Alpha blocker

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Alpha_blocker 

 

Alpha blockers α-blockers
Drug class
Class identifiers
Use	• Hypertension  • Vasoconstriction  • BPH  • Raynaud's Disease  • Pheochromocytoma  • CHF  • Erectile Dysfunction
Mechanism of action	• Receptor antagonist  • Inverse agonist  • Neutral antagonist
Biological target	α-adrenoceptors
In Wikidata

Specific locations and functions of the α receptors. Image from Basic and Clinical Pharmacology by Bertram Katzung, et al.

Alpha-blockers, also known as α-blockers or α-adrenoreceptor antagonists, are a class of pharmacological agents that act as antagonists on α-adrenergic receptors (α-adrenoceptors).

Historically, alpha-blockers were used as a tool for pharmacologic research to develop a greater understanding of the autonomic nervous system. Using alpha blockers, scientists began characterizing arterial blood pressure and central vasomotor control in the autonomic nervous system. Today, they can be used as clinical treatments for a limited number of diseases.

Although alpha blockers can only treat a small range of diseases, some of them have clinical uses, such as having the ability to treat hypertension, Raynaud's disease, and erectile dysfunction. Generally speaking, all of these treatments function by binding an α-blocker to α receptors in the arteries and smooth muscle. Ultimately, depending on the type of alpha receptor, this relaxes the smooth muscle or blood vessels, which increases fluid flow in these entities.

Classification

Schematic of G Protein Coupled Receptor Signaling, representing Gi GPCR signaling, Gs GPCR signaling, and Gq GPCR signaling.

• α₁-blockers act on α₁-adrenoceptors
• α₂-blockers act on α₂-adrenoceptors

When the term "alpha blocker" is used without further qualification, it can refer to an α₁ blocker, an α₂ blocker, a nonselective blocker (both α₁ and α₂ activity), or an α blocker with some β activity. However, the most common type of alpha blocker is usually an α₁ blocker. 

Non-selective α-adrenergic receptor antagonists include:

• Phenoxybenzamine
• Phentolamine
• Tolazoline
• Trazodone

Selective α₁-adrenergic receptor antagonists include:

• Alfuzosin
• Doxazosin
• Prazosin (inverse agonist)
• Tamsulosin
• Terazosin
• Silodosin

Selective α₂-adrenergic receptor antagonists include:

• Atipamezole
• Idazoxan
• Mirtazapine
• Yohimbine

Finally, the agents carvedilol and labetalol are both α and β-blockers.

Medical uses

While there are limited clinical α-blocker uses, in which most α-blockers are used for hypertension or benign prostatic hyperplasia , α-blockers can be used to treat a few other diseases, such as Raynaud's disease, congestive heart failure (CHF), pheochromocytoma, and erectile dysfunction.

Furthermore, α-blockers can occasionally be used to treat anxiety and panic disorders, such as posttraumatic stress disorder (PTSD) induced nightmares. Studies have also had great medical interest in testing alpha blockers, specifically α₂ blockers, to treat Type II diabetes and psychiatric depression.

Hypertension

Hypertension is due to an increase in vascular resistance and vasoconstriction. Using α₁ selective antagonists, such as prazosin, has been efficacious in treating mild to moderate hypertension. This is because they can decrease vascular resistance and decrease pressure. However, while these drugs are generally well tolerated, they have the potential to produce side effects such as orthostatic hypotension and dizziness.

Another treatment for hypertension is using drugs that have both α₁ blocking activity, as well as nonselective β activity, such as Labetalol or carvedilol. In low doses, labetalol and carvedilol can decrease the peripheral resistance and block the effects of isoprenaline to reduce hypertensive symptoms.

Pheochromocytoma

An image of a patient with pheochromocytoma. In patients with this disease, a catecholamine secreting tumor is formed, and causes excess CNS stimulation, such as excess sweating and tachycardia. Nonselective alpha blockers, such as phenoxybenzamine or phentolamine, can be used to mitigate this disease.

 

Pheochromocytoma is a disease in which a catecholamine secreting tumor develops. Specifically, norepinephrine and epinephrine are secreted by these tumors, either continuously or intermittently. The excess release of these catecholamines increases central nervous system stimulation, thus causing blood vessels to increase in vascular resistance, and ultimately giving rise to hypertension. In addition, patients with these rare tumors are often subject to headaches, heart palpitations, and increased sweating.

Phenoxybenzamine, a nonselective α₁ and α₂ blocker, has been used to treat pheochromocytoma. This drug blocks the activity of epinephrine and norepinephrine by antagonizing the alpha receptors, thus decreasing vascular resistance, increasing vasodilation, and decreasing blood pressure overall.

Congestive heart failure

Blockers that have both the ability to block both α and β receptors, such as carvedilol, bucindolol, and labetalol, have the ability to mitigate the symptoms in congestive heart failure. By binding to both the α and β receptors, these drugs can decrease the cardiac output and stimulate the dilation of blood vessels to promote a reduction in blood pressure.

