xenobiotics
Side effects : orthostatic systemic arterial hypotension
.
Table of contents :
Anti-systemic
arterial hypertension
xenobiotics
Side effects : orthostatic
systemic arterial hypotension.
inhibitors (CAI) inhibit NaHCO3 reabsorption.
(inhibition of carbonic anhydrase in eye), urine alkalinization to improve
urinary clearance of some toxics
,
metabolic
acidosis,
hypothyroidism
due to inhibition of iodine uptake.
=> slow administration
(cardiovascular surgery, Mb-mediated crush syndrome, surgery in patients
with jaundice), dialysis
dysequilibrium syndrome,
reduction of IOP (acute attacks of glaucoma,
preoperative and postoperative short-term reduction), cerebral
edema
(before and after neurosurgery)
,
acute
pulmonary edema,
severe dehydratation, chronic
renal failure
with stabilized anemia (poorly filtered => would increase ECF volume !)
,
nausea
and vomiting
inhibitors / loop diuretics / high-ceiling diuretics (e.g. furosemide)
: effective within 10' IV, 1 hr PO; effective even if GFR < 30 mL/min
(when thiazides are uneffective) and pH-independent (unaffected by metabolic
acidosis in acute renal failure),
chronic pulmonary edema unresponsive to other drugs, hypercalcemia,
hyperkalemia
,
hyponatremia,
hypokalemia,
hypomagnesemia,
hypocalcemia,
GI or cutaneous atopy, thrombocytopenia,
leukopenia,
CNS impairment, deafness, allergic interstitial nephritis (do not co-administer
with aminoglycosides).
inhibitors (e.g. thiazide diuretics),
urolithiasis,
and osteopenia/osteoporosis
(they cause hypercalcemia
and hypocalciuria),
less potent than loop diuretics => used in chronic systemic arterial hypertension,
mild edema
,
intoxication from Digitalis
glycosides,
hypokalemia
(not when associated with ACEI !) => IGT => diabetes
mellitus,
hypercalcemia,
dizziness,
headache,
abdominal
cramping,
insomnia,
depression,
drug
rash with eosinophilia and systemic symptoms (DRESS)
inhibitors : K+-sparing diuretics sensu strictu
antagonists,
hypokalemia
,
hyperkalemia,
metabolic
acidosis,
sexual
impotence,
dysmenorrhoea.
antagonists
antagonists,
2,
3,
and 6
inhibitors
inhibitors).
channel activators
incretion (minoxidil
: hirsutism).
agonists.,
pulsating headache
,
palpitations (dose-dependent)
agonists
agonists))
and associated with diuretics
reduces HR, CO, and PVR; a TTS formulation is available for once a week
dose; rebound phenomenon (withdrawal crises) => gradual suspension.,
xerostomia,
constipation,
ejaculation, diplopia,
sedation, sleep disorders
(lethargy),
sinusal
bradycardia,
depression
antagonists
blocks NE exocytosis in both central and peripheral noradrenergic neurons.
and acts as an inactive substitute neurotransmitter
inhibitors-antagonists
directly vasodilate peripheral arteries and veins and also act centrally
by increasing [NE]synaptic space => increased negative feedback
on a2
receptors => no tachycardia. They improve dyslipidemias and benign
prostatic hypertrophy (BPH).
Hepatic clearance
within 90' from first dose ("first-dose phenomenon"), compensatory
tachycardia,
sleepiness, headache, nasal congestion, xerostomia
-antagonists
incretion in juxtaglomerular cells-antagonists
only at low doses) are preferred in patients with bronchial
asthma,
COPD or peripheral vasculopathies; e.g. bisoprolol (b1/b2
ratio = 75), atenolol and metoprolol (b1/b2
ratio = 35), acebutolol and esmolol
and b2
antagonists)-agonists)
:
-
and 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 b1 antagonist
activity. No effects on lipid profile and glucose tolerance, antioxidant
properties
(reduction of oxygen consumption and contractility), secondary prevention
of AMI,
systemic
arterial hypertension
(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,
tachycardia,
tremor (dopants in precision exercises)
(reduce symptoms from mechanisms that compesate iatrogenic insulin-induced
hypoglycemia),
bronchial
asthma,
SA
and/or AV node dysfunctions,
CHF
(even if they are useful if monitorated !), Raynaud
phenomenon,
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)
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,
facial
flushing,
malleolar angioedema (dose-dependent), palpitations (reflexed
tachycardia),
gastrointestinal disturbances (vomiting, constipation),
gingival hypertrophy (rare)
,
gingival hypertrophy (rare)
,
CHF,
atrioventricular
blocks,
headache,
constipation
(reduced muscle tone), gingival hypertrophy (rare)
(verapamil, diltiazem)
(verapamil, diltiazem, but also amlodipine)
(inhibit the initial vasoconstriction followed by vasodilation) (verapamil)
inhibitors
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 AT2
receptors..
