Pharmacology 3rd stage
Adrenergic system
Autonomic nervous system composed of sympathetic and parasympathetic nervous system .Sympathetic system also known as adrenergic system ,while parasympathetic system known as cholinergic system ,the action or the effects of these two systems are completely opposite to each other .
The neurons of autonomic nervous system are found in the brain and spinal cord, the efferent fibers emerging from these neurons known as preganglionic and all of these fibers (sympathetic and parasympathetic) are cholinergic which means they synthesize and release acetylcholine.
These fibers will terminate in the body of second group of neurons that are located in the autonomic ganglia, fibers from these ganglia known as postganglionic fibers end to the target organs (glands and viscera.)
The neurotransmitter in the postganglionic fibers of parasympathetic division is acetylcholine, while in sympathetic division is noradrenaline (nor epinephrine).
Adrenal medulla, release adrenaline (epinephrine), and lesser amount of noradrenaline.
The nuclei of sympathetic system are located in thoraco-lumbar region of spinal cord(T1-L2)) ,while the nuclei of parasympathetic system are located in the craniosacral region (S2,S3, and S4 ).
The adrenoceptors (adrenergic receptors ):-
Noradrenalin will act on two types of receptors (alpha α) and (beta β) receptors, which are further subdivided into-
alpha 1 → A, B, D, and L sub types .
alpha2→A,B,and C subtypes .
Beta adrenoceptors subdivided into β1 , β2 and β3 .
Synthesis of noradrenaline :-
The precursor substance is an amino acid known as Tyrosine , the exogenous source of tyrosine is from diet while the endogenous source is from phenyl alanine .
Tyrosine is hydroxylated to form L-dopa ,this reaction is mediated by tyrosine hydroxylase which is considered the rate –limiting step, the L-dopa will undergo decarboxylation to form Dopamine which will undergo another hydroxylation to form Noradrenaline .
Dopamine is one of the neurotransmitter ,usually it's found in CNS rather than peripheral nervous system , its receptors D receptors two families D1 , D2 and recently D3 .
dopa decarboxylase Dopamine hydroxylase Tyrosine hydroxylase Tyrosine →→→→→→ L-dopa →→→→→→dopamine→→→→→→ Noradrenaline .
In adrenal medulla ,a process of methylation is added by enzyme ( phenyl ethanolamine N – methyl transferase )- PNMT – to produce adrenaline from noradrenaline .
Storage :-
After synthesis ,noradrenaline will be stored in vesicles which are found in cytoplasm of post ganglionic neuron ,while adrenaline will be stored in adrenal medulla .
Release :-
An action potential arriving triggers ,an influx of calcium ions into cytoplasm of the neurons and causes vesicles to fuse with cell membrane and expel their contents into the synaptic space .
Binding by receptors :-
After release ,noradrenaline will bind with its receptors to form (Agonist-receptors complex ) this binding will stimulate Adenylate cyclase ( the second messenger), Adenylate cyclase will convert -ATP-into cyclic AMP(c AMP) , c AMP is the active form of ATP and it is destroyed by the enzyme ( phosphodiesterase ) .
Adenylate cyclase Phosphodiesterase
ATP→→→→→→→→→c AMP→→→→→→→→→→→→ simple AMP .
Elimination :-
80% of the released noradrenaline will go back to the nerve endings and stored in the same manner ,this process known as (re-uptake 1 ) ,or into perisynaptic glial cells or smooth muscle cells (re-uptake 2).
The re-uptake by the neural membrane involve Na+-K+ activated ATPase that can be inhibited by Tricyclic antidepressants (TCA ) or cocaine ,(noradrenaline reuptake inhibitors ) .
The remaining 20 % ,will be destroyed either by monoamine oxidase (MAO) ,or by catechole-o-methyl transferase (COMT) ,these two enzymes control the response of adrenergic system COMT , is predominantly found in the liver ,kidney, plasma, and intestinal mucosa and this is the reason why catecholamines can't be used orally .