Erectile dysfunction

Yohimbine, an α₂ blocker derived from the bark of the Pausinystalia johimbe tree, has been tested to increase libido and treat erectile dysfunction. The proposed mechanism for yohimbine is blockade of the adrenergic receptors that are associated with neurotransmitters inhibition, including dopamine and nitric oxide, and thus aiding with penile erection and libido. By doing so, they can alter the blood flow in the penis to aid in achieving an erection. However, some side effects can occur, such as palpitation, tremor, elevated blood pressure, and anxiety. Yohimbe bark contains both alpha-1 and alpha-2 adrenergic receptors blocking alkaloids.

Phentolamine, a non-selective alpha blocker, has also been tested to treat erectile dysfunction. By reducing vasoconstriction in the penis, there appears to be increased blood flow that aids in penile erection. Side effects associated with phentolamine include headache, flushing, and nasal congestion.

Benign prostate hyperplasia, a disease in which urinary retention becomes an issue. Alpha-1 blockers can be used, but it can result in side effects such as increased urination and retrograde ejaculation.

Benign prostatic hyperplasia

In benign prostatic hyperplasia (BPH), men experience urinary obstruction and are unable to urinate, thus leading to urinary retention. α₁ specific blockers have been used to relax the smooth muscle in the bladder and enlarged prostate. Prazosin, doxazosin, and terazosin have been particularly useful for patients with BPH, especially in patients with hypertension. In such patients, these drugs can treat both conditions at the same time. In patients without hypertension, tamsulosin can be used, as it has the ability to relax the bladder and prostate smooth muscle without causing major changes in blood pressure.

Raynaud's disease

Patients with Raynaud's syndrome experience cut off blood flow from the fingers causing a large decrease in oxygen, which leads to the discoloration of the fingers. Using alpha blockers aids in restoring blood flow and treating the syndrome by stimulating the dilation of blood vessels.

 

Both α₁ blockers and α₂ blockers have been examined to treat Raynaud's disease. Although α₁ blockers, such as prazosin, have appeared to give slight improvement for the sclerotic symptoms of Raynaud's disease, there are many side effects that occur while taking this drug. Conversely, α₂ blockers, such as Yohimbine, appear to provide significant improvement of the sclerotic symptoms in Raynaud's Disease without excessive side effects.

Post traumatic stress disorder

Patients with posttraumatic stress disorder (PTSD) have often continued to be symptomatic despite being treated with PTSD-specific drugs. In addition, PTSD patients often have debilitating nightmares that continue, despite their treatments. High doses of the α₁ blocker, prazosin, have been efficacious in treating patients with PTSD induced nightmares due to its ability to block the effects of norepinephrine.

Adverse effects of prazosin to treat PTSD nightmares include dizziness, First Dose Effect (a sudden loss of consciousness), weakness, nausea, and fatigue.

Adverse effects

Although alpha blockers have the ability to reduce some disease pathology, there are some side effects that come with these alpha blockers. However, because there are several structural compositions that make each alpha blocker different, the side effects are different for each drug. Side effects that arise when taking alpha blockers can include the first dose effect, cardiovascular side effects, genitourinary side effects, as well as other side effects.

First dose effect

One of the most common side effects with alpha blockers is the first dose effect. This is a phenomenon in which patients with hypertension take an alpha blocker for the first time, and suddenly experience an intense decrease in blood pressure. Ultimately, this gives rise to orthostatic hypotension, dizziness, and a sudden loss of consciousness due to the drastic drop in blood pressure.

Alpha blockers that possess these side effects include prazosin, doxazosin, and terazosin.

Cardiovascular side effects

There are some alpha blockers that can give rise to changes in the cardiovascular system, such as the induction of reflex tachycardia, orthostatic hypotension, or heart palpitations via alterations of the QT interval.

Alpha blockers that may have these side effects include yohimbine, phenoxybenzamine, and phentolamine.

Genitourinary side effects

When alpha blockers are used to treat BPH, it causes vasodilation of blood vessels on the bladder and the prostate, thus increasing urination in general. However, these alpha blockers can produce the exact opposite side effect, in which edema, or abnormal fluid retention, occurs.

In addition, due to the relaxation of the prostate smooth muscle, another side effect that arises in men being treated for BPH is impotence, as well as the inability to ejaculate. However, if any ejaculation activity does occur, oftentimes, it results in a phenomenon called retrograde ejaculation, in which semen flows into the urinary bladder instead of exiting through the urethra.

Drugs that may produce such side effects include prazosin, terazosin, tamsulosin, and doxazosin.

Other side effects

Finally, there are other general side effects that can be caused by most alpha blockers (however, more frequently in alpha-1 blockers). Such side effects include dizziness, drowsiness, weakness, fatigue, psychiatric depression, and dry mouth.

Contraindications

There is only one compelling indication for alpha blockers, which is for benign prostatic hyperplasia. Patients who need alpha blockers for BPH, but have a history of hypotension or postural heart failure, should use these drugs with caution, as it may result in an even greater decrease in blood pressure or make heart failure even worse. The most compelling contraindication is urinary incontinence and overall fluid retention. To combat such fluid retention, patients can take a diuretic in combination with the alpha-blocker.

In the absence of compelling indications or contraindications, patients should take alpha blockers as a step 4 therapy to reduce blood pressure, but only if the use of ACE inhibitors, angiotensin-II receptor blockers, calcium channel blockers, or thazide diuretics (in full dose or in combinations) have not been efficacious.

