.org/stpgipcrs.html#AT2> receptor
agonists_

*Anti-sexual dysfunction xenobiotics *:

* *_anti-_penile erectile dysfunction (ED)
<http://focosi.altervista.org/pathohomotissuereproductive.html#penile%20erectile%20dysfunction%20%28ED%29>
<http://focosi.altervista.org/pathohomotissuereproductive.html#penile%20erectile%20dysfunction%20%28ED%29>_
xenobiotics_*
o _penile arteries and corpus cavernosum vasodilators_
+ _PDE5A
<http://focosi.altervista.org/enzymes.html#PDE5A>
<http://focosi.altervista.org/enzymes.html#PDE5A>
inhibitors_

Side effects :
# due to inhibition of PDE5 in other tissues :
headache
<http://focosi.altervista.org/senseorgans.html#Headache>
<http://focosi.altervista.org/senseorgans.html#Headache>,
facial flushing
<http://focosi.altervista.org/pathohomotissueskin.html#flushing>
<http://focosi.altervista.org/pathohomotissueskin.html#flushing>,
thinitis, dyspepsia due to relaxation of the LES
# due to inhibition of PDE6 : changes in the
perception of color hue or brightness
# potentiation of effect of NO^. -releasing
molecules
<http://focosi.altervista.org/stp.htm#spontaneous%20and%20bioreductive%20NO.%20donors%20:>
<http://focosi.altervista.org/stp.htm#spontaneous%20and%20bioreductive%20NO.%20donors%20:>
administered within 24 hours
# prolongation of cardiac repolarization by
blocking I_Kr
# sterility
<http://focosi.altervista.org/pathohomotissuereproductive.html#sterility>
<http://focosi.altervista.org/pathohomotissuereproductive.html#sterility>
: mice given the equivalent of a human Viagra
dose fertilized roughly 30% fewer female eggs
than normal, and many of the eggs fertilized
grew more slowly, in contrast to human studies,
which have found no adverse effects on
fertility. Around 23 million men worldwide have
taken Viagra since its launch in 1998. The exact
proportion trying to conceive is not known, but
according to the manufacturer, Pfizer, the
majority of users are over 50 years old. But
younger people are increasingly using it,
sometimes as a recreational drug. After adding
Viagra to mouse sperm in a test-tube, the sperm
swam more vigorously but matured too early,
regurgitating enzymes that normally help them
invade the egg. Researchers say they do not yet
know if Viagra might have long-term effects on
mouse fertility, or any effects at all on
fertility in humans. It is also unclear whether
the drug might affect the fertility of women,
who sometimes take Viagra to increase their
arousal. Should the finding prove applicable to
humans, it might be affecting the success rate
of IVF
<http://focosi.altervista.org/exvivo.html#In%20vitro%20fertilization%20and%20embryo%20transfer%20%28FIVET%29>
<http://focosi.altervista.org/exvivo.html#In%20vitro%20fertilization%20and%20embryo%20transfer%20%28FIVET%29>
: men are sometimes given Viagra to help them
produce a sperm sample in fertility clinics
# anti-impotence drugs could be forced to carry
warnings about possible links to sexually
transmitted diseases
<http://focosi.altervista.org/pathohomotissuereproductive.html#sexually%20transmitted%20diseases%20%28STD%29>
<http://focosi.altervista.org/pathohomotissuereproductive.html#sexually%20transmitted%20diseases%20%28STD%29>.
Anti-impotence drugs increased gay men's
abilities to have more sex, sometimes with more
partners. Drugs like Viagra also countered the
temporary impotence caused by other drugs such
as crystal meth. Because of the increased
duration of erection, the increased blood flow,
it actually increases the physical risk of
getting an STD or HIV infection when having sex
with an infected partner. Pfizer would oppose
the extra labelling saying people needed to take
personal responsibility for their sexual behaviour.
+ Uprima^® (Ixense, TAK-251, apomorphine HCl)
+ Alibra^®
+ Alprox-TD^® (Befar^® )
+ apomorphine (nasal delivery)
+ GPI 1485
+ PT-141
+ TA-1790
+ PGE_1
<http://focosi.altervista.org/chemotherapynonxeno.html#PGE1>
<http://focosi.altervista.org/chemotherapynonxeno.html#PGE1>
+ VML 670
+ product development suspended/terminated Vasomax^®
(phentolamine mesylate, Z-MAX)
+ non-selective D agonists (e.g. apomorphine
<http://focosi.altervista.org/stpgipcrs.html#apomorphine>
<http://focosi.altervista.org/stpgipcrs.html#apomorphine>).
Side effects : _nausea and vomiting
<http://focosi.altervista.org/pathohomotissuegastro.html#Vomiting>_
<http://focosi.altervista.org/pathohomotissuegastro.html#Vomiting>
+ D_4 antagonists
<http://focosi.altervista.org/stpgipcrs.html#D4>
<http://focosi.altervista.org/stpgipcrs.html#D4> (e.g.
ABT-724^ref <http://dx.doi.org/10.1073/pnas.0308292101> )
* *anti-female sexual dysfunction (FSD) / female sexual arousal
disorder
<http://focosi.altervista.org/psychiatry.html#female%20sexual%20arousal%20disorder>
<http://focosi.altervista.org/psychiatry.html#female%20sexual%20arousal%20disorder>
xenobiotics *:
o PGE_1
<http://focosi.altervista.org/chemotherapynonxeno.html#PGE1>
<http://focosi.altervista.org/chemotherapynonxeno.html#PGE1>
o AR agonists
<http://focosi.altervista.org/stpnuclear.html#androgen%20receptor>
<http://focosi.altervista.org/stpnuclear.html#androgen%20receptor>
o MC1R agonists
<http://focosi.altervista.org/stpgspcrs.html#MC1R>
<http://focosi.altervista.org/stpgspcrs.html#MC1R>
(PT-141)^ref <http://dx.doi.org/10.1073/pnas.0400491101>
o product development suspended/terminated : Vasofem^(TM)
(phentolamine mesylate)

*Anti-premature ejaculation (PE)
<http://focosi.altervista.org/psychiatry.html#premature%20ejaculation>
<http://focosi.altervista.org/psychiatry.html#premature%20ejaculation>
xenobiotics *:

* dapoxetine
* VI-0134
* VI-0162

*_Antiarrhythmic xenobiotics_* (vs. cardiac arrhythmias
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#arrhythmias>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#arrhythmias>,
expecially used to treat PSVT
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#paroxysmal%20supraventricular%20tachycardia%20%28PSVT%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#paroxysmal%20supraventricular%20tachycardia%20%28PSVT%29>
and AF
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#atrial%20fibrillation%20%28AF%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#atrial%20fibrillation%20%28AF%29>)
: _Vaughan Williams' classification_^ref
<http://circ.ahajournals.org/cgi/ijlink?linkType=ABST&journalCode=jclinpharm&resid=24/4/129>

* _class I agents_ : _IV voltage-gated Na^+ channel
<http://focosi.altervista.org/stpion.html#Na+%20channel>
<http://focosi.altervista.org/stpion.html#Na+%20channel> blockers_
(block the channel in the open configuration) in tissue with fast
response action potentials reduce maximal velocity of phase of
depolarization (V_max )
o _Ia_ : decreased maximal rate of depolarization (MRD) at all
HR, increased action potential duration (APD), increased ERP
(slow recovery), decreased AV conduction rate, decreased
contractility
+ disopyramide
<http://focosi.altervista.org/stpion.html#disopyramide>
<http://focosi.altervista.org/stpion.html#disopyramide>

Side effects :
# nonarrhythmic toxicity : anticholinergic actions
: dry mouth, urinary retention, visual
disturbances (avoid in narrow-angle glaucoma),
constipation, congestive heart failure
# proarrhytmic toxicity : torsades de pointes
(2%), atrial flutter with 1:1 atrioventricular
conduction (+), VT/VF (++), bradycardia (+)
+ procainamide
<http://focosi.altervista.org/stpion.html#procainamide>
<http://focosi.altervista.org/stpion.html#procainamide>
=> /N/-acetyl procainamide (NAPA) (class III)

