Ephedrine:
non catecholamine, mixed action (mainly indirect).
It is a plant alkaloid , now it is made synthetically.
It differs from adrenaline in the following :
It is a mixed action adrenergic agent. It does not only release stored noradrenaline from nerve endings (indirect) , but also stimulate alpha & beta receptors (direct).
It is about 100 times less potent than adrenaline (potency is not important clinically but efficacy is more important).
Has along duration of action because it is a poor substrate for COMT & MAO. (t½ = 4 hours).
Excellent absorption orally (while catecholamines are poor).
Penetrates to CNS causing mild stimulation ( ↑ alertness ,↓fatigue).
Raises both systolic and diastolic blood pressure. (like Nor.)
While adrenaline ↑ systolic & ↓ diastolic (slightly).
Tachyphylaxis occurs.
Therapeutic uses :
As a presser agent (to raise blood pressure).
As a nasal decongestant.(while Nor. is not)
As a mydriatic agent. (alpha₁ action)
Chronic treatment of asthma (produce bronchodilation).(it is used only in chronic cases due to its slow action). acute→ Subcutaneous admininistration of Adrenaline.
Stress incontinence: because it constricts the neck of the bladder (sphincter) by alpha₁ receptors.
Heart block thus enhances contractility. (beta action)
Myasthenia gravis : ephedrine improves motor function because of its anti-curare action.
Adverse effects :
1.tachycardia.
2.arrhythmia.
3.hypertension .
4. Worsening angina.
5.tremor.
6. Hyperglycemia.
Metaraminol:
Mixed action (but direct is more) adrenergic drug with action similar to noradrenaline. This agent has been used in treatment of shock and acute hypotension ).
Amphetamine: (non catecholamine, indirect action).
It is the best example of an indirect acting sympathomimetic drug that releases intracellular stores of catecholamines. It also blocks MAO,
Action and adverse effects :
1 . CNS : it has a marked central stimulatory action leads to ↑ alertness (euphoria), ↓ fatigue , depress appetite and insomnia.
* it may causes weakness , delirium , tremor , dizziness , panic states and suicidal tendencies.
* in higher doses it causes convulsions . chronic use produces a state of psychosis resembles an acute schizophrenic attack.
2. Sympathetic nervous system :
* It acts indirectly through noradrenaline release causing :
a) hypertension (from α effect on vasculature “↑PR” & β effect on heart “↑CO” ).
b) cardiac arrhythmias.
c) anginal pains.
d) headache .
e) excessive sweating.
Therapeutic uses :
Factors that limit the therapeutic usefulness of amphetamine include psychological and physical dependence and development of tolerance to euphoric and anorectic effects with chronic use.
attention deficit syndrome : mainly in children , some young children are hyperkinetic and lack the ability to be involved in anyone activity for longer than few minutes.
Narcolepsy :it is a disorder marked by uncontrollable desire for sleep.
Anorexiant :to control or suppress appetite.
Depression : used as psycho stimulant. (because it stimulates CNS).
Note: there are three drugs similar to amphetamine:
Methamphetamine (very similar to Amphetamine).
Methylpenidate : (Amphetamine derivative) used in hyperkinetic children with attention deficit syndrome.
Hydroxyamphetamine : used to differentiate between preganglionic and postganglionic lesions (Horner΄s syndrome : loss of sympathetic stimulation due to destruction of the superior cervical sympathetic ganglion). If the lesion is postganglionic , it will not dilate the abnormally constricted pupil because catecholamines have been lost from the nerve endings in the iris.
to explain : in postganglionic lesion (Hydroxyamphetamine) has no effect because there is no stored Na & Hydroxyamphetamine function is moving out Na to treat the disease.
While in preganglionic lesion Hydroxyamphetamine has effect similar to amphetamine effect (because its a derivative ) and cause mydriasis by moving out Na ( not like in postganglionic lesions “the pupil constricted” ).
Anorexigenic drugs:
1. Amphetamine : has temporary effect , it causes tolerance and antagonizes antihypertensive drugs.
2. fenfluramine and dexfenfluramine : it causes serotonin release and inhibited reuptake and also stimulated (5-HT) receptors.
→ serotonin acts on satiety center .
→ unfortunately, this drug induces pulmonary hypertension and valvular lesion were reported.
β-agonist :
1.non-selective agonist: e.g.: adrenaline , ephedrine, isoprenaline.
2.slective agonist: either β₁ or β₂ agonist.
Selective β₁ agonist : 2 drugs:
1.dobutamine : mentioned before.
2.xamoterol :it is a partial agonist at β₁ adrenoceptors.