Drug interactions

As with any drug, there are drug interactions that can occur with alpha blockers. For instance, alpha blockers that are used for the reduction of blood pressure, such as phenoxybenzamine or phentolamine can have synergy with other drugs that affect smooth muscle, blood vessels, or drugs used for erectile dysfunction (i.e. sildenafil, tamsulosin, etc.). This stimulates exaggerated hypotension.

Alternative alpha blockers, such as prazosin, tamsulosin, doxazosin, or terazosin can have adverse interactions with beta blockers, erectile dysfunction drugs, anxiolytics, and antihistamines. Again, these interactions can cause dangerous hypotension. Furthermore, in rare cases, drug interactions can cause irregular, rapid heartbeats or an increase blood pressure.

Yohimbine can interact with stimulants, hypertension drugs, naloxone, and clonidine. Interactions with such drugs can cause either an unintended increase in blood pressure or potentiate an increase in blood pressure.

Finally, in drugs with both alpha and beta blocking properties, such as carvedilol and labetalol, interactions with other alpha or beta blockers can exaggerate a decrease in blood pressure. Conversely, there are also drug interactions with carvedilol or labetalol in which blood pressure is increased unintentionally (such as with cough and cold medications). Finally, there may also be some alpha/beta blocker drug interactions that can worsen previous heart failure.

Mechanism of action

Alpha blockers work by blocking the effect of nerves in the sympathetic nervous system. This is done by binding to the alpha receptors in smooth muscle or blood vessels. α-blockers can bind both reversibly and irreversibly.

There are several α receptors throughout the body where these drugs can bind. Specifically, α₁ receptors can be found in most vascular smooth muscle, the pupillary dilator muscle, the heart, the prostate, and pilomotor smooth muscle. On the other hand, α₂ receptors can be found in platelets, cholinergic nerve terminals, some vascular smooth muscle, postsynaptic CNS neurons, and fat cells.

The structure of α receptors is a classic G protein–coupled receptors (GPCRs) consisting of 7 transmembrane domains, which form three intracellular loops and three extracellular loops. These receptors couple to heterotrimeric G proteins composed of α, β, and γ subunits. Although both of the α receptors are GPCRs, there are large differences in their mechanism of action. Specifically, α₁ receptors are characterized as G_q GPCRs, signaling through Phospholipase C to increase IP₃ and DAG, thus increasing the release of calcium. Meanwhile, α₂ receptors are labeled as G_i GPCRs, which signal through adenylyl cyclase to decrease cAMP.

Because the α₁ and α₂ receptors have different mechanisms of action, their antagonists also have different effects. α₁ blockers can inhibit the release of IP₃ and DAG to decrease calcium release, thus, decreasing overall signaling. On the other hand, α₂ blockers prevent the reduction of cAMP, thus leading to an increase in overall signaling.

Beta blocker

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Beta_blocker 

 

Beta blockers
Drug class
Skeletal formula of propranolol, the first clinically successful beta blocker
Class identifiers
Synonyms	beta-blockers, β-blockers, beta-adrenergic blocking agents, beta antagonists, beta-adrenergic antagonists, beta-adrenoreceptor antagonists, beta adrenergic receptor antagonists, BB
Use	Hypertension, arrhythmia, etc.
ATC code	C07
Biological target	beta receptors
Clinical data
Drugs.com	Drug Classes
Consumer Reports	Best Buy Drugs
WebMD	MedicineNet  RxList
External links
MeSH	D000319

Beta blockers (beta-blockers, β-blockers, etc.) are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack (myocardial infarction) after a first heart attack (secondary prevention). They are also widely used to treat high blood pressure (hypertension), although they are no longer the first choice for initial treatment of most patients.

Beta blockers are competitive antagonists that block the receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response. Some block activation of all types of β-adrenergic receptors and others are selective for one of the three known types of beta receptors, designated β₁, β₂ and β₃ receptors. β₁-adrenergic receptors are located mainly in the heart and in the kidneys. β₂-adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β₃-adrenergic receptors are located in fat cells.

Beta receptors are found on cells of the heart muscles, smooth muscles, airways, arteries, kidneys, and other tissues that are part of the sympathetic nervous system and lead to stress responses, especially when they are stimulated by epinephrine (adrenaline). Beta blockers interfere with the binding to the receptor of epinephrine and other stress hormones, and weaken the effects of stress hormones.

In 1964, James Black synthesized the first clinically significant beta blockers—propranolol and pronethalol; it revolutionized the medical management of angina pectoris and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.

For the treatment of primary hypertension, meta-analyses of studies which mostly used atenolol have shown that although beta blockers are more effective than placebo in preventing stroke and total cardiovascular events, they are not as effective as diuretics, medications inhibiting the renin–angiotensin system (e.g., ACE inhibitors), or calcium channel blockers.

Medical uses

Large differences exist in the pharmacology of agents within the class, thus not all beta blockers are used for all indications listed below. 