Side effects :
# nonarrhythmic toxicity : lupus
erythematosus-like syndrome, anorexia, nausea
# proarrhytmic toxicity : torsades de pointes
(2%), atrial flutter with 1:1 atrioventricular
conduction (+), VT/VF (++), bradycardia (+)
+ quinidine
<http://focosi.altervista.org/stpion.html#quinidine>
<http://focosi.altervista.org/stpion.html#quinidine>

Side effects :
# nonarrhythmic toxicity : anorexia, nausea,
vomiting, diarrhea, cinchonism, tinnitus,
hearing and visual changes, thrombocytopenia,
hemolytic anemia, rash, potentiation of digoxin
levels
# proarrhytmic toxicity : torsades de pointes
(2%), atrial flutter with 1:1 atrioventricular
conduction (++), VT/VF (++), bradycardia (+)
o _Ib_ : decreased MRD in partially depolarized cells with
fast response action potentials (little effect at slow HR in
normal tissue), no change or decreased APD, very increased
ERP (rapid recovery), unmodified SA rate and AV conduction
rate, unmodified contractility. Effects increased at faster
rates
+ lidocaine / lignocaine
<http://focosi.altervista.org/stpion.html#lidocaine>
<http://focosi.altervista.org/stpion.html#lidocaine>
(expecially used in emergecies after defibrillation
<http://focosi.altervista.org/electrotherapy.html#Defibrillation>
<http://focosi.altervista.org/electrotherapy.html#Defibrillation>
to prevent pulseless VF and SVT) : negative
bathmotropic and dromotropic effects. Hepatic
catabolism. 1-5 mg / Kg.

Side effects :
# nonarrhythmic toxicity : dizzines, confusion,
delirium, seizures
<http://focosi.altervista.org/pathohomotissuecns.html#seizure>
<http://focosi.altervista.org/pathohomotissuecns.html#seizure>,
coma, transplacental passage
# proarrhytmic toxicity : bradycardia (may
suppresss sinus node function in patients with
underlying sinus node dysfunction. May suppress
escape foci in patients with complete heart block)
+ mexiletine
<http://focosi.altervista.org/stpion.html#mexiletine>
<http://focosi.altervista.org/stpion.html#mexiletine>

Side effects :
# nonarrhythmic toxicity : dizziness, nausea
# proarrhytmic toxicity : torsades de pointes
(rare), atrial flutter with 1:1 atrioventricular
conduction (+++), VT/VF (++), bradycardia (++)
+ morizicine
<http://focosi.altervista.org/stpion.html#morizicine>
<http://focosi.altervista.org/stpion.html#morizicine>^ref
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1377359&dopt=Abstract>

+ propafenone
<http://focosi.altervista.org/stpion.html#propafenone>
<http://focosi.altervista.org/stpion.html#propafenone>
p.o.

Contraindications : avoid in patients with prior
myocardial infarction and depressed left ventricular
function. Use in combination with AV nodal blocking
agent to limit risk of atrial flutter with 1:1
atrioventricular conduction
Side effects :
# nonarrhythmic toxicity : taste disturbance,
bronchospasm
# proarrhytmic toxicity : torsades de pointes
(rare), atrial flutter with 1:1 atrioventricular
conduction (+++), VT/VF (++), bradycardia (++)
? : _aprindine_, _AR-LH 31_, _CCI 22277_, _sparteine_,
_debrisoquine_ (Declinax^® )
Negative chronotropic and dromotropic effects (in both
nodes; may cause reentry !), PR and QRS lengthening.
Side effects : taste disorders, headache
<http://focosi.altervista.org/senseorgans.html#Headache>
<http://focosi.altervista.org/senseorgans.html#Headache>,
constipation
<http://focosi.altervista.org/pathohomotissuegastro.html#Constipation>
<http://focosi.altervista.org/pathohomotissuegastro.html#Constipation>,
_nausea and vomiting
<http://focosi.altervista.org/pathohomotissuegastro.html#Vomiting>
<http://focosi.altervista.org/pathohomotissuegastro.html#Vomiting>_,
conduction disorders (AV block, ...), heart failure
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>,
bradycardia, /angina pectoris/. 90% are RM, 10% SM. _class II agents_ are anti-sympathetic nervous system agents : b_1
* <http://focosi.altervista.org/stpgspcrs.html#b1>_
<http://focosi.altervista.org/stpgspcrs.html#b1> antagonists
(esmolol, propranolol, and metoprolol : _sotalol
<http://focosi.altervista.org/stpgspcrs.html#sotalol>
<http://focosi.altervista.org/stpgspcrs.html#sotalol>_ is also
class III)) => decreased automaticity of SA node, increased AV
nodal refractoriness, decreased or unmodified AV conduction
velocity, unmodified MRD, unmodified APD, unmodified ERP, very
decreased contractility.

Side effects : CHF
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>,
bronchospasm from nonselective b-agonists, sexual impotence, lack
* of symptoms of iatrogenic insulin-induced hypoglicemia. _class III
agents_ affect potassium (K^+ ) influx : unmodified MRD, /very
increased APD in tissue with fast-response action potentials/,
very increased ERP, decreased AV conduction rate, unmodified or
very decreased contractility, don't act on depolarization phase I
=> not used in fibrillations. Class III antiarrhythmic agents
exhibit reverse use dependent prolongation of the action potential
duration (_reverse use-dependence_). This means that the
refractoriness of the ventricular myocyte increases at lower heart
rates. This increases the susceptibility of the myocardium to
early after-depolarizations (EADs) at low heart rates.
Antiarrhythmic agents that exhibit reverse use-dependence are more
efficacious at preventing a tachyarrhythmia that converting
someone into normal sinus rhythm. Because of the reverse
use-dependence of class III agents, at low heart rates class III
antiarrhythmic agents may paradoxically be more arrhythmogenic.
o voltage-gated K^+ channel
<http://focosi.altervista.org/stpion.html#K+%20channel>
<http://focosi.altervista.org/stpion.html#K+%20channel>
blockers :
+ _amiodarone IV (fast) or PO (slow)_ also blocks Na^+
<http://focosi.altervista.org/stpion.html#Na+%20channel>^
<http://focosi.altervista.org/stpion.html#Na+%20channel>
and L-type Ca^2+
<http://focosi.altervista.org/stpion.html#Ca2+%20channel>^
<http://focosi.altervista.org/stpion.html#Ca2+%20channel>
voltage-dependent channels and acts as an antagonist
of both a- and b_1
<http://focosi.altervista.org/stpgspcrs.html#b1>_
<http://focosi.altervista.org/stpgspcrs.html#b1> -AR
(has effects consistent with all of the first 4
classes !) => lengthening of PR and QT tracts,
negative bathmotropic and chronotropic effects,
reduced PVR, increased EF (+42% after 2 years).
Hepatic catabolism. Half-life : 53 days.