Metabolism :-
The end result of metabolism of adrenaline and noradrenaline by (COMT) and (MAO) is a chemical substance known as Vanillyl mandelic acid VMA, which is excreted in urine and used as a test for activity of adrenergic system ,(by 24 hrs. urine sample collection) .
There are intermediate substances of metabolism known as Metanephrine and Normetanephrine, their concentrations are increased in more than 95%in patients with Pheochromocytoma (a benign functioning tumor of adrenal gland .) .
The adrenoceptors (Adrenergic receptors ) :-
The adrenergic system contains two major types of receptors , (alpha α and beta β) which are further subdivided into α1 and α2 ,β1 and β2 .
Alpha 1→ A, B , D, and L subtypes .
Alpha 2→ A, B, and C subtypes .
Alpha 1 adrenoceptors :-
They are present on post synaptic membrane of the effecter organs; their functions :-
On vessels :- Cause smooth muscle contraction so there will be vasoconstriction of blood vessels found in skin ,splanchnic vessels and skeletal muscles ,this will cause pallor and increased peripheral vascular resistance .
On eyes :- Contraction of radial muscles of the iris due to α1 receptors stimulation lead to mydriasis
GIT:- relaxes the smooth muscles with increase sphincter tone lead to constipation .
Genitourinary system :- relaxes the bladder ,increase sphincter tone lead to closure of bladder neck lead to promote urine retention .
Contraction of the smooth muscle of the vas deferens and seminal vesicles resulting in ejaculation .
Sweat gland- it is the only gland that has dual innervation (cholinergic +adrenergic)
Skin :- contraction of the pilomotor smooth muscle lead to goose skin lead to erects hair .
Heart :- increased force of contraction (not important ) .
Metabolic functions:- the effect on the liver is stimulation of lipolysis, gluconeogenesis and glycogenlysis and k+ release .
Alpha 2 adrenoceptors :-
Alpha 2 is the reverse of alpha 1 ,the location and actions are :-
1:- Presynaptic receptors on adrenergic nerve terminals (auto receptors ),they inhibit noradrenaline release .
2:- Presynaptic receptors are present on cholinergic nerve terminals ,they are called (Heteroreceptors ) , their stimulation lead to relaxation of GIT smooth muscle ,due to Presynaptic inhibition of parasympathetic activity .
3:- CNS adrenoceptors are present in the brain stem ,lead to decrease sympathetic stimulation .
4:- On the beta cells of pancreas , alpha 2 are inhibitory ,they decrease insulin release .
5:- On plate lets ,they produce aggregation .
6:- On fat cells , they inhibit of lipolysis .
Alpha 2 causes vasodilatation lead to hypotension ,α 2 receptor agonist as Clonidine and alpha methyl dopa .
Beta adrenoceptors :-
They are subdivided into three subtypes Beta1, Beta2, and Beta3 .Beta 1 receptors ; present mainly in heart and kidney
In heart :- lead to increase automaticity of SA node with increase heart rate ,increased conductivity of AV node with increased contractility of the myocardium ,result in increased stroke volume with C.O.P. and this lead to increase systolic blood pressure
In kidney :- stimulation beta 1 receptors on the juxtaglomerular cells ,increase renin release which increase aldosterone secretion that lead to increase intravascular fluid → increase diastolic volume → increase in venous return to the heart → increase stroke volume → increase in systolic blood pressure indirectly ,Renin also convert angiotensinogen to angiotensin 1 .
Beta 2 receptors :-
1) Blood vessels → the skeletal muscles vessels are relaxed ,renal and visceral vessels are also dilated ,this lead to decrease TPR .
2) lung → the bronchiolar smooth muscle is relaxed ,and there is bronchodilatation
3) GIT→ the smooth muscle wall of the intestine is relaxed .
4) Genitourinary system → there is relaxation of the bladder wall , the pregnant uterus is relaxed lead to delay of premature labour .