Indications for beta blockers include:

• Angina pectoris (contraindicated for Prinzmetal's angina)
• Atrial fibrillation
• Cardiac arrhythmia
• Congestive heart failure
• Essential tremor
• Glaucoma (As eye drops, they decrease intraocular pressure by lowering aqueous humor secretion.)
• Hypertension, although they are generally not preferred as an initial treatment.
• Hyperthyroidism
• Migraine prophylaxis
• Mitral valve prolapse
• Myocardial infarction
• Phaeochromocytoma, in conjunction with α-blocker
• Postural orthostatic tachycardia syndrome
• Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism
• Theophylline overdose

Beta blockers have also been used for:

• Acute aortic dissection
• Hypertrophic obstructive cardiomyopathy
• Long QT syndrome
• Marfan syndrome (treatment with propranolol slows progression of aortic dilation and its complications)
• Prevention of variceal bleeding in portal hypertension
• Possible mitigation of hyperhidrosis
• Social and other anxiety disorders
• Controversially, for reduction of perioperative mortality in non-cardiac surgery, but the best evidence suggests that they increase mortality when used this way

Congestive heart failure

Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition due to their effect of decreasing cardiac contractility, studies in the late 1990s showed their efficacy at reducing morbidity and mortality. Bisoprolol, carvedilol, and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure, although at doses typically much lower than those indicated for other conditions. Beta blockers are only indicated in cases of compensated, stable congestive heart failure; in cases of acute decompensated heart failure, beta blockers will cause a further decrease in ejection fraction, worsening the patient's current symptoms.

Beta blockers are known primarily for their reductive effect on heart rate, although this is not the only mechanism of action of importance in congestive heart failure. Beta blockers, in addition to their sympatholytic β1 activity in the heart, influence the renin–angiotensin system at the kidneys. Beta blockers cause a decrease in renin secretion, which in turn reduces the heart oxygen demand by lowering extracellular volume and increasing the oxygen-carrying capacity of blood. Heart failure characteristically involves increased catecholamine activity on the heart, which is responsible for a number of deleterious effects, including increased oxygen demand, propagation of inflammatory mediators, and abnormal cardiac tissue remodeling, all of which decrease the efficiency of cardiac contraction and contribute to the low ejection fraction. Beta blockers counter this inappropriately high sympathetic activity, eventually leading to an improved ejection fraction, despite an initial reduction in ejection fraction.

Trials have shown beta blockers reduce the absolute risk of death by 4.5% over a 13-month period. In addition to reducing the risk of mortality, the numbers of hospital visits and hospitalizations were also reduced in the trials.

Therapeutic administration of beta blockers for congestive heart failure ought to begin at very low doses (1/8 of target) with gradual escalation of the dose. The heart of the patient must adjust to decreasing stimulation by catecholamines and find a new equilibrium at a lower adrenergic drive.

Anxiety

Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration. However, many controlled trials in the past 25 years indicate beta blockers are effective in anxiety disorders, though the mechanism of action is not known. The physiological symptoms of the fight-or-flight response (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand. 

Musicians, public speakers, actors, and professional dancers have been known to use beta blockers to avoid performance anxiety, stage fright, and tremor during both auditions and public performances. The application to stage fright was first recognized in The Lancet in 1976, and by 1987, a survey conducted by the International Conference of Symphony Orchestra Musicians, representing the 51 largest orchestras in the United States, revealed 27% of its musicians had used beta blockers and 70% obtained them from friends, not physicians. Beta blockers are inexpensive, said to be relatively safe, and on one hand, seem to improve musicians' performances on a technical level, while some, such as Barry Green, the author of "The Inner Game of Music" and Don Greene, a former Olympic diving coach who teaches Juilliard students to overcome their stage fright naturally, say the performances may be perceived as "soulless and inauthentic".

Cardiac surgery

The use of beta blockers around the time of cardiac surgery decreases the risk of heart dysrhythmias. Starting them around the time of other types of surgery, however, may worsen outcomes.

Performance-enhancing use

Because they promote lower heart rates and reduce tremors, beta blockers have been used in professional sports where high accuracy is required, including archery, shooting, golf and snooker. Beta blockers are banned by the International Olympic Committee. In the 2008 Summer Olympics, 50-metre pistol silver medalist and 10-metre air pistol bronze medalist Kim Jong-su tested positive for propranolol and was stripped of his medals.

For similar reasons, beta blockers have also been used by surgeons.

Adverse effects

Adverse drug reactions associated with the use of beta blockers include: nausea, diarrhea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, alopecia (hair loss), abnormal vision, hallucinations, insomnia, nightmares, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed α₁/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema. Due to the high penetration across the blood–brain barrier, lipophilic beta blockers, such as propranolol and metoprolol, are more likely than other less lipophilic beta blockers to cause sleep disturbances, such as insomnia, vivid dreams and nightmares.

Adverse effects associated with β₂-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with β₁-selective (often termed "cardioselective") agents, but receptor selectivity diminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macula densa, inhibits renin release, thus decreasing the release of aldosterone. This causes hyponatremia and hyperkalemia.

Hypoglycemia can occur with beta blockade because β2-adrenoceptors normally stimulate glycogen breakdown (glycogenolysis) in the liver and pancreatic release of the hormone glucagon, which work together to increase plasma glucose. Therefore, blocking β2-adrenoceptors lowers plasma glucose. β1-blockers have fewer metabolic side effects in diabetic patients; however, the fast heart rate that serves as a warning sign for insulin-induced low blood sugar may be masked, resulting in hypoglycemia unawareness. This is termed beta blocker induced hypoglycemia unawareness. Therefore, beta blockers are to be used cautiously in diabetics.