Indications : indicated for the treatment of
refractory VT or VF, particularly in the setting of
acute ischemia. Amiodarone is also safe to use in
individuals with cardiomyopathy and atrial
fibrillation, to maintain normal sinus rhythm.
However, it does not cardiovert individuals from
atrial fibrillation to normal sinus rhythm.
Side effects (lasting for > 6 months after suspension
due to accumulation in fatty tissue) :
# nonarrhythmic toxicity : interstitial pneumonia
<http://focosi.altervista.org/pathohomotissuerespiratory.html#interstitial%20or%20primary%20atypical%20pneumonia>
<http://focosi.altervista.org/pathohomotissuerespiratory.html#interstitial%20or%20primary%20atypical%20pneumonia>
=> pulmonary fibrosis, skin hyperpigmentation
<http://focosi.altervista.org/pathohomotissueskin.html#hyperpigmentation>
<http://focosi.altervista.org/pathohomotissueskin.html#hyperpigmentation>,
hepatitis, primary hypothyroidism
(Wolff-Chaikoff effect => inhibition of
5'deiodinase and TR)
<http://focosi.altervista.org/pathohomotissueendocrine.html#primary%20hypothyroidism>
<http://focosi.altervista.org/pathohomotissueendocrine.html#primary%20hypothyroidism>
(39% of /M/_r consists of iodide; prevalence of
disease = 13% in iodine-rich areas, < 6% in
iodine-poor areas) or primary hyperthyroidism
(Jod-Basedow phenomenon, thyroiditis, or Graves'
disease)
<http://focosi.altervista.org/pathohomotissueendocrine.html#primary%20hyperthyroidism>
<http://focosi.altervista.org/pathohomotissueendocrine.html#primary%20hyperthyroidism>
(_amiodarone-induced thyrotoxicosis (AIT)_,
worsening arrhythmias and coronaropathies : 10%
in iodine-poor areas; 2% in iodine-rich areas),
photosensitivity, peripheral neuropathy, tremor,
cornea verticillata
<http://focosi.altervista.org/pathohomotissuecns.html#cornea%20verticillata>
<http://focosi.altervista.org/pathohomotissuecns.html#cornea%20verticillata>,
sleep disorders
<http://focosi.altervista.org/psychiatry.html#sleep%20disorders>
<http://focosi.altervista.org/psychiatry.html#sleep%20disorders>
# proarrhytmic toxicity : torsades de pointes
(rare), atrial flutter with 1:1 atrioventricular
conduction (+++), VT/VF (+++), bradycardia (+++
: atrioventricular blocks
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#atrioventricular%20%28AV%29%20block>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#atrioventricular%20%28AV%29%20block>)
+ _dofetilide_^ref
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10907968>

+ _ibutilide_ is the only antiarrhythmic agent currently
approved by the FDA for acute conversion of atrial
fibrillation to sinus rhythm.
+ _sotalol
<http://focosi.altervista.org/stpgspcrs.html#sotalol>
<http://focosi.altervista.org/stpgspcrs.html#sotalol>_
(also class II) for treatment of atrial or ventricular
tachyarrhythmias, and AV re-entrant arrhythmias
o NRI <http://focosi.altervista.org/stptransporters.html#NRI>
<http://focosi.altervista.org/stptransporters.html#NRI>
+ _bretylium_ tosylate (Bretylol^® )
o _/N/-acetyl procainamide (NAPA)_ (a catabolyte of
procainamide, a class Ia agent)
o _azimilide_ (Stedicor^® ) p.o. for treating both
supraventricular and ventricular tachyarrhythmias^ref
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15720225>

o _clofilium_ (Clofilium^® )
* _class IV agents_ affect the AV node : non-DHP _L-type
voltage-gated Ca^2+ channels blockers (CCB)_
<http://focosi.altervista.org/stpion.html#benzothiazepines>_
<http://focosi.altervista.org/stpion.html#benzothiazepines>_
(verapamil, diltiazem) => unmodified MRD,/ very decreased APD/,
unmodified ERP, very decreased AV conduction velocity in tissue
with slow-response action potentials (indicated in atrial
fibrillation
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#atrial%20fibrillation%20%28AF%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#atrial%20fibrillation%20%28AF%29>),
very decreased contractility => contraindicated in patients with
congestive heart failure
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>

Side effects : systemic arterial hypotension
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#vascular%20hypotension>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#vascular%20hypotension>
=> reflex tachycardia
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#tachycardia>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#tachycardia>.
* _class V agents_ work by other or unknown mechanisms (added /a
posteriori/)
o adenosine
<http://focosi.altervista.org/chemotherapynonxeno.html#adenosine>
<http://focosi.altervista.org/chemotherapynonxeno.html#adenosine>
(negative bathmotropic and dromotropic effect).

Torsades de pointes (TDP) occurs most often in the setting of slow heart
rates, QT prolongation, and hypokalemia or hypomagnesemia and at the
time of conversion from atrial fibrillation to sinus rhythm. QT
prolongation and torsades de pointes are not dose-related phenomena. QRS
prolongation is a dose-related phenomenon also and will occur at toxic
concentration. QT and WRS interval should be monitored and dose
reductions made for interval prolongations.

*Anti-chronic stable angina
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#stable%20angina%20pectoris>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#stable%20angina%20pectoris>
xenobiotics *:

drug

usual dose

side effects

contraindications

nitrates sublingual nitroglycerin 0.3-0.6 mg flushing, headache
intolerance of side effects
isosorbide dinitrate
<http://focosi.altervista.org/drugsrenal.html#isosorbide%20dinitrate>
slow release oral 10-60 mg q8h flushing, headache, tolerance after
24 h as above, worsening ischemia on withdrawal
isosorbide dinitrate slow release oral SR 2.5-10 mgq4-6h
transdermal nitroglycerin
<http://focosi.altervista.org/stpgipcrs.html#A1> patch 0.4-1.2 mg/h for
12-14 h
isosorbide-5-mononitrate
<http://focosi.altervista.org/drugsrenal.html#isosorbide%205-mononitrate>
oral 20-30 mg bid
isosorbide-5-mononitrate oral slow release 60-240 mg once daily
b-blockers propanolol
<http://focosi.altervista.org/stpgspcrs.html#propanolol>
<http://focosi.altervista.org/stpgspcrs.html#propanolol> 20-80 mg qid
depression, constipation, impotence, bronchospasm, heart failure,
bradycardia asthma, AV conduction block, heart failure
metoprolol <http://focosi.altervista.org/stpgspcrs.html#metoprolol>
<http://focosi.altervista.org/stpgspcrs.html#metoprolol> 25-200 mg bid
atenolol <http://focosi.altervista.org/stpgspcrs.html#atenolol>
<http://focosi.altervista.org/stpgspcrs.html#atenolol> 50-150 mg once
daily
CCB nifedipine <http://focosi.altervista.org/stpion.html#nifedipine>
<http://focosi.altervista.org/stpion.html#nifedipine> slow release
preparation 30-90 mg daily hypotension, flushing, edema, worsening
angina hypotension, intolerance of side effects
diltiazem <http://focosi.altervista.org/stpion.html#diltiazem>
<http://focosi.altervista.org/stpion.html#diltiazem> slow release
60-120 mg bid constipation, AV conduction block, worsening heart
failure AV conduction block, impaired LV function, bradycardia
verapamil <http://focosi.altervista.org/stpion.html#verapamil>
<http://focosi.altervista.org/stpion.html#verapamil> slow release
180-240 mg daily constipation, AV conduction block, worsening heart
failure AV conduction delay, impaired LV function, bradycardia
amlodipine <http://focosi.altervista.org/stpion.html#amlodipine>
<http://focosi.altervista.org/stpion.html#amlodipine> slow release 5.10
mg daily edema intolerance of side effects

*_Anti-congestive heart failure (CHF)
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#%28congestive%29%20heart%20failure%20%28CHF%29>
xenobiotics_*

* diuretics <http://focosi.altervista.org/drugsrenal.html#diuretics>
o _A_1 <http://focosi.altervista.org/stpgipcrs.html#A1>_
<http://focosi.altervista.org/stpgipcrs.html#A1> antagonists_
* _positive inotropic drugs_
o _b_1 <http://focosi.altervista.org/stpgspcrs.html#b1>_
<http://focosi.altervista.org/stpgspcrs.html#b1> agonists_
o _IV Na^+ / K^+ ATPase
<http://focosi.altervista.org/enzymes.html#3%20Na+%20/%202%20K+%20ATPase>
<http://focosi.altervista.org/enzymes.html#3%20Na+%20/%202%20K+%20ATPase>
inhibitors_ (digoxin) => indirect inhibition of Na^+ /Ca^2+
antiporter => positive inotropic effect.