Partial agonist : means that it acts as agonist or antagonist according to certain circumstances particularly the level of sympathetic autonomic activity present. (i.e. if sympathetic action is high it’s antagonist but if sympathetic action is low it’s agonist).
At low level of sympathetic activity, it acts as agonist → ↑ heart rate, contractility..it may benefit:
1-mild chronic heart failure: it is likely to worsen moderate and sever heart failure.
2- chronic orthostatic hypotension.
β₂ agonists : 1of 3 drugs :
Vasodilators : they are used in peripheral vascular diseases e.g. Isoxsuprine, nylidrine.
Uterine relaxants : they relax the pregnant uterus and are used in premature labour to delay it e.g. Ritodrine.
Bronchodilators (in bronchial asthma ): e.g. salbutamol & terbutaline (both t½ = 3 hours), fenoterol (t½ =12 hours) are adminstrated orally (chronic cases) or may be inhaled (acute cases )or IV (in status asthmaticus).
Unlike Isoprenaline , they have long duration of action and significant selectivity to β₂ (so it is more preffered than Isoprenaline).
Side effect is minimal by inhalation route : headache (due to vasodilation), anxiety , tremor, tachycardia and hypotension.
Others are albuterol, salmeterol,metaproterenol.
α-agonists :
α₁-agonists : mainly used as vasoconstrictors. They include:
1.phenylephrine (α₁ & slightly β₁ effect )
2.methoxamine (only α₁ effect )
3. metaraminol (direct α₁ & some indirect sympathomimetic effect).
Therapeutic uses :
Nasal decongestant : they are used locally as drops to the nose (also to the eye).
To raise the blood pressure :they are used systemically either subcutaneously or I.V. in cases of shock or following spinal anesthesia.
They are not destroyed by MAO or COMT.
Phenylephrine has additional uses :
Open angle glaucoma :it reduces production of aqueous humor by vasoconstriction.
Mydriatic agent for ophthalmological examination of the eye.
Supraventricular tachycardia treatment : it causes marked vasoconstriction & lead to raise B.P. → a reflex vagal discharge is evoked that may convert the arrhythmia to sinus rhythm.
Nasal decongestants :
Therapeutic uses :
Common cold.
Allergy.
Sinusitis : to enhance drainage of sinus.
Prevent otitic barotrauma to open eustachian tube.(i.e. it prevent otitic barotrauma by opening eustachian tube ).
Mode of adminstration :
Nasal drops.
Sprays.
Tubes.
Oral preparations ; there are different types of oral preparation:
Short acting (2 hrs.) : phenylephrine, phenylpropanolamine.
Intermediate acting : ephedrine , pseudoephedrine.
Long acting (8-12 hrs) “imidazoline group” : oxymetazolines , imidazolines , xylometazoline.(e.g. of imidazoline is naphezoline )
Adverse effect :
Rebound congestion with hypertrophy of nasal mucous membrane.
Local ischemia :if used more than 3-hourly & for above 3 weeks the mucous membrane is likely to be damaged.
Lipoid pneumonia : oily drops or sprays , used frequently & long term may enter the lungs.
Allergy (with prolonged use).
Interaction with antihypertensive drugs leading to failure of therapy.
Interaction with MAO inhibitors (so it may cause hypertension).
Hypotension with imidazolines..especially : naphezoline as it enters the CNS & acts on α₂ receptors suppressing the sympathetic outflow.
It should never be used in children (this is general for imidazolines “ especially naphezolines “ ).
Chronic orthostatic hypotension :
It occurs most commonly with age , in primary progrssive autonomic failure & secondary to other diseases as parkinsonism and diabetes.
Treatment :
Using elastic support stocking to reduce venous pooling.
Increasing sodium intake.
Using sodium retaining adrenocortical steroids (fludrocortisones).
β₁ - adrenocepters agonist e.g. Xamoterol to ↑ cardiac output.
Ephedrine to ↑ Na release by nerve endings ( indirect sympathomimetic).
Intake of tyramine rich food e.g. cheese. Some of the tyramine escapes the destruction by MAO in the intestine.
( to explain : eating cheese → no hypertension (because tyramine which ↑ B.P. will be destroyed in the intestine by MAO. So if we take MAO inhibitor WE ARE NOT supposed to eat cheese because it will get absorbed easily and...)
α₂ - receptor blocker.e.g.Yohimbine.
Dopamine (D₂) receptor blocker . e.g. Metoclopramide.
Caffeine : substantial doses of caffeine (coffee ) can reduce postprandial redistribution of blood to splanchnic area probably due to block of splanchnic vasodilator adenosine receptors
α₂-agonists :
they have an important ability to decrease blood pressure through actions in CNS e.g. Clonidine & Methyldopa are useful in treatment of hypertension.
non catecholamine, mixed action (mainly indirect).
