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This lecture is the continuation for the previous one, If you want to follow up with the slides this

lecture starts at page 8 2. Noradrenalin. In the last lecture we talked about the physiological aspect of the ANS, and then we started do discuses individual drugs which can act on this system. We started with the Sympathetic drugs those drugs which have sympathetic activity and effect as the stimulation of the sympathetic NS; we started with the first drug which was Adrenalin. There are some points to remember from the previous lecture: The main Neuron transmitter of the post-ganglonic prasympthtic nervous system is Acetyl choline The main Neuron transmitter of the post-Ganglonic sympathetic nervous system is the Epinephrine and Norepinephrine (Adrenaline and Noradrenalin respectively ) Termination of the effect of Acetyl choline is mainly enzymatic and it is by an enzyme called Acytel choline esterase or cholinesterase Termination of the effect of Epinephrine and Norepinephrine is mainly by Active reuptake mechanism. While the minor termination is by Enzymatic Depredation which is produced by two specific enzymes one of them which is COMT (catechol-o-amine transferase) and MAO

(monoamine oxidase).

Now Lets start with this lecture and continue our talk about Sympathomimetic Drugs :

2- Noradrenalin
Noradrenalin can produce generalized/Wide spread Vasoconstriction and this Vasoconstriction will lead to an increase in the Systolic blood pressure (SPB) and also the Dystolic blood pressure (DPB). As compared to Adrenalin, adrenalin can only increase the systolic blood pressure while there is little or no effect on the DPB.

Noradrenalin is mainly given via intravenous infusion (why?) because of the rapid enzymatic inactivation in the plasma or serum, this is why we give it by infusion to produce a continues effect. The drawback of this generalized vasoconstriction is as follows: That it might decrees the blood flow to the kidneys. Renal patients should be treated carefully if taken this drug. If the solution of Noradrenalin becomes outside the injection site due to the vasoconstriction, this might lead to local tissue damage or sloughing. Ulceration of the injected site

3- Isoprinaline :
When we discussed the physiology of the sympathetic system we said that there are a1 a2, b1 b2. Consider the following examples of drugs: A drug is called B stimulant means that the drug can stimulate that B receptors If the drugs effect cannot differentiate between b1 and b2 in this case it is called non-selective B stimulant or Agonist ,meaning it can act both in similar ways on b1 and b2 If a drug can bind only to b1 we call it selective b1 agonist, a drug which can only bind to b2 we call it b2 agonist Now back to Isoprinaline: It is non-selective B stimulant or Agonist (agonist is a drug that can bind a receptor to produce an effect already discussed). This drug can be taken sublingually or by Inhalation, notice not oral and this is due to the high first pass effect. This drug can relax the bronchial smooth muscles (bronchial dilatation) and stimulate the heart (tarchrdya) , this stimulation might produce fetal arrthyma.

Note that the heart is supplied by B1 receptors while the bronchial is supplied by B2 receptors , This explains why this drug affect the heart , it has no selectivity for either B1 or B2 and it might affect both of them , from all of the above Isoprinaline is rarely used these days and it is replace by another Bselective drug (e.g. salbutamol , which is our next drug )

It is a selective B2 agonist; the main use of this drug is in the treatment of bronchial asthma it has a powerful bronchodilator effect with minimum side effects on the heart. Although B2 agonist drugs are used in treatment of Asthma, sometimes this drug can be used to relax the uterus of a pregnant woman. This is used during abortion to relax the contracted muscle of uterus and prevent the threatened abortion. So the two main uses Asthma and the treatment of threatened abortion. Usually given by inhalation (via inhaler) or orally (via tablets or syrup) and rarely IV injections. The inhaler is held between the thumb downward and the other fingers upward and the outlet should be located between the lips and the patient is asked not to bite the outlet, but just to put it on the lips. After that you ask the patient to expire forcefully and then while taking deep inspiration the patient should press the inhaler, a release of a buff of the drug will happen due to the pressure.

Look at the table below it is compassion between Salbuatmol taken Inhaled or orally a few things must be noted:

You can notice if we are looking for a fast drug to treat Acute asthma we go with the Inhalation method due to its small effect time ( 10-15 min ) On the other hand if we want to prevent subsequent sets of attacks of asthma we give the drug orally Inhalation Small dose Maximum effect : 10-15 min Low plasma conc. Few side effects Side effects of Salbutamol : Tacrhdya Palpatration Arrthyma Small ( fine) traumas in the hands or muscular spasms Oral Larger dose ( due to high first pass effect ) Maximum effect : 1-2 hrs ( due to GIT absorption time needed ) High plasma conc. ( due to the larger doses) More side effects

There is a drug similar to Salbutamol , Salmeterol it is also B2 selective agonist but the difference is that it has longer duration of action and it is taken only orally. So if we want a drug for subsequent attacks of asthma we can use Salbutamol orally or Salmeterol orally.