*_Vasoprotectants_*

* _S-5682_ : 90% micronized diosmin + 10% flavonoids expressed as
hesperidin (Daflon 500^® ) inhibits leukocyte activation,
trapping, and migration => reduces permeability for
macromolecules induced by ischemia-reperfusion => reduces
postischemic edema formation in the early reperfusion period. No
general effect on the inflammatory process could be observed as
assessed by levels of cytokines and soluble adhesion molecules.
Possible explanations for these findings could be that a decreased
number of primed granulocytes leave the circulation due to a
changed WBC/endothelial cell interaction or that flavonoids have a
direct effect on granulocytes.
* _diosmin_ (Arvesum^® , Venosmine^® )
* _hesperidin_
* _hydrosoluble flavonoids_ (Alven^® , Doven^® , Diosven^® ,
Arvenum^® , Daflon^® )
* _anthocyanosides in anthocyanidine_ (Tegens^® )
* escin <http://focosi.altervista.org/chemicalcauses.htm#aescin>
<http://focosi.altervista.org/chemicalcauses.htm#aescin> (Reparil^® )
* _triterpenes in /Centella asiatica/_
o _asiaticoside_
o _asiatic acid_
o _madecassoside_
o _madecassic acid_ (Centellase^® )
o _terminolic acid_
o _asiaticoside-B_
* _/O/-[b-hydroxyethyl]-rutosides_ (Venoruton^® )
* p.o. _chromocarbe diethylamine_ (Fludarene^® )
* _sulfomucopolysaccharide_ (Erevan^® )
* p.o. _tribenoside / ethyl-3,5,6-tri-/O/-benzyl-D-glucofuranoside
(TBGF)_ (Glyvenol^® )
* _naftazone_ (Etioven^® )
* denaturate alcohol, aqua, butylene glycole, methyl laccate,
propylene glycol, menthol, /Vaccinium myrtillus
<http://www.ncbi.nlm.nih.gov/htbin-post/Taxonomy/wgetorg?name=vaccinium+myrtillus>/
extract (a.k.a. whortleberry, bilberry), limonane, /Mentha
arvensis
<http://www.ncbi.nlm.nih.gov/htbin-post/Taxonomy/wgetorg?name=mentha+arvensis>/
leaf oil, /Citrus medica
<http://www.ncbi.nlm.nih.gov/htbin-post/Taxonomy/wgetorg?name=citrus+medica>
limonum/ peel oil (a.k.a. Buddha's hand, citron), /Cupressus
sempervirens
<http://www.ncbi.nlm.nih.gov/htbin-post/Taxonomy/wgetorg?name=cupressus+sempervirens>/
oil, /Lavandula
<http://www.ncbi.nlm.nih.gov/htbin-post/Taxonomy/wgetorg?name=lavandula>
hybrida/ oil, /Cistus ladaniferus/ oil (Tegevens^® )

*_Chondro-protective, chondro-stimulatory or chondro-nutritive agents
_*are able to inhibit enzymatic breakdown of articular cartilage,
stimulate anabolic processes in cartilage, and to enhance the supply of
nutritional and energy substrates for the cartilage cells

* Arteparon
* Rumalon
* Dona 200-S
* tribenoside (Glyvenol^® )
* pentosan polysulfate

*_Sclerosing agents or solutions / sclerosants_* (for sclerotherapy of
varices
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#varices>
<http://focosi.altervista.org/pathohomotissuecardiovascular.html#varices>)
: the best imaginable sclerosant would have no systemic toxicity. It
would be effective only above some threshold concentration, so that its
effects could be precisely localized through dilution. It would require
a long period of contact to be effective, so that it would be relatively
more effective in areas of stasis and relatively safer in the deep veins
where there is high flow. It would be non-allergenic. It would be strong
enough to sclerose even the largest vessels, yet it would produce no
local tissue injury if extravasated. It would not cause staining or
scarring. It would not cause telangiectatic matting. It would be
perfectly soluble in normal saline. It would be painless upon injection.
It would be inexpensive. It would be approved by the United States Food
and Drug Administration.