A 2007 study revealed diuretics and beta blockers used for hypertension increase a patient's risk of developing diabetes mellitus, while ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers) actually decrease the risk of diabetes. Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta blockers as first-line treatment of hypertension due to the risk of diabetes.

Beta blockers must not be used in the treatment of selective alpha-adrenergic agonist overdose. The blockade of only beta receptors increases blood pressure, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha-adrenergic system stimulation unopposed. Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity from a methamphetamine overdose. The mixed alpha- and beta blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine. The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta blockers for treatment of methamphetamine toxicity. Other appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant overdose are vasodilators such as nitroglycerin, diuretics such as furosemide, and alpha blockers such as phentolamine.

Weight gain

Weight gain can occur as a side effect of some beta blockers, especially the older ones, such as cardioselective beta blockers including atenolol (Tenormin) and metoprolol (Lopressor, Toprol-XL). The average weight gain is about 2.6 pounds (about 1.2 kilograms). Newer beta blockers, such as carvedilol (Coreg), don't usually cause weight gain as a side effect. Weight may rise in the first weeks of taking the beta blocker and then generally stabilizes.

Contraindications

Contraindications for beta-blockers include:

• Abrupt discontinuations
• Acute bronchospasm
• Acute heart failure
• Asthma
• AV block
• Bradycardia
• Bronchitis
• Cardiogenic shock
• Cerebrovascular disease
• Chronic obstructive pulmonary disease (COPD)
• Diabetes mellitus
• Emphysema
• Hepatic disease
• Hypersensitivity
• Hyperthyroidism
• Hypotension
• Myopathy
• Pheochromocytoma
• Psoriasis
• Kidney failure
• Stroke
• Thyroid disease
• Vasospastic angina
• Wolff-Parkinson-White Syndrome

Asthma

The 2007 National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines recommend against the use of non-selective beta blockers in asthmatics, while allowing for the use of cardioselective beta blockers.

Cardioselective beta-blocker (β1 blockers), if really required, can be prescribed at the least possible dose to those with mild to moderate respiratory symptoms. β2-agonists can somewhat mitigate β-Blocker-induced bronchospasm where it exerts greater efficacy on reversing selective β-blocker-induced bronchospasm than the nonselective β-blocker-induced worsening asthma and/or COPD.

Cocaine

Beta blockers should not be used as a first-line treatment in the acute setting for cocaine-induced acute coronary syndrome (CIACS). No recent studies have been identified that show the benefit of beta blockers in reducing coronary vasospasm, or coronary vascular resistance, in patients with CIACS. In the multiple case studies identified, the use of beta blockers in CIACS resulted in detrimental outcomes, and the discontinuation of beta blockers used in the acute setting led to improvement in clinical course. The guidelines by the American College of Cardiology/American Heart Association also support this idea, and recommend against the use of beta blockers in cocaine-induced ST-segment elevation myocardial infarction (MI) because of the risk of coronary vasospasm. Though, in general, beta blockers improve mortality in patients who have suffered MI, it is unclear whether patients with CIACS will benefit from this mortality reduction because no studies assess the use of beta blockers in the long term, and because cocaine users may be prone to continue to abuse the substance, thus complicating the effect of drug therapy.

Diabetes mellitus

Epinephrine signals early warning of the upcoming hypoglycemia.

Beta-blockers' inhibition on epinephrine's effect can somewhat exacerbate hypoglycemia by interfering with glycogenesis and mask signs of hypoglycemia such as tachycardia, palpitations, diaphoresis, and tremors. Diligent blood glucose level monitoring is necessary for a patient with diabetes mellitus on beta-blocker.

Hyperthyroidism

Though beta-blockers can be useful to manage acute symptoms in thyrotoxic patients to reduce tachycardia, tremor, and anxiety, beta-blockers should be used with caution as tachycardia is a useful monitoring parameter in thyroid disease. Abrupt withdrawal can result in thyroid storm.

Bradycardia or AV block

Unless a pacemaker is present, beta-blockers can severely depress conduction in the AV node, resulting in reduction of heart rate and cardiac output. Usage of beta-blockers in tachycardic patients with Wolff-Parkinson-White Syndrome can result in severe bradycardia, necessitating treatment with a pacemaker.

Toxicity

Glucagon, used in the treatment of overdose, increases the strength of heart contractions, increases intracellular cAMP, and decreases renal vascular resistance. It is, therefore, useful in patients with beta blocker cardiotoxicity. Cardiac pacing is usually reserved for patients unresponsive to pharmacological therapy.

People experiencing bronchospasm due to the β₂ receptor-blocking effects of nonselective beta blockers may be treated with anticholinergic drugs, such as ipratropium, which are safer than beta agonists in patients with cardiovascular disease. Other antidotes for beta blocker poisoning are salbutamol and isoprenaline.

β-receptor antagonism

Stimulation of β₁ receptors by epinephrine and norepinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation of β₁ receptors on the kidney causes renin release. Stimulation of β₂ receptors induces smooth muscle relaxation, induces tremor in skeletal muscle, and increases glycogenolysis in the liver and skeletal muscle. Stimulation of β₃ receptors induces lipolysis.