It is a plant alkaloid , now it is made synthetically.
It differs from adrenaline in the following :
It is a mixed action adrenergic agent. It does not only release stored noradrenaline from nerve endings (indirect) , but also stimulate alpha & beta receptors (direct).
It is about 100 times less potent than adrenaline (potency is not important clinically but efficacy is more important).
Has along duration of action because it is a poor substrate for COMT & MAO. (t½ = 4 hours).
Excellent absorption orally (while catecholamines are poor).
Penetrates to CNS causing mild stimulation ( ↑ alertness ,↓fatigue).
Raises both systolic and diastolic blood pressure. (like Nor.)
While adrenaline ↑ systolic & ↓ diastolic (slightly).
Tachyphylaxis occurs.
Therapeutic uses :
As a presser agent (to raise blood pressure).
As a nasal decongestant.(while Nor. is not)
As a mydriatic agent. (alpha₁ action)
Chronic treatment of asthma (produce bronchodilation).(it is used only in chronic cases due to its slow action). acute→ Subcutaneous admininistration of Adrenaline.
Stress incontinence: because it constricts the neck of the bladder (sphincter) by alpha₁ receptors.
Heart block thus enhances contractility. (beta action)
Myasthenia gravis : ephedrine improves motor function because of its anti-curare action.
Adverse effects :
1.tachycardia.
2.arrhythmia.
3.hypertension .
4. Worsening angina.
5.tremor.
6. Hyperglycemia.
Metaraminol:
Mixed action (but direct is more) adrenergic drug with action similar to noradrenaline. This agent has been used in treatment of shock and acute hypotension ).
Amphetamine: (non catecholamine, indirect action).
It is the best example of an indirect acting sympathomimetic drug that releases intracellular stores of catecholamines. It also blocks MAO,
Action and adverse effects :
1 . CNS : it has a marked central stimulatory action leads to ↑ alertness (euphoria), ↓ fatigue , depress appetite and insomnia.
* it may causes weakness , delirium , tremor , dizziness , panic states and suicidal tendencies.
* in higher doses it causes convulsions . chronic use produces a state of psychosis resembles an acute schizophrenic attack.
2. Sympathetic nervous system :
* It acts indirectly through noradrenaline release causing :
a) hypertension (from α effect on vasculature “↑PR” & β effect on heart “↑CO” ).
b) cardiac arrhythmias.
c) anginal pains.
d) headache .
e) excessive sweating.
Therapeutic uses :
Factors that limit the therapeutic usefulness of amphetamine include psychological and physical dependence and development of tolerance to euphoric and anorectic effects with chronic use.
attention deficit syndrome : mainly in children , some young children are hyperkinetic and lack the ability to be involved in anyone activity for longer than few minutes.
Narcolepsy :it is a disorder marked by uncontrollable desire for sleep.
Anorexiant :to control or suppress appetite.
Depression : used as psycho stimulant. (because it stimulates CNS).
Note: there are three drugs similar to amphetamine:
Methamphetamine (very similar to Amphetamine).
Methylpenidate : (Amphetamine derivative) used in hyperkinetic children with attention deficit syndrome.
Hydroxyamphetamine : used to differentiate between preganglionic and postganglionic lesions (Horner΄s syndrome : loss of sympathetic stimulation due to destruction of the superior cervical sympathetic ganglion). If the lesion is postganglionic , it will not dilate the abnormally constricted pupil because catecholamines have been lost from the nerve endings in the iris.
to explain : in postganglionic lesion (Hydroxyamphetamine) has no effect because there is no stored Na & Hydroxyamphetamine function is moving out Na to treat the disease.
While in preganglionic lesion Hydroxyamphetamine has effect similar to amphetamine effect (because its a derivative ) and cause mydriasis by moving out Na ( not like in postganglionic lesions “the pupil constricted” ).
Anorexigenic drugs:
1. Amphetamine : has temporary effect , it causes tolerance and antagonizes antihypertensive drugs.
2. fenfluramine and dexfenfluramine : it causes serotonin release and inhibited reuptake and also stimulated (5-HT) receptors.
→ serotonin acts on satiety center .
→ unfortunately, this drug induces pulmonary hypertension and valvular lesion were reported.
β-agonist :
1.non-selective agonist: e.g.: adrenaline , ephedrine, isoprenaline.
2.slective agonist: either β₁ or β₂ agonist.
Selective β₁ agonist : 2 drugs:
1.dobutamine : mentioned before.
2.xamoterol :it is a partial agonist at β₁ adrenoceptors.