and bilateral renal
artery stenosis (RAS)
=> acute renal
failure
(the high ABP aimed to maintain an adequate GFR) in patients with CHF,
hyperkalemia
(in patients with CRF and assuming potassium-sparing diuretics; not when
associated with thiazide diuretics), foetopathies, angioedema
(of the arytenoidsref),
dry
cough
(10-20% due to decreased cleavage of bradykinin and substance P; dose-independent),
neutropenia,
hepatotoxicity, rarely parageusias,
bullous
pemphigus,
fatigue, vertigo, dysphonia. Shift to 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
inhibitors
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
as they increase uricuria
,
dry
cough,
angioedema
receptor agonists
xenobiotics
inhibitors,
facial
flushing,
thinitis, dyspepsia due to relaxation of the LES
administered within 24 hours
: 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
: men are sometimes given Viagra to help them produce a sperm sample in
fertility clinics.
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.).
Side
effects : nausea
and vomiting
(e.g. ABT-724ref)
xenobiotics :
(PT-141)ref
xenobiotics :
,
expecially used to treat PSVT
and AF)
: Vaughan Williams' classificationref
blockers (block the channel in the open configuration) in tissue with
fast response action potentials reduce maximal velocity of phase of depolarization
(Vmax)
=> N-acetyl procainamide (NAPA) (class III)
(expecially used in emergecies after defibrillation
to prevent pulseless VF and SVT) : negative bathmotropic and dromotropic
effects. Hepatic catabolism. 1-5 mg / Kg.,
coma, transplacental passage
p.o.ref
p.o.,
constipation,
nausea
and vomiting,
conduction disorders (AV block, ...), heart
failure,
bradycardia, angina pectoris. 90% are RM, 10% SM.
antagonists (esmolol, propranolol, and metoprolol : 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.,
bronchospasm from nonselective b-agonists, sexual
impotence, lack of symptoms of iatrogenic insulin-induced hypoglicemia.
blockers :
and L-type Ca2+
voltage-dependent channels and acts as an antagonist of both a-
and 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.
=> pulmonary fibrosis, skin
hyperpigmentation,
hepatitis, primary
hypothyroidism (Wolff-Chaikoff effect => inhibition of 5'deiodinase and
TR)
(39% of Mr 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)
(amiodarone-induced thyrotoxicosis (AIT), worsening arrhythmias
and coronaropathies : 10% in iodine-poor areas; 2% in iodine-rich areas),
photosensitivity, peripheral neuropathy, tremor,
cornea
verticillata,
sleep
disorders)
(also class II) for treatment of atrial or ventricular tachyarrhythmias,
and AV re-entrant arrhythmias
(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),
very decreased contractility => contraindicated in patients with congestive
heart failure
=> reflex tachycardia.
(negative bathmotropic and dromotropic effect).,
facial
flushing,
thoracic
pain
antagonists are used in cardiac
arrest
to annihilate the effect of vagus nerve. Atropine is contraindicated in
patients with glaucoma]Anti-chronic
stable angina
xenobiotics :
|
|
|
|
|
|
| nitrates | sublingual nitroglycerin | 0.3-0.6 mg | flushing, headache | intolerance of side effects |
| isosorbide dinitrate 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
patch |
0.4-1.2 mg/h for 12-14 h | |||
| isosorbide-5-mononitrate oral | 20-30 mg bid | |||
| isosorbide-5-mononitrate oral slow release | 60-240 mg once daily | |||
| b-blockers | propanolol |
20-80 mg qid | depression, constipation, impotence, bronchospasm, heart failure, bradycardia | asthma, AV conduction block, heart failure |
| metoprolol |
25-200 mg bid | |||
| atenolol |
50-150 mg once daily | |||
| CCB | nifedipine
slow release preparation |
30-90 mg daily | hypotension, flushing, edema, worsening angina | hypotension, intolerance of side effects |
| diltiazem
slow release |
60-120 mg bid | constipation, AV conduction block, worsening heart failure | AV conduction block, impaired LV function, bradycardia | |
| verapamil
slow release |
180-240 mg daily | constipation, AV conduction block, worsening heart failure | AV conduction delay, impaired LV function, bradycardia | |
| amlodipine
slow release |
5.10 mg daily | edema | intolerance of side effects | |
Anti-congestive
heart failure (CHF)
xenobiotics
antagonists
agonists
inhibitors (digoxin) => indirect inhibition of Na+/Ca2+
antiporter => positive inotropic effect.
),
respiratory and cardiac disturbance,
lidocaine
for arrhtyhmias.
inhibitors
(Reparil®))
: 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.
Copyright © 2001-2014 Daniele Focosi.
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