Beta blockers inhibit these normal epinephrine- and norepinephrine-mediated sympathetic actions, but have minimal effect on resting subjects. That is, they reduce the effect of excitement or physical exertion on heart rate and force of contraction, and also tremor, and breakdown of glycogen. Beta blockers can have a constricting effect on the bronchi of the lungs, possibly worsening or causing asthma symptoms.

Since β₂ adrenergic receptors can cause vascular smooth muscle dilation, beta blockers may cause some vasoconstriction. However, this effect tends to be small because the activity of β₂ receptors is overshadowed by the more dominant vasoconstricting α₁ receptors. By far the greatest effect of beta blockers remains in the heart. Newer, third-generation beta blockers can cause vasodilation through blockade of alpha-adrenergic receptors.

Accordingly, nonselective beta blockers are expected to have antihypertensive effects. The primary antihypertensive mechanism of beta blockers is unclear, but may involve reduction in cardiac output (due to negative chronotropic and inotropic effects). It may also be due to reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity (for those beta blockers that do cross the blood–brain barrier, e.g. propranolol).

Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand. Negative chronotropic properties of beta blockers allow the lifesaving property of heart rate control. Beta blockers are readily titrated to optimal rate control in many pathologic states.

The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade—resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade. 

Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin–angiotensin–aldosterone system, with a resultant decrease in blood pressure due to decreased sodium and water retention.

Intrinsic sympathomimetic activity

Also referred to as intrinsic sympathomimetic effect, this term is used particularly with beta blockers that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent (beta blocker) and the concentration of the antagonized agent (usually an endogenous compound, such as norepinephrine). See partial agonist for a more general description.

Some beta blockers (e.g. oxprenolol, pindolol, penbutolol, labetalol and acebutolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low-level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy.

Agents with ISA are not used after myocardial infarctions, as they have not been demonstrated to be beneficial. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia.

α₁-receptor antagonism

Some beta blockers (e.g., labetalol and carvedilol) exhibit mixed antagonism of both β- and α₁-adrenergic receptors, which provides additional arteriolar vasodilating action.

Examples

Dichloroisoprenaline, the first beta blocker

Nonselective agents

Nonselective beta blockers display both β₁ and β₂ antagonism.

• Propranolol
• Bucindolol (has additional α₁-blocking activity)
• Carteolol
• Carvedilol (has additional α₁-blocking activity)
• Labetalol (has additional α₁-blocking activity)
• Nadolol
• Oxprenolol (has intrinsic sympathomimetic activity)
• Penbutolol (has intrinsic sympathomimetic activity)
• Pindolol (has intrinsic sympathomimetic activity)
• Sotalol (not considered a "typical beta blocker")
• Timolol

β₁-selective agents

β₁-selective beta blockers are also known as cardioselective beta blockers.

• Acebutolol (has intrinsic sympathomimetic activity, ISA)
• Atenolol
• Betaxolol
• Bisoprolol
• Celiprolol (has intrinsic sympathomimetic activity)
• Metoprolol
• Nebivolol
• Esmolol

β₂-selective agents

• Butaxamine
• ICI-118,551

β₃-selective agents

• SR 59230A

β₁ selective antagonist and β₃ agonist agents

• Nebivolol 

Comparative information

Pharmacological differences

• Agents with intrinsic sympathomimetic action (ISA)
  • Acebutolol, pindolol, labetalol, mepindolol, oxprenolol, celiprolol, penbutolol
• Agents organized by lipid solubility (lipophilicity)
  • High lipophilicity: propranolol, labetalol
  • Intermediate lipophilicity: metoprolol, bisoprolol, carvedilol, acebutolol, timolol, pindolol
  • Low lipophilicity (also known as hydrophilic beta blockers): atenolol, nadolol, and sotalol
• Agents with membrane stabilizing effect
  • Carvedilol, propranolol > oxprenolol > labetalol, metoprolol, timolol

Indication differences

• Agents specifically labeled for cardiac arrhythmia
  • Esmolol, sotalol, landiolol (Japan)
• Agents specifically labeled for congestive heart failure
  • Bisoprolol, carvedilol, sustained-release metoprolol
• Agents specifically labeled for glaucoma
  • Betaxolol, carteolol, levobunolol, timolol, metipranolol
• Agents specifically labeled for myocardial infarction
  • Atenolol, metoprolol (immediate release), propranolol (immediate release), timolol, carvedilol (after left ventricular dysfunction), bisoprolol (preventive treatment before and primary treatment after heart attacks)
• Agents specifically labeled for migraine prophylaxis
  • Timolol, propranolol

Propranolol is the only agent indicated for control of tremor, portal hypertension, and esophageal variceal bleeding, and used in conjunction with α-blocker therapy in phaeochromocytoma.

Other effects

Beta blockers, due to their antagonism at beta-1 adrenergic receptors, inhibit both the synthesis of new melatonin and its secretion by the pineal gland. The neuropsychiatric side effects of some beta blockers (e.g. sleep disruption, insomnia) may be due to this effect.