5) Skeletal muscles → activation of beta 2 receptors → tremor and increase k + uptake by skeletal muscles → hypokalemia .
6) Mast cells → decreased histamine release and other vasoactiveamines e.g. bradykinine ,substance p .
7) Liver → increased gluconeogenesis and glycogenolysis → hyperglycemia .
Beta 3 receptors are found on fat cells ,their action is lipolysis .
Dopamine receptors :- there are 5 subtypes of dopamine receptors D1, D2, D3, D4, and D5 stimulation D1 family → stimulation of adenylyl cyclase → smooth muscle relaxation and dilatation of the renal blood vessels .
Stimulation of D2 family → inhibit adenylyl cyclase activity → open potassium channels → modulate transmitter release in nerve endings .
Adrenergic agonists :-
1:- According to chemical structure .
2:- According to receptor sensitivity .
3:- According to their mode of action .
According to chemical structure :-
1:- Catecholamines ,they are sympathomimetic amines that contain 3,4-dihydroybenzen group such as adrenaline ,noradrenaline ,dopamine, dobutamine , and Isoprenaline ;the latter two are synthetic .Characteristics :-
1:- show the highest potency .
2:- very short half life (2 min.)
3:- do not readily penetrate into CNS.
4:- metabolized by COMT and MAO .
5:- they are ineffective when given orally except Isoprenaline .
2:-Non- catecholamines (Phenalisopropylamines),they are compound lacking the catechol hydroxyl groups and include Phenylephrine , Ephedrine, and Amphetamine .
Characteristics :-
1:- Not metabolized by COMT and poor substrates for MAO.
2:- They can be given orally .
3:- Have prolong duration of action .
4:- Have increased lipid solubility .
5:- Have greater access to CNS .
According to receptor sensitivity ,into
1:- Alpha –agonist .2:- Beta –agonist .
According to their mode of action :-
1:- Direct acting agonists e.g. (Catecholamine and Phenylephrine ).These drugs act directly on alpha or beta receptors .
2:- Indirectly acting agonist e.g. (Amphetamine, Tyramine) ;these drugs are taken up into the Presynaptic neurons and cause the release of noradrenaline from cytoplasmic pool or vesicles of adrenergic neuron .
3:- Mixed action agonist e.g. ( Ephedrine ,Metaraminol );have the capacity both to direct stimulate adrenoceptors and to release noradrenaline from adrenergic neuron .
Noradrenaline :-
A natural neurotransmitter secreted by postganglionic sympathetic nerve endings ,mainly affects alpha receptors ,has an effect on beta 1 receptors ,but no effect on beta 2 receptors .So ,it causes vasoconstriction lead to increase TPR → increase diastolic pressure . it has a short half life (2-5 min.) .
Therapeutic uses of noradrenaline :-
1:- Shock ; it is used to treated shock e.g. hypovolemic shock ,because it increases vascular resistance and therefore , increases blood pressure ;it is not used in case of cardiogenic shock → cardiac arrest and not used in septicemic shock .(given with drip 2-5mic/ml/min.) .2:- Combine with local anesthesia ,to produce vasoconstriction and this causes delayed onset of L. A.
Side effects :-
1:- Cardiac arrhythmias .
2:- Angina pectoris .
3:- Hypertension .
4:- If the drug escape to the tissue away from the vein ,it causes tissue necrosis .
Adrenaline :-
Its use is much more common than noradrenaline , it works on both α and β .Therapeutic uses :-
1:- Anaphylactic shock :- type 1 hypersensitivity reactions in response to allergens leading to degranulation and release of histamine and other mediators ,it is a drug of choice given i.m. Adrenaline act as physiological antagonist to histamine .
2:- Acute asthma :- In the presence of bronchoconstriction ,the respiratory exchange is greatly improve within few minutes after subcutaneous administration of adrenaline (beta 2 action ) .