* _detergent_ sclerosants work by a mechanism known as protein theft
denaturation, in which an aggregation of detergent molecules forms
a lipid bilayer in the form of a sheet, a cylinder or a micelle,
which then disrupts the cell surface membrane and may steal away
essential proteins from the cell membrane surface. The loss of
these essential cell surface proteins causes a delayed cell death:
when endothelial cell membranes are exposed to detergent micelles,
irreversible cellular morphological changes are seen within
minutes by scanning electron microscopy, but the fatal cellular
changes that are visible by normal light microscopy do not become
apparent for many hours. Unlike many other agents, the detergent
sclerosants do not cause hemolysis, nor do they provoke direct
intravascular coagulation. Determinants of activity of detergent
solutions
o concentration : at low concentrations, most detergent
molecules are individually dissolved in solution, and there
are very few micellar aggregates. When the concentration
reaches some threshold (_critical micellar concentration
(CMC)_ nearly all further detergent molecules added to the
solution will enter into micelles. Micelles can cause
protein theft denaturation, but individual detergent
molecules have no toxicity to the vascular endothelium, thus
for each detergent sclerosant, there is some threshold
concentration below which the agent causes no injury. This
physical property means that detergent sclerosants offer
significant benefits over most of the agents previously
used, because they are potent agents that nonetheless have a
clear-cut threshold below which they have absolutely no
injurious effect on venous endothelium.
o temperature : the solubility of detergents is inversely
temperature dependent. Because of the highly polar nature of
water, and the entropic dependence of the hydrophobic
effect, detergent molecules are much more soluble in cold
solutions than in hot ones. This effect is easily seen in
everyday life: dishwashing detergent produces a large amount
of persistent foam in warm water, while cold water rinses
away the soapy foam easily. The solubility of sclerosing
agents such as polidocanol is likewise much higher in cold
solutions, and because single dissolved molecules are
ineffective, the strength of the sclerosing effect is higher
at warmer temperatures.
o mixing : detergent micellar formation can reach a maximum
level based upon the temperature and upon the concentration
of the detergent in solution. Micellar formation is a steric
process, however, and the geometry of macroassemblages often
prevents maximal micellar formation. The surface area of
lipid bilayer structures such as sheets, cylinders, and
micelles is maximized when the solution is shaken to produce
a foam. Because it is the surface of these structures that
causes protein theft denaturation, a solution that has been
shaken will be a more effective sclerosant than one that has
not. Unfortunately, foamy bubbles that are injected into
spider veins or varicose veins can pass through a patent
foramen ovale to lodge in the ocular and cerebral
circulation, where they have produced temporary ischemic
attacks with temporary blindness and other central nervous
system effects.
Currently available detergent agents :
o _sodium morrhuate_ : this detergent sclerosant is made up of
a mixture of saturated and unsaturated fatty acids extracted
from cod liver oil. It was introduced in 1920s, and is still
available today. Because it was in general use before there
was any requirement to demonstrate safety or efficacy it has
been exempted from the need for approval by the FDA for sale
in the United States, but there are several problems with
the product that make it a less than ideal agent for
sclerotherapy. It is a biological extract rather than a
synthetic preparation, and the composition varies somewhat
from lot to lot. Its components have been incompletely
characterized, and a significant fraction of its fatty acids
and alcohols are of chain lengths that probably do not
contribute to its effectiveness as a sclerosant. It is
unstable in solution, causes extensive cutaneous necrosis if
extravasated, and has been responsible for many cases of
anaphylaxis
o _ethanolamine oleate_ : ethanolamine oleate, a synthetic
preparation of oleic acid and ethanolamine, has weak
detergent properties because its attenuated hydrophobic
chain lengths make it excessively soluble and decrease its
ability to denature cell surface proteins. High
concentrations of the drug are necessary for effective
sclerosis, and its effectiveness in esophageal varices
depends upon mural necrosis. Allergic reactions are
uncommon, but there have been reports of pneumonitis,
pleural effusions, and other pulmonary symptoms following
the injection of ethanolamine oleate into esophageal
varices. Like sodium morrhuate, this agent was exempted from
the need for approval by the FDA for sale in the United
States. The principal disadvantages of the drug are a high
viscosity that makes injection difficult, a tendency to
cause red cell hemolysis and hemoglobinuria, the occasional
production of renal failure at high doses, the possibility
of pulmonary complications, and a relative lack of strength
compared with other available sclerosants.
o _sotradecol / sodium tetradecyl sulfate (codium
1-isobutyl-4-ethyloctyl sulfate)_ is a synthetic long chain
fatty acid that has seen extensive industrial use as a
synthetic surfactant (soap). It is sold for medical use as a
solution of up to 3% concentration with 2% benzoyl alcohol
used as a stabilant. It is effective as a venous sclerosing
agent in concentrations from 0.1% to 3%. Like sodium
morrhuate and ethanolamine oleate, it was 'grandfathered' by
the FDA for sale in the United States, but unlike sodium
morrhuate, sotradecol has proven to be a reliable, safe and
effective sclerosant. The principal clinical problems with
the drug are a tendency to cause hyperpigmentation in up to
30% of patients, a significant incidence of epidermal
necrosis upon extravasation, and occasional cases of anaphylaxis
o _polidocanol / hydroxy-polyethoxy-dodecane_ is a synthetic
long-chain fatty alcohol sold under many trade names
(Sclerovein^® , Aetoxysclerol^® , Aethoxysklerol^® ,
_/*Etoxisclerol*/_^® , Sotrauerix^® , Laureth 9^® ). All
commercially available formulations contain some small
quantity of ethanol. The drug was originally developed and
marketed in the 1950s under the name Sch 600^® as a
non-amide, non-ester local anaesthetic that was useful for
injected local anaesthesia as well as for epidural
anaesthesia and for topical mucosal anaesthesia. It was
first used as a sclerosing agent in Germany in the 1960s,
and was quickly adopted for that use in most countries. The
drug is not yet approved by the FDA for sale in the United
States as a sclerosing agent, but is nonetheless widely used
because it offers certain advantages over many other
available drugs. As a local anaesthetic, Polidocanol is
painless upon injection. It does not produce necrosis if
injected intradermally, and has been reported to have a very
low incidence of allergic reactions. The drug has been
intensely studied and extremely well characterized, and has
a high therapeutic index. The LD50 in rabbits is 200 mg/kg
(approximately 5 times greater than that of novocaine), and
the LD50 in mice is even greater, at 1200 mg/kg. *For human
use the German manufacturer of polidocanol recommends a
maximum daily dose of 2 mg per kg, although at least one
author has reported the routine use of much higher doses.
For all its advantages, polidocanol is not without problems
as a sclerosant. Occasional anaphylactic reactions have been
reported. In some patients it may produce hyperpigmentation,
although to a lesser extent than many other agents.
Telangiectatic matting after sclerotherapy with polidocanol
is as common as with any other agent.*
o Scleremo^® : a compound of 72% chromated glycerin, is a
polyalcohol that often is considered a chemical irritant
sclerosant. It is classified here with the detergents
because it is similar to the detergents in the way it causes
cell surface protein denaturation. It is very popular in
Europe, but it has not been approved by the FDA for use in
the United States, where it is virtually unknown. Compared
to other sclerosants it is a very weak sclerosant (it is
approximately 1/4 the strength of Polidocanol at the same
concentration and volume) and is principally useful in the
sclerosis of small vessels. Its principal advantage is that
it rarely causes hyperpigmentation or telangiectatic
matting, and that it very rarely causes extravasation
necrosis. The main problems with scleremo are that it is
hard to work with because it is extremely viscous, that it
can be quite painful on injection, that the chromate moiety
is highly allergenic, and that it has occasionally been
reported to cause ureteral colic and hematuria.
* _hypertonic and ionic solutions_ : strong solutions of hypertonic
saline and other salt solutions are part of a class of solutions
that are often referred to as osmotic sclerosants. These solutions
have long been regarded as causing endothelial death by osmotic
cellular dehydration. Although it is true that osmotic dehydration
at the point of injection is sufficient to rupture red blood cells
and to dehydrate some nearby endothelial cells, the evidence
suggests that these sclerosants are effective even after dilution
has reduced the osmotic gradient far too low to account for the
effects seen. Thermodynamic and physical chemical calculations
suggest that these and other strong ionic solutions probably work
by causing conformational denaturation of cell membrane proteins
in situ. Like the detergents, they can be diluted to the point
where they have no further cellular toxicity.
o _hypertonic saline_ : hypertonic solutions of saline became
popular agents for sclerotherapy after they were adopted for
that use by Linser in 1926. The most common preparations are
a 20% or 23.4% solution. The principal advantage of the
agent is the fact that it is a naturally occurring bodily
substance with no molecular toxicity. It has not been
approved by the FDA for use in sclerotherapy, but it has
been used successfully for that purpose by several
generations of physicians. There are several reasons why it
is not universally accepted as a desirable sclerosing agent.
Because of dilutional effects, it is difficult to achieve
adequate sclerosis of large vessels without exceeding a
tolerable salt load. It can cause significant pain on
injection, and significant cramping after a treatment
session. If extravasated, it almost invariably causes
significant necrosis. Because it causes immediate red blood
cell hemolysis and rapidly disrupts vascular endothelial
continuity, it is prone to cause marked hemosiderin staining
that is not very cosmetically acceptable. All of these
problems can be overcome to some extent by meticulous
technique and with experience, but patient satisfaction
remains lower than with some other available agents. In an
effort to reduce the complications, hypertonic saline has
been mixed with procaine and heparin in a compound known as
Heparsol^® . This approach has not proven effective, and is
rarely used today.
o Sclerodex^® is a mixture of 25% dextrose and 10% sodium
chloride, with a small quantity of phenethyl alcohol. A
primarily hypertonic agent, its effects are similar to those
of pure hypertonic saline, but the reduced salt load offers
certain benefits. It is not approved by the FDA for sale in
the United States. Like pure hypertonic saline, it is
somewhat painful on injection, and epidermal necrosis
continues to be the rule whenever extravasation occurs.
o _polyiodinated iodine_ (Variglobin^® , Sclerodine^® ) is a
mixture of elemental iodine with sodium iodide, along with a
small amount of benzyl alcohol. It is rapidly ionized and
rapidly protein-bound when injected, and most likely works
by localized ionic disruption of cell surface proteins/ in
situ/. /In vivo/ conversion of ionized iodine to iodide
renders the solution ineffective as a sclerosant, thus
localizing the sclerosing effects to the immediate area of
injection. The agent is not approved by the FDA for sale in
the USA, but is widely used in Europe. The problems with
this agent are its high tendency to cause extravasation
necrosis, its limited effectiveness at a distance from the
injection site, and the risks of anaphylaxis and of renal
toxicity that are associated with ionic iodinated solutions.
* cellular toxins : other chemical sclerosants exist that probably
act by a direct or indirect chemical toxicity to endothelial
cells: by poisoning some aspect of cellular activity that is
necessary for endothelial cell survival. Such agents are less
useful to the extent that they also poison other bodily cells.
They also lack another of the key attributes of a good sclerosant:
they remain toxic to some degree even after extreme dilution, so
that there is no real threshold below which injury will not occur

------------------------------------------------------------------------
<http://focosi.altervista.org/index.html>/Copyright © 2001-2005 Daniele
Focosi <http://focosi.altervista.org/autobiography.htm>. All rights
reserved /
<http://www.healthlinks.net/>

Kemudian:

*Mechanism of action of sclerosing agents
and rationale for selection of a sclerosing solution *

------------------------------------------------------------------------

Goals of sclerotherapy

When we treat varicosities and telangiectasias, we want to remove or
obliterate the abnormal vessels that carry retrograde flow, without
damaging adjacent or connected vessels that carry normal antegrade flow.
Obliterating a vessel is not easy: a small amount of damage will produce
intravascular thrombus, but thrombosis alone usually does not result in
obliteration of the vessel. Intact endothelium aggressively lyses
thrombus, and a thrombosed vessel with intact endothelium will not be
sclerosed.