Some pre-clinical and clinical research suggests that some beta blockers may be beneficial for cancer treatment. However, other studies do not show a correlation between cancer survival and beta blocker usage. Also, a 2017 meta-analysis failed to show any benefit for the use of beta blockers in breast cancer.

Beta blockers have also been used for the treatment of schizoid personality disorder. However, there is limited evidence supporting the efficacy of supplemental beta-blocker use in addition to antipsychotic drugs for treating schizophrenia.

Contrast media are not contraindicated in patients receiving beta blockers.

Pesticide residue

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Pesticide_residue 

 

Pesticide residue refers to the pesticides that may remain on or in food after they are applied to food crops. The maximum allowable levels of these residues in foods are often stipulated by regulatory bodies in many countries. Regulations such as pre-harvest intervals also often prevent harvest of crop or livestock products if recently treated in order to allow residue concentrations to decrease over time to safe levels before harvest. Exposure of the general population to these residues most commonly occurs through consumption of treated food sources, or being in close contact to areas treated with pesticides such as farms or lawns.

Many of these chemical residues, especially derivatives of chlorinated pesticides, exhibit bioaccumulation which could build up to harmful levels in the body as well as in the environment. Persistent chemicals can be magnified through the food chain and have been detected in products ranging from meat, poultry, and fish, to vegetable oils, nuts, and various fruits and vegetables.

Definition

A pesticide is a substance or a mixture of substances used for killing pests: organisms dangerous to cultivated plants or to animals. The term applies to various pesticides such as insecticide, fungicide, herbicide and nematocide. Applications of pesticides to crops and animals may leave residues in or on food when it is consumed, and those specified derivatives are considered to be of toxicological significance.

Background

From post-World War II era, chemical pesticides have become the most important form of pest control. There are two categories of pesticides, first-generation pesticides and second-generation pesticide. The first-generation pesticides, which were used prior to 1940, consisted of compounds such as arsenic, mercury, and lead. These were soon abandoned because they were highly toxic and ineffective. The second-generation pesticides were composed of synthetic organic compounds. The growth in these pesticides accelerated in late 1940s after Paul Müller discovered DDT in 1939. The effects of pesticides such as aldrin, dieldrin, endrin, chlordane, parathion, captan and 2,4-D were also found at this time. Those pesticides were widely used due to its effective pest control. However, in 1946, people started to resist to the widespread use of pesticides, especially DDT since it harms non-target plants and animals. People became aware of problems with residues and its potential health risks. In the 1960s, Rachel Carson wrote Silent Spring to illustrate a risk of DDT and how it is threatening biodiversity.

Regulations

Each country adopts their own agricultural policies and Maximum Residue Limits (MRL) and Acceptable Daily Intake (ADI). The level of food additive usage varies by country because forms of agriculture are different in regions according to their geographical or climatical factors.

Pre-harvest intervals are also set to require a crop or livestock product not be harvested before a certain period after application in order to allow the pesticide residue to decrease below maximum residue limits or other tolerance levels. Likewise, restricted entry intervals are the amount of time to allow residue concentrations to decrease before a worker can reenter an area where pesticides have been applied without protective equipment.

International

Some countries use the International Maximum Residue Limits -Codex Alimentarius to define the residue limits; this was established by Food and Agriculture Organization of the United Nations (FAO) and World Health Organization (WHO) in 1963 to develop international food standards, guidelines codes of practices, and recommendation for food safety. Currently the CODEX has 185 Member Countries and 1 member organization (EU).

The following is the list of maximum residue limits (MRLs) for spices adopted by the commission.

Pesticide	Group or sub-group of spices	MRL (mg/kg)
Acephate	Entire Group 028	0.2
Azinphos-methyl	Entire Group 028	0.5
Chlorpyrifos	Seeds Fruits or berries Roots or rhizomes	5 1 1
Chlorpyrifos-methyl	Seeds Fruits or berries Roots or rhizomes	1 0.3 5
Cypermethrin	Fruits or berries Roots or rhizomes	0.1 0.2
Diazinon	Seeds Fruits Roots or rhizomes	5 0.1 0.5
Dichlorvos	Entire Group 028	0.1
Dicofol	Seeds Fruits or berries Roots or rhizomes	0.05 0.1 0.1
Dimethoate	Seeds Fruits or berries Roots or rhizomes	5 0.5 0.1
Disulfoton	Entire Group 028	0.05
Endosulfan	Seeds Fruits or berries Roots or rhizomes	1 5 0.5
Ethion	Seeds Fruits or berries Roots or rhizomes	3 5 0.3
Fenitrothion	Seeds Fruits or berries Roots or rhizomes	7 1 0.1
Iprodione	Seeds Fruits or berries Roots or rhizomes	7 1 0.1
Malathion	Seeds Fruits or berries Roots or rhizomes	2 1 0.5
Metalaxyl	Seeds	5
Methamidophos	Entire Group 028	0.1
Parathion	Seeds Fruits or berries Roots or rhizomes	0.1 0.2 0.2
Parathion-methyl	Seeds Fruits or berries Roots or rhizomes	5 5 0.3
Permethrin	Entire Group 028	0.05
Phenthoate	Seeds	7
Phorate	Seeds Fruits or berries Roots or rhizomes	0.5 0.1 0.1
Phosalone	Seeds Fruits or berries Roots or rhizomes	2 2 3
Pirimicarb	Seeds	5
Pirimiphos-methyl	Seeds sub group Fruits sub group	3 0.5
Quintozene	Seeds sub group Fruits or berries Roots or rhizomes	0.1 0.02 2
Vinclozolin	Entire spice group	0.05

European Union

In September 2008, the European Union issued new and revised Maximum Residue Limits (MRLs) for the roughly 1,100 pesticides ever used in the world. The revision was intended to simplify the previous system, under which certain pesticide residues were regulated by the Commission; others were regulated by Member States, and others were not regulated at all.