Partial agonist : means that it acts as agonist or antagonist according to certain circumstances particularly the level of sympathetic autonomic activity present. (i.e. if sympathetic action is high it’s antagonist but if sympathetic action is low it’s agonist).
At low level of sympathetic activity, it acts as agonist → ↑ heart rate, contractility..it may benefit:
1-mild chronic heart failure: it is likely to worsen moderate and sever heart failure.
2- chronic orthostatic hypotension.
β₂ agonists : 1of 3 drugs :
Vasodilators : they are used in peripheral vascular diseases e.g. Isoxsuprine, nylidrine.
Uterine relaxants : they relax the pregnant uterus and are used in premature labour to delay it e.g. Ritodrine.
Bronchodilators (in bronchial asthma ): e.g. salbutamol & terbutaline (both t½ = 3 hours), fenoterol (t½ =12 hours) are adminstrated orally (chronic cases) or may be inhaled (acute cases )or IV (in status asthmaticus).
Unlike Isoprenaline , they have long duration of action and significant selectivity to β₂ (so it is more preffered than Isoprenaline).
Side effect is minimal by inhalation route : headache (due to vasodilation), anxiety , tremor, tachycardia and hypotension.
Others are albuterol, salmeterol,metaproterenol.
α-agonists :
α₁-agonists : mainly used as vasoconstrictors. They include:
1.phenylephrine (α₁ & slightly β₁ effect )
2.methoxamine (only α₁ effect )
3. metaraminol (direct α₁ & some indirect sympathomimetic effect).
Therapeutic uses :
Nasal decongestant : they are used locally as drops to the nose (also to the eye).
To raise the blood pressure :they are used systemically either subcutaneously or I.V. in cases of shock or following spinal anesthesia.
They are not destroyed by MAO or COMT.
Phenylephrine has additional uses :
Open angle glaucoma :it reduces production of aqueous humor by vasoconstriction.
Mydriatic agent for ophthalmological examination of the eye.
Supraventricular tachycardia treatment : it causes marked vasoconstriction & lead to raise B.P. → a reflex vagal discharge is evoked that may convert the arrhythmia to sinus rhythm.
Nasal decongestants :
Therapeutic uses :
Common cold.
Allergy.
Sinusitis : to enhance drainage of sinus.
Prevent otitic barotrauma to open eustachian tube.(i.e. it prevent otitic barotrauma by opening eustachian tube ).
Mode of adminstration :
Nasal drops.
Sprays.
Tubes.
Oral preparations ; there are different types of oral preparation:
Short acting (2 hrs.) : phenylephrine, phenylpropanolamine.
Intermediate acting : ephedrine , pseudoephedrine.
Long acting (8-12 hrs) “imidazoline group” : oxymetazolines , imidazolines , xylometazoline.(e.g. of imidazoline is naphezoline )
Adverse effect :
Rebound congestion with hypertrophy of nasal mucous membrane.
Local ischemia :if used more than 3-hourly & for above 3 weeks the mucous membrane is likely to be damaged.
Lipoid pneumonia : oily drops or sprays , used frequently & long term may enter the lungs.
Allergy (with prolonged use).
Interaction with antihypertensive drugs leading to failure of therapy.
Interaction with MAO inhibitors (so it may cause hypertension).
Hypotension with imidazolines..especially : naphezoline as it enters the CNS & acts on α₂ receptors suppressing the sympathetic outflow.
It should never be used in children (this is general for imidazolines “ especially naphezolines “ ).
Chronic orthostatic hypotension :
It occurs most commonly with age , in primary progrssive autonomic failure & secondary to other diseases as parkinsonism and diabetes.
Treatment :
Using elastic support stocking to reduce venous pooling.
Increasing sodium intake.
Using sodium retaining adrenocortical steroids (fludrocortisones).
β₁ - adrenocepters agonist e.g. Xamoterol to ↑ cardiac output.
Ephedrine to ↑ Na release by nerve endings ( indirect sympathomimetic).
Intake of tyramine rich food e.g. cheese. Some of the tyramine escapes the destruction by MAO in the intestine.
( to explain : eating cheese → no hypertension (because tyramine which ↑ B.P. will be destroyed in the intestine by MAO. So if we take MAO inhibitor WE ARE NOT supposed to eat cheese because it will get absorbed easily and...)
α₂ - receptor blocker.e.g.Yohimbine.
Dopamine (D₂) receptor blocker . e.g. Metoclopramide.
Caffeine : substantial doses of caffeine (coffee ) can reduce postprandial redistribution of blood to splanchnic area probably due to block of splanchnic vasodilator adenosine receptors
α₂-agonists :
they have an important ability to decrease blood pressure through actions in CNS e.g. Clonidine & Methyldopa are useful in treatment of hypertension.
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