<http://veins.com/pix/cycle.gif>

Recanalization of thrombosed vessels <http://veins.com/pix/cycle.gif>

Vascular fibrosis and obliteration only occurs in response to
irreversible endothelial cellular destruction and exposure of the
underlying subendothelial cell layer.

If an injected sclerosant is too weak, there may be no endothelial
injury at all. If the sclerosant is a little stronger, the varicose
vessel is damaged, but recanalization occurs and an incompetent pathway
for retrograde blood flow persists. If the injected sclerosant is too
strong, the varicose vessel endothelium is destroyed, but the sclerosant
also flows into adjacent normal vessels and causes damage there as well.
The key goal is to deliver a _minimum _volume and concentration of
sclerosant that will cause irreversible damage to the endothelium of the
abnormal vessel to be sclerosed, while leaving adjacent normal vessels
untouched. It is important to protect normal superficial vessels, and it
is critically important to avoid injuring the endothelium of deep veins,
because deep vein thrombosis places patients at risk of death from
thromboembolism, as well as causing permanent disability from chronic
deep venous valvular insufficiency. The rational treatment of
varicosities and telangiectasias by chemical sclerosis depends upon our
ability to produce vascular endothelial damage that is irreversible in
the area under treatment, but that does not extend to adjacent normal
vessels.

To limit endothelial injury to a controlled area, we exploit differences
in flow dynamics between the abnormal veins being perfused with
sclerosant and the adjacent normal vessels that should not be sclerosed.
A thorough understanding of the mechanism of action of the principal
sclerosing agents is essential, as is a firm grasp of the biophysical
principles underlying the techniques of sclerotherapy.

Volume dilution and patient positioning

Sclerosant is diluted with blood as it diffuses away from the site of
injection, thus if a strong sclerosant is injected there will be three
zones of action. In zone 1, vascular endothelium is irreversibly
injured: the vessel will be fully sclerosed and eventually will be
completely replaced by a fibrous tissue. In zone 2, vascular endothelium
is injured, and the vessel will be partially or completely thrombosed
but will eventually recanalize. In zone 3 the sclerosant will be diluted
below its injurious concentration, and there will be no endothelial injury.

<http://veins.com/pix/diffus1a.gif>

Dilution by diffusion from the injection site
<http://veins.com/pix/diffus1a.gif>

Because dilution of the sclerosant with blood occurs immediately upon
injection, the original injected concentration is of no real importance.
What is important is the diluted concentration of sclerosant at the
surface of the endothelium. An injected concentration that is perfectly
effective in a spider vein (where sclerosant displaces blood rather than
mixing with it) may be ineffective in a reticular feeding vein or a
truncal varix simply because dilution reduces the final concentration so
low that there will be no endothelial injury whatsoever (no zone I or
zone II). If the injected concentration is too high, dilution will leave
the final concentration so high that endothelial damage will occur where
it is not wanted (zone I and zone II are too large). If the injected
concentration is just right, dilution will leave a final concentration
that is sufficient to injure the local varicose endothelium, but not
high enough to damage normal superficial or deep veins (most of the
varicose vessel falls into zone I, a small amount falls into zone II,
and all normal vessels fall into zone III).

When we select a particular volume and concentration of a chemical agent
with which to sclerose a vessel, we are explicitly or implicitly
adjusting the injected concentration and volume to take into account the
dilution that will occur when the sclerosant is mixed with blood
immediately after injection. We also must take into account the further
dilution that will occur as the sclerosant flows or diffuses away from
the site of injection. The importance of patient positioning in
determining dilutional volume often is not properly appreciated by the
novice in phlebology.

Because of the cylindrical geometry of blood vessels, the volume
contained in a vessel depends on the square of the vesel radius: the
volume of any cylinder is calculated as pi * r2 * L (where r is the
radius and L is the length of the vessel). Vessels collapse to a smaller
radius when the legs are elevated, thus the volume contained is reduced
dramatically. For this reason, the position of the patient has a very
powerful effect on the final diluted concentration of sclerosant at the
surface of the vessel endothelium.

<http://veins.com/pix/tilt-1b.gif>

Effect of position on varicose geometry <http://veins.com/pix/tilt-1b.gif>

Standing

For a standing patient with a superficial varicosity of 2 cm in
diameter, the final concentration at a distance from the injection site
of 10 cm (4 inches) is 30 times lower than the initial concentration.
Doubling the initial concentration serves only to double the final
concentration, which will still be 15 times weaker than the
concentration in the syringe. In other words, if 1 cc of a 3% solution
is injected, the final concentration at the endothelial surface is 1% at
a distance of 1 cm from the injection point, 0.5% at a distance of 2cm,
0.25% at a distance of 4 cm, and 0.2% at a distance of 5cm (2 inches)
from the injection point. As we shall see, this means that it is very
difficult to achieve sclerosis of a large vessel by injecting detergent
sclerosants with the patient in a standing position: if the highest
available concentration is injected, the dilution factor may still drop
the final concentration below the threshold of effectiveness within 1.5
inches from the injection site.

Supine

What about the supine position? Varicose vessels that bulge when the
patient is standing may collapse when the patient is supine, but duplex
ultrasound readily demonstrates that the veins are not empty of blood.
Both varicose and normal vessels contain a significant volume of blood
with the legs extended in the supine position. A bulging varicosity that
has a diameter of 2 cm in the standing position may have a diameter of 1
cm in the supine position and of 0.5 cm or less when the legs are
elevated as high as possible. With such a patient in the supine
position, injection of 1 cc of a 3% solution leads to a final
concentration of approximately 1.7% at a distance of 1 cm and a
concentration of about 0.6% at a distance of 5 cm (2 inches). This
supine technique limits dilution enough to allow successful sclerosis of
large vessels using detergent solutions, so long as sufficient
concentrations and volumes of sclerosants are injected. The only problem
is that if an injection of sclerosant at a high initial concentration is
made directly into a perforating vessel, so that sclerosant flows
directly into the deep system, dilution within the deep vessel will
still permit zone I and zone II endothelial injury for a short distance
within the deep vein. This can lead to deep vein valve damage and
chronic venous insufficiency, to deep vein thrombosis, and to
life-threatening pulmonary embolism.

Legs elevated

In contrast to the standing and supine positions, when a patient lies
supine and the legs are raised vertically so that they are well above
the central circulation, most superficial varices collapse to the point
where they no longer contain any significant volume of blood. Repeating
the calculation above for a patient in this position, injection of 1cc
of a 3% solution leads to a final concentration of 2.5% at a distance of
1 cm from the injection, and a final concentration of 1.6% at a distance
of 5 cm (2 inches). In fact, the final concentration will still be above
1% at a distance of 10cm from the injection site. Because the
superficial varicosity is collapsed, there is very little dilution with
distance so long as the sclerosant stays within the floppy-walled
varicosity.

<http://veins.com/pix/graph01b.gif>

Graph: volume of dilution vs distance from injection site
<http://veins.com/pix/graph01b.gif>

What happens when sclerosant passes through into normal vessels?
Although flow measurements reveal little or no spontaneous flow through
varices and smaller superficial veins when the patient is in the leg-up
position, a substantial intravenous volume and a substantial rate of
flow still persists in the deep veins and in normal larger superficial
veins, which have less collapsible walls. This difference between the
volumes contained in floppy superficial varicose veins and the volumes
contained in normal surface veins and deep veins may be exploited to
cause damage that is almost perfectly localized to superficial varices.
If an elevated, empty varicose vessel is perfused with a concentration
of sclerosant _so low_ that even without dilution it is just barely
sufficient to cause endothelial injury, then any further dilution will
reduce the concentration below the threshold of injury. Because larger
superficial vessels and deep vessels continue to carry a volume of blood
in the leg-up position, any sclerosant passing into these vessels will
immediately be diluted to a safe and noninjurious concentration, sparing
the endothelium of vessels that we wish to preserve. Injection of this
'threshold' concentration directly into a perforating vein (or even
directly into a deep vein) will not cause any deep vein injury.