New Zealand

Food Standards Australia New Zealand develops the standards for levels of pesticide residues in foods through a consultation process. The New Zealand Food Safety Authority publishes the maximum limits of pesticide residues for foods produced in New Zealand.

United Kingdom

Monitoring of pesticide residues in the UK began in the 1950s. From 1977 to 2000 the work was carried out by the Working Party on Pesticide Residues (WPPR), until in 2000 the work was taken over by the Pesticide Residue Committee (PRC). The PRC advise the government through the Pesticides Safety Directorate and the Food Standards Agency (FSA).

United States

In the US, tolerances for the amount of pesticide residue that may remain on food are set by the EPA, and measures are taken to keep pesticide residues below the tolerances. The US EPA has a web page for the allowable tolerances. In order to assess the risks associated with pesticides on human health, the EPA analyzed individual pesticide active ingredients as well as the common toxic effect that groups of pesticides have, called the cumulative risk assessment. Limits that the EPA sets on pesticides before approving them includes a determination of how often the pesticide should be used and how it should be used, in order to protect the public and the environment. In the US, the Food and Drug Administration (FDA) and USDA also routinely check food for the actual levels of pesticide residues.

A US organic food advocacy group, the Environmental Working Group, is known for creating a list of fruits and vegetables referred to as the Dirty Dozen; it lists produce with the highest number of distinct pesticide residues or most samples with residue detected in USDA data. This list is generally considered misleading and lacks scientific credibility because it lists detections without accounting for the risk of the usually small amount of each residue with respect to consumer health. In 2016, over 99% of samples of US produce had no pesticide residue or had residue levels well below the EPA tolerance levels for each pesticide.

Japan

In Japan, pesticide residues are regulated by the Food Safety Act. 

Pesticide tolerances are set by the Ministry of Health, Labour and Welfare through the Drug and Food Safety Committee. Unlisted residue amounts are restricted to 0.01ppm.

China

In China, the Ministry of Health and the Ministry of Agriculture have jointly established mechanisms and working procedures relating to maximum residue limit standards, while updating them continuously, according to the food safety law and regulations issued by the State Council. From GB25193-2010 to GB28260-2011, from Maximum Residue Limits for 12 Pesticides to 85 pesticides, they have improved the standards in response to Chinese national needs.

Health impacts

Many pesticides achieve their intended use of killing pests by disrupting the nervous system. Due to similarities in brain biochemistry among many different organisms, there is much speculation that these chemicals can have a negative impact on humans as well. There are epidemiological studies that show positive correlations between exposure to pesticides through occupational hazard, which tends to be significantly higher than that ingested by the general population through food, and the occurrence of certain cancers. Although most of the general population may not exposed to large portion of pesticides, many of the pesticide residues that are attached tend to be lipophilic and can bio-accumulate in the body.

According to the American Cancer Society there is no evidence that pesticide residues increase the risk of people getting cancer. Pesticide exposure cannot be studied in placebo controlled trials as this would be unethical. A definitive cause effect relationship therefore cannot be established. The ACA advises washing fruit and vegetables before eating to remove both pesticide residue and other undesirable contaminants.

Chinese incidents

In China, a number of incidents have occurred where state limits were exceeded by large amounts or where the wrong pesticide was used. In August 1994, a serious incident of pesticide poisoning of sweet potato crops occurred in Shandong province, China. Because local farmers were not fully educated in the use of insecticides, they used the highly-toxic pesticide named parathion instead of trichlorphon. It resulted in over 300 cases of poisoning and 3 deaths. Also, there was a case where a large number of students were poisoned and 23 of them were hospitalized because of vegetables that contained excessive pesticide residues.

Child neurodevelopment

Children are thought to be especially vulnerable to exposure to pesticide residues, especially if exposure occurs at critical windows of development. Infants and children consume higher amounts of food and water relative to their body-weight have higher surface area (i.e. skin surface) relative to their volume, and have a more permeable blood-brain barrier, and engage in behaviors like crawling and putting objects in their mouths, all of which can contribute to increased risks from exposure to pesticide residues through food or environmental routes. Neurotoxins and other chemicals that originate from pesticides pose the biggest threat to the developing human brain and nervous system. Presence of pesticide metabolites in urine samples have been implicated in disorders such as attention deficit hyperactivity disorder (ADHD), autism, behavioral and emotional problems, and delays in development. There is a lack of evidence of a direct cause-and-effect relationship between long-term, low-dose exposure to pesticide residues and neurological disease, partly because manufacturers are not always legally required to examine potential long-term threats.