3:- Glaucoma :- Adrenaline solution may be used topically to reduce I.O.P. ,in open angle glaucoma .; it reduces the production of aqueous humor by vasoconstriction of the cilliary body blood vessels and it probably enhance outflow .
4:- Cardiac arrest ; adrenaline is given by intra cardiac injection .
5:- Epistaxis :- very weak solution of adrenaline can also be used topically to vasoconstrict mucus membrane to control oozing of capillary blood .
6:- Combine with local anesthesia to increase duration of local anesthesia by producing vasoconstriction at the site of injection ; and to control bleeding during surgery e.g. dental extraction .
Contraindications of Adrenaline :-
1:- Patients with IHD; by its action on both receptors ,( α cause vasoconstriction and β that cause increase heart rate) .2:- Hypertension ;(hypertensive crisis ) .
3:- Patients taking tricyclic antidepressant drugs ;these drugs inhibit amines re-uptake from synaptic space lead to potentiate adrenaline action .
4:- with using of Halogenated general anesthetics e.g. Halothane that sensitize the heart for adrenaline and this lead to increase cardiac arrhythmias .
5:- Thyrotoxicosis; (the patient already have overactive adrenergic system ) .
Side effects of adrenaline :-
1:- Cardiac arrhythmias .2:- Angina .
3:- Hypertension .
4:- If use adrenaline I.V. lead to ventricular fibrillation → cardiac arrest .
Isoprenaline :- A synthetic sympathomimetic drug ,having a β non selective activity (on β1 and β2 ),its action on alpha receptors is insignificant .
Clinical uses :-
1:- Complete heart block (stokes-Adams attack ) .
2:- Beta blockers poisoning ;Isoprenaline is used as antidote .
3:- Acute asthma ; (has β2 agonistic action ), but its problem is that also have β1 agonistic action ;so it causes palpitation .
Dopamine:-
It is the metabolic precursor of noradrenaline , occur naturally in the CNS, in the basal ganglia as well as in the adrenal medulla . Dopamine activates D1 receptors in the peripheral mesenteric and renal vascular beds ,which leads to vasodilatation ,the activation of Presynaptic D2 receptors on adrenergic neurons which suppresses noradrenaline release .Therapeutic uses :-
1:- A continuous I.V. infusion of Dopamine in small doses (2-5mico/kg/min.), causesincreased renal blood flow ,so used in case of acute renal failure .
2:- As the dose raise ,(5-15 micro/kg/min.) Dopamine activates beta(β1) receptors in the
heart with tachycardia and increase contractility and cardiac output(used in cardiogenic
shock and congestive heart failure ) .
3:- Higher doses (more than 15 micro/kg/min.) can causes vasoconstriction and
hypertension by activating α receptors ,(used in hypovolemic shock ) .
Side effects :-
1:- Tachycardia –β1- ,arrhythmias-β1-, and angina –β1 and α1 .2:- Slightly increase in systolic blood pressure ,and slightly decrease in diastolic blood pr.
3:- nausea and vomiting ,the cause is central by CTZ .
4:- Tissue necrosis from leak of fluid outside the vein ; by α receptors stimulation .
Dobutamine :-
It is a synthetic direct acting catecholamine, that is beta 1 receptor agonist ; it stimulates the heart with few vascular effects ,the drug increases the cardiac output with little tachycardia i.e.; it has greater inotropic than chronotropic effects on the heart .Therapeutic uses :-
1:- Congestive heart failure .
2:- Shock in patients with ischemic heart disease .
Non- catecholamine synthetic drugs
1:- Ephedrine :-It is a plant alkaloid extract from plant called ( Ephedra) , now it is made synthetically ,it is mixed action adrenergic agent ,it not only release stored noradrenaline from nerve endings ,but also directly stimulates both alpha and beta receptors ,it has unselectivity like adrenaline ,but:-
1:- it is less potent than adrenaline (about 100 time ) .
2:- It has long duration of action because it