Types of sclerosants

Virtually any foreign substance can be utilized to cause venous
endothelial damage. Historical methods for producing venous endothelial
trauma have included '/a slender rod of iron/', reportedly used by
Hippocrates himself, /absolute alcohol/, introduced by Monteggio and by
Leroy D'Etoilles in the 1840s, and /ferric chloride/, introduced by
Charles-Gabriel Pravaz in 1851. In 1910 it was noted that the injection
of antisyphilitic mercurial drugs caused obliteration of antecubital
veins, and these agents were adapted for use in sclerotherapy. There
were many other drugs and techniques used for venous sclerosis during
these years, but all of them suffered from one or another problem that
made them unacceptable for modern use. Early sclerosing agents caused
many deaths from sepsis and from pulmonary embolism, as well as a high
incidence of allergic reactions, local tissue necrosis, pain, and failed
sclerosis.

The perfect sclerosant

The best imaginable sclerosant would have no systemic toxicity. It would
be effective only above some threshold concentration, so that its
effects could be precisely localized through dilution. It would require
a long period of contact to be effective, so that it would be relatively
more effective in areas of stasis and relatively safer in the deep veins
where there is high flow. It would be non-allergenic. It would be strong
enough to sclerose even the largest vessels, yet it would produce no
local tissue injury if extravasated. It would not cause staining or
scarring. It would not cause telangiectatic matting. It would be
perfectly soluble in normal saline. It would be painless upon injection.
It would be inexpensive. It would be approved by the United States Food
and Drug Administration.

No currently available sclerosant possesses all of the attributes of the
perfect sclerosing agent. All currently available sclerosants fall short
in one way or another, yet the variety of available agents is such that
virtually every situation in which sclerotherapy is indicated can be
safely and effectively handled by one or another of the available
sclerosants, used alone or in combination.

Detergents

In the 1930's the class of drugs known as detergents, or as fatty acids
and fatty alcohols, came into use with the introduction of /sodium
morrhuate/ and /sodium tetradecyl sulphate/. Detergent sclerosants work
by a mechanism known as protein theft denaturation, in which an
aggregation of detergent molecules forms a lipid bilayer in the form of
a sheet, a cylinder, or a micelle, which then disrupts the cell surface
membrane and may steal away essential proteins from the cell membrane
surface.

<http://veins.com/pix/pol4b.gif>

Self-assembly of a cylindrical macroaggregate of polidocanol
<http://veins.com/pix/pol4b.gif>

The loss of these essential cell surface proteins causes a delayed cell
death: when endothelial cell membranes are exposed to detergent
micelles, irreversible cellular morphological changes are seen within
minutes by scanning electron microscopy, but the fatal cellular changes
that are visible by normal light microscopy do not become apparent for
many hours. Unlike many other agents, the detergent sclerosants do not
cause hemolysis, nor do they provoke direct intravascular coagulation.

Determinants of activity of detergent solutions

1) Concentration

At low concentrations, most detergent molecules are individually
dissolved in solution, and there are very few micellar aggregates. When
the concentration reaches some threshold (known as the critical micellar
concentration, or CMC) nearly all further detergent molecules added to
the solution will enter into micelles. Micelles can cause protein theft
denaturation, but individual detergent molecules have no toxicity to the
vascular endothelium, thus for each detergent sclerosant, there is some
threshold concentration below which the agent causes no injury. This
physical property means that detergent sclerosants offer significant
benefits over most of the agents previously used, because they are
potent agents that nonetheless have a clear-cut threshold below which
they have absolutely no injurious effect on venous endothelium.

2) Temperature

The solubility of detergents is inversely temperature dependent. Because
of the highly polar nature of water, and the entropic dependence of the
hydrophobic effect, detergent molecules are much more soluble in cold
solutions than in hot ones. This effect is easily seen in everyday life:
dishwashing detergent produces a large amount of persistent foam in warm
water, while cold water rinses away the soapy foam easily. The
solubility of sclerosing agents such as polidocanol is likewise much
higher in cold solutions, and because single dissolved molecules are
ineffective, the strength of the sclerosing effect is higher at warmer
temperatures.

3) Mixing

Detergent micellar formation can reach a maximum level based upon the
temperature and upon the concentration of the detergent in solution.
Micellar formation is a steric process, however, and the geometry of
macroassemblages often prevents maximal micellar formation. The surface
area of lipid bilayer structures such as sheets, cylinders, and micelles
is maximized when the solution is shaken to produce a foam. Because it
is the surface of these structures that causes protein theft
denaturation, a solution that has been shaken will be a more effective
sclerosant than one that has not. Unfortunately, foamy bubbles that are
injected into spider veins or varicose veins can pass through a patent
foramen ovale to lodge in the ocular and cerebral circulation, where
they have produced temporary ischemic attacks with temporary blindness
and other central nervous system effects.

Currently available detergent agents

A) Sodium morrhuate

This detergent sclerosant is made up of a mixture of saturated and
unsaturated fatty acids extracted from cod liver oil. It was introduced
in 1920's, and is still available today. Because it was in general use
before there was any requirement to demonstrate safety or efficacy it
has been exempted from the need for approval by the Food and Drug
Administration (FDA) for sale in the United States, but there are
several problems with the product that make it a less than ideal agent
for sclerotherapy. It is a biological extract rather than a synthetic
preparation, and the composition varies somewhat from lot to lot. Its
components have been incompletely characterized, and a significant
fraction of its fatty acids and alcohols are of chain lengths that
probably do not contribute to its effectiveness as a sclerosant. It is
unstable in solution, causes extensive cutaneous necrosis if
extravasated, and has been responsible for many cases of anaphylaxis.

B) Ethanolamine oleate

Ethanolamine oleate, a synthetic preparation of oleic acid and
ethanolamine, has weak detergent properties because its attenuated
hydrophobic chain lengths make it excessively soluble and decrease its
ability to denature cell surface proteins. High concentrations of the
drug are necessary for effective sclerosis, and its effectiveness in
esophageal varices depends upon mural necrosis. Allergic reactions are
uncommon, but there have been reports of pneumonitis, pleural effusions,
and other pulmonary symptoms following the injection of ethanolamine
oleate into esophageal varices. Like sodium morrhuate, this agent was
exempted from the need for approval by the Food and Drug Administration
(FDA) for sale in the United States. The principal disadvantages of the
drug are a high viscosity that makes injection difficult, a tendency to
cause red cell hemolysis and hemoglobinuria, the occasional production
of renal failure at high doses, the possibility of pulmonary
complications, and a relative lack of strength compared with other
available sclerosants.

C) Sotradecol

Sodium tetradecyl sulfate (Sodium 1-isobutyl-4-ethyloctyl sulfate) is a
synthetic long chain fatty acid that has seen extensive industrial use
as a synthetic surfactant (soap). It is sold for medical use as a
solution of up to 3% concentration with 2% benzoyl alcohol used as a
stabilant. It is effective as a venous sclerosing agent in
concentrations from 0.1% to 3%. Like sodium morrhuate and ethanolamine
oleate, it was 'grandfathered' by the Food and Drug Administration (FDA)
for sale in the United States, but unlike sodium morrhuate, sotradecol
has proven to be a reliable, safe and effective sclerosant. The
principal clinical problems with the drug are a tendency to cause
hyperpigmentation in up to 30% of patients, a significant incidence of
epidermal necrosis upon extravasation, and occasional cases of anaphylaxis.

D) Polidocanol

Polidocanol (hydroxy-polyethoxy-dodecane) is a synthetic long-chain
fatty alcohol sold under many trade names (Sclerovein, Aetoxysclerol,
Aethoxysklerol, Etoxisclerol, Sotrauerix, Laureth 9).