Other sympathomimetic agents

We have amphetamine and dexamphetamine. These two drugs, their main effects are on the brain, on CNS by acting as a stimulatory effects and producing stimulation. Note that adrenalin and noradrenalin, main effects was on blood and Salbutamol and salmeterol their effects on bronchi and uterus CNS stimulation can produce euphoria which is a state of extreme happiness , decrease fatigue , increased mental activity and can suppress appetite , all of these two drugs actions seems improvements to the human and not harmful things , but the real danger is in the prolonged use or Addiction (dependence). The main use of these two drugs comes from their ability to stimulate CNS , There is a condition called Narcolepsy in which the patient goes through an irresistible attack of deep sleep (in appropriate time). So to treat them we give amphetamine and dexamphetamine to relieve this sleepiness The second use is in the hyperactive children, you have to know that there is a balance between stimulatory neuron and inhibitory neuron in CNS. In adults amphetamine can stimulate stimulatory neuron and the results are CNS stimulation. While in children, amphetamine stimulates inhibitory neuron. So, the results are a inhibition. That is suppression of hyperactivity.

Adrenergic blocking agents :

We have already talked about the agonist and we have named them symphatomimetic drugs, now we will focus on the Antagonists they can be either named beta antagonists or beta blockers. Agonist have both affinity and activity : it can bind to receptor and produce an effect , so that is both affinity to that receptor and activity of the effect. Antagonists have only affinity and no activity : It can bind to receptor but doesnt produce an effect thus preventing normal agonist from binding to receptor So, beta adrenergic antagonists or blockers can bind to adrenergic receptor, preventing the endogenous sympathetic amines from binding to these receptors. If the blocker act on Alpha receptor it is called Alpha blocker, if it acts on Beta receptor it is called Beta blocker

1- Alpha Blockers:
As prazosin and phentolamin , the main uses for theses two drugs are : In hypertension, because vasoconstriction is produce by alpha receptor. If we block alpha receptor, the end results is vasodilation. Benign prostatic hyperplasia condition . We all know that the prostate gland is found at the orifice of male bladder and it is surrounded by a capsule , this capsule is supplied via Alpha receptor. So in this condition the prostate is hypertrophied ; larger , the capsule is contracted and we will have urethral obstruction espically in old patients . To treat this we use Alpha blockers to relax the capsule in order to ease the obstruction.

2-Beta blockers:
Here we have both selective and non-selective Agonist and Antagonist beta blockers : nonselective as propanalol (inderal) : can block both b1 and b2. Selective as atenolol ( tenorm ) : can block b1 , but it is not entirely or 100 % selective sometimes it can bind to b2 but in a very low occasions , We say it is selective because it is mainly and most of the time it is bound to b1

The effects of Beta blockers : Let us conclude the effect of beta blockers. Can we? The agonist of sympathetic nervous system I said can increase the heart rate. By blocking this the following effects might happen : Decrease heart rate. A condition called bradycardia. Decrease cardiac output and decrease work of heart. Can produce bronchospasm decrease blood pressure can prevent rise in blood glucose level Can produce sedation. Antianxiety : Tachycardia, increase blood pressure, tremor. Keep in mind that the above effects are for the blockers , but if we want to for example compare them with Beta stimulates we would have : Stimulating beta receptor, bronchodilation in blockers it was bronchospasm Stimulant, increase blood pressure in blockers it lead to decrease blood pressure

Stimulant can produce hyperglycemia in blockers it prevents rise in blood glucose level Stimulant can produce CNS stimulation (e.g. amphetamine and dexamphetamine ) in blockers we will have anxiety

Therapeutic uses of Beta blockers: 1. Because the decrees the work of the heart we use them in antianginal to relieve angina pectoris. 2. Because it decrees the excitability of the heart they are used in arrhythmia as antiarrhythmia. 3. Because of the decrees the make in the blood pressure they are used as Antihypertensive. 4. In the treatment of anxiety. And the treatment thyrotoxicosis , thyrotoxicosis is the hyperfunction of thyroid gland. Which is also manifested by sympathetic stimulation? To treat this symphathetic overactivity, we give beta blocker. 5. Pheochromacytoma. You know the adrenal gland? Adrenal gland is composed of adrenal cortex and adrenal medulla. The tumor of adrenal medulla is called pheochromacytoma. In other word, tumor of adrenal medulla leads to excess secretion of adrenalin and noradrenaline to the secretion. To block this release of cathecolamine, we give beta blocker. Not alone here, we put combine beta blocker with alpha blocker. Why? If we give beta blocker only, we will block beta receptor alone leaving with unblocked alpha receptor. There might be excessive effect the release of cathecolamine on alpha receptor. And what are the results of overstimulation of alpha receptor? Is severe attack of hypertension? Therefore, in treatment of pheochromacytoma, not only beta blocker, but together with alpha blocker. Which is propanolol plus prazosin or phentolamin? 6. Treatment of tremor

7. Prophylaxis of migraine. Migraine is a severe headache. Usually on one side of head we also use beta blockers here 8. Glaucoma, drug of choice in treatment is timold. Now lets ask this question when we discussed adrenaline we said that it can also act as a treatment of Glaucoma, how is also beta blockers are a treatment for Glaucoma ? The agonist and antagonist could be use in treatment of same condition. Glaucoma is increase in intraocular pressure. Intraocular pressure, the pressure of aqueous humor is increased. Aqueous humor is the fluid in the anterior part of eyes. Intraocular pressure is determined by formation and absorption of the fluid. Usually there is the formation of the fluid and then the reabsorption of fluid into colliery body of the eye. So, there is a continues process of formation and absorption to keep a normal intraocular pressure. This intraocular pressure can be increased by either increase the formation or decrease the reabsorption. Increase in formation ultimately end up by increase intraocular pressure. And even the formation is normal, but the reabsorption is reduced, it also can increase intraocular pressure. What the agonist or adrenaline will do? Inhibiting the formation. And what trepenolol or beta blocker will do? Increasing the absorption.

The side effects of beta blockers: 1. Bronchospasm: this might be very dangerous or fatal in asthmatic patient. Because the selective beta blocker, it is not absolute selective to beta-1 only, but also have little effects on beta-2. So, it cannot be use in asthmatic patients. So, whether beta blockers are selective or nonselective should not be used in asthmatic patients. 2. Nightmares and hallucinations 3. Cold extremities 4. Sexual dysfunction in males ; Erectile dysfunction in males

5. Masking hypoglycemic symptoms: A diabetic patients, who is on insulin therapy, one of side effect of insulin therapy is hypoglycemia. Blood sugar level reduced from normal limit. It leads to hypoglycemia. Manifestation of hypoglycemia is sympathetic stimulation. Most diabetic patients who have hypoglycemia, they can feel it by tremor, sweating, palpitation. So, when they feel these symptoms, they should take glucose. The patients who take beta blockers, they might have hypoglycemia, but these symptoms is blocked, or masked by beta blocker. So, it is dangerous who have diabetes type 1 taking beta blockers. You have to note that you should not stop the Beta blocker suddenly ( why ? ) The patients who are taking beta blocker for example, hypertensive patient, they should take it for the rest of their life. For very long time of medication. In these types of patients, they might be severe attack of sudden rise of blood pressure. And there might be sudden occurrence of arrhythmia. So, keep this in mind, treatment for treatment of prolong take of beta blockers is should not be stopped suddenly. How? For the patients who are taking beta blockers chronically, we should use what is called, tapering. Tapering means gradual reduction of the dose of beta blockers. Patients who are taking beta blockers 40mg per day, should not bring it down to zero, but we should ask them to take 30mg, then 20 mg gram, then 10mg, then zero mg. process of termination of the therapy might take one to two weeks. This is called tapering. The tapering is gradual reduction of the dose. Not a sudden reduction, but gradual.

Parasympathomimetic drugs:

Having discuss this sympathetic drugs, now we are going to other the drugs of other branch of autonomic nervous system which is parasympathomimetic drugs.

1- Acetylcholine:
It is not used therapeutically in here is why: Because it has a very short duration of action. In a matter of second (time). So, we cannot use it therapeutically. Other reasons why it cannot be used therapeutically because it has a very wide, generalized effects. Its effects not on specific tissue, but it might effect on all body tissue

2- carbacol and bethanechol :

They have similar action of acethylcholine but the different is they have longer duration of action. Why acethylcholine have short duration of action and carbacol have longer? Because its action is rapidly terminated by the enzyme called cholinesterase these two drugs (carbacol and bethanechol) are more resistance from hydrolysis by cholinesterase. That is why they have more prolong effects. They are synthetic, similar action to acetylcholine, not broken down by cholinesterase. These properties will lead to prolong the duration of action. They are given subcutaneously or orally. For treatment of urinary retention after surgical operation or after childbirth. After dominant surgery, there might be complication from this surgery or postoperative complications in form of urinary retention. What is mean by urinary retention? Inability of the patients to pass urine. This is because postoperative effects or surgical manipulations effect on the bladder, can produce relaxation of the body and constriction of the sphincter. Leading to urinary retention. Contraction of the sphincter lead to urinary retention, but I will ask you this question.

Presence of stone in the urethral or the outlet of the bladder can produce inability of passing urine, but its not urinary retention, it is called urinary obstruction. I said urinary retention is relaxation of the body of bladder and contraction of sphincter. Cholinergic stimulation whether physiologic or by drugs can produce contraction of the body and opening or relaxation of the sphincter. This process will facilitate urination. Carbacol can be used as eye drops in treatment of glaucoma. Here carbacol can reduce intraocular pressure which is the manifestation of glaucoma. Side effects, colic. Abdominal colic, intestinal colic. Due to contraction of smooth muscle, diarrhea, hypotension. These side effects, if they are severe they can be blocked by parasympathetic blocker, it is atropine. The subject of parasympathetic blockers will be discussing in next lecture.

Done by : Osama Yousef and Mohammad abu bakar.