<http://veins.com/pix/pol1c.gif>

Structure of polidocanol monomer <http://veins.com/pix/pol1c.gif>

All commercially available formulations contain some small quantity of
ethanol. The drug was originally developed and marketed in the 1950s
under the name /Sch 600/ as a non-amide, non-ester local anaesthetic
that was useful for injected local anaesthesia as well as for epidural
anaesthesia and for topical mucosal anaesthesia. It was first used as a
sclerosing agent in Germany in the 1960's, and was quickly adopted for
that use in most countries. The drug is not yet approved by the FDA for
sale in the United States as a sclerosing agent, but is nonetheless
widely used because it offers certain advantages over many other
available drugs. As a local anaesthetic, Polidocanol is painless upon
injection. It does not produce necrosis if injected intradermally, and
has been reported to have a very low incidence of allergic reactions.
The drug has been intensely studied and extremely well characterized,
and has a high therapeutic index. The LD50 in rabbits is 200 mg/kg
(approximately 5 times greater than that of novocaine), and the LD50 in
mice is even greater, at 1200 mg/kg. For human use the German
manufacturer of polidocanol recommends a maximum daily dose of 2 mg per
kg, although at least one author has reported the routine use of much
higher doses.{1353} For all its advantages, polidocanol is not without
problems as a sclerosant. Occasional anaphylactic reactions have been
reported. In some patients it may produce hyperpigmentation, although to
a lesser extent than many other agents. Telangiectatic matting after
sclerotherapy with polidocanol is as common as with any other agent.

E) Scleremo

Scleremo, a compound of 72% chromated glycerin, is a polyalcohol that
often is considered a chemical irritant sclerosant. It is classified
here with the detergents because it is similar to the detergents in the
way it causes cell surface protein denaturation. It is very popular in
Europe, but it has not been approved by the FDA for use in the United
States, where it is virtually unknown. Compared to other sclerosants it
is a very weak sclerosant (it is approximately 1/4 the strength of
Polidocanol at the same concentration and volume) and is principally
useful in the sclerosis of small vessels. Its principal advantage is
that it rarely causes hyperpigmentation or telangiectatic matting, and
that it very rarely causes extravasation necrosis. The main problems
with scleremo are that it is hard to work with because it is extremely
viscous, that it can be quite painful on injection, that the chromate
moiety is highly allergenic, and that it has occasionally been reported
to cause ureteral colic and hematuria.

Hypertonic and ionic solutions

Strong solutions of hypertonic saline and other salt solutions are part
of a class of solutions that are often referred to as /osmotic
sclerosants/. These solutions have long been regarded as causing
endothelial death by osmotic cellular dehydration. Although it is true
that osmotic dehydration at the point of injection is sufficient to
rupture red blood cells and to dehydrate some nearby endothelial cells,
the evidence suggests that these sclerosants are effective even after
dilution has reduced the osmotic gradient far too low to account for the
effects seen. Thermodynamic and physical chemical calculations suggest
that these and other strong ionic solutions probably work by causing
conformational denaturation of cell membrane proteins in situ. Like the
detergents, they can be diluted to the point where they have no further
cellular toxicity.

A) Hypertonic saline

Hypertonic solutions of saline became popular agents for sclerotherapy
after they were adopted for that use by Linser in 1926. The most common
preparations are a 20% or 23.4% solution. The principal advantage of the
agent is the fact that it is a naturally occurring bodily substance with
no molecular toxicity. It has not been approved by the FDA for use in
sclerotherapy, but it has been used successfully for that purpose by
several generations of physicians. There are several reasons why it is
not universally accepted as a desirable sclerosing agent. Because of
dilutional effects, it is difficult to achieve adequate sclerosis of
large vessels without exceeding a tolerable salt load. It can cause
significant pain on injection, and significant cramping after a
treatment session. If extravasated, it almost invariably causes
significant necrosis. Because it causes immediate red blood cell
hemolysis and rapidly disrupts vascular endothelial continuity, it is
prone to cause marked hemosiderin staining that is not very cosmetically
acceptable. All of these problems can be overcome to some extent by
meticulous technique and with experience, but patient satisfaction
remains lower than with some other available agents. In an effort to
reduce the complications, hypertonic saline has been mixed with procaine
and heparin in a compound known as /Heparsol/. This approach has not
proven effective, and is rarely used today.

B) Sclerodex

Sclerodex is a mixture of 25% dextrose and 10% sodium chloride, with a
small quantity of phenethyl alcohol. A primarily hypertonic agent, its
effects are similar to those of pure hypertonic saline, but the reduced
salt load offers certain benefits. It is not approved by the FDA for
sale in the United States. Like pure hypertonic saline, it is somewhat
painful on injection, and epidermal necrosis continues to be the rule
whenever extravasation occurs.

C) Polyiodinated iodine

Polyiodinated iodine (Variglobin, Sclerodine) is a mixture of elemental
iodine with sodium iodide, along with a small amount of benzyl alcohol.
It is rapidly ionized and rapidly protein-bound when injected, and most
likely works by localized ionic disruption of cell surface proteins in
situ. In vivo conversion of ionized iodine to iodide renders the
solution ineffective as a sclerosant, thus localizing the sclerosing
effects to the immediate area of injection. The agent is not approved by
the FDA for sale in the United States, but is widely used in Europe. The
problems with this agent are its high tendency to cause extravasation
necrosis, its limited effectiveness at a distance from the injection
site, and the risks of anaphylaxis and of renal toxicity that are
associated with ionic iodinated solutions.

Cellular toxins

Other chemical sclerosants exist that probably act by a direct or
indirect chemical toxicity to endothelial cells: by poisoning some
aspect of cellular activity that is necessary for endothelial cell
survival. Such agents are less useful to the extent that they also
poison other bodily cells. They also lack another of the key attributes
of a good sclerosant: they remain toxic to some degree even after
extreme dilution, so that there is no real threshold below which injury
will not occur.

Summary

The guiding principle of modern sclerotherapy is to cause irreversible
endothelial injury in the desired location, while avoiding any damage to
normal vessels that may be interconnected with the abnormal vessel we
are treating. Our aim is to deliver the minimum volume and minimum
concentration of the most appropriate sclerosant, and to inject it under
conditions that will achieve the minimum effective exposure. Sclerosant
concentration, volume, temperature, mixing, and patient positioning are
more important in this endeavor than the choice of the actual sclerosing
agent. With attention to these details, an accomplished phlebologist can
achieve good results with virtually any currently available sclerosing
agent.

Jadi pertanyaannya apakah obat ini utk thyroid?
Dan apakah benar menggunakan injection tersebut menyelesaikan persoalan
dg pembengkakan jaringan thyroid, atau anda berada pada status sebagi
kelinci percobaan?

Sallam,

Amani Goland wrote:
> Wah.., kagak ada yang tanggapin nih.
>
> Padahal rencananya obat ini hendak disuntikkan ke thyroid saya yang
> membengkak.
>
> Hanya saya memang agat takut, karena dari 4 dokter yang saya tanyai,
> hanya satu yang mengetahui obat ini.
>
> dan ketika saya membeli obat di Pramuka. Toko apotiknya bilang kalau
> obat ini Illegal. Itu yang membuat saya menjadi takut.
>
> Dan searching di internet, sepertinya fungsinya adalah
> untuk "HARDENER", sehingga saya takut jika saya disuntik dan masuk
> ke pembuluh darah apakah akan menyebabkan darah menjadi kental ?
>
>
>
> Salam
>
> Anton Goland.
>
> --- In dokter_umum@yahoogroups.com, "Amani Goland" <goland_mail@...>
> wrote:
>
>> Saya mau tanya dong.
>>
>> Apakah fungsi dari Obat EtoxiSclerol.
>>
>> Apakah obat tersebut bisa digunakan untuk penyembuhan Thyroid Cyst.
>>
>> Komposisi obat.
>>
>> 1. Polidacanol
>> 2. Etanol
>> 3. Agua para inyectable c.s.p
>>
>>
>> Salam
>>
>> Goland
>>
>>
>
>
>
> ------------------------------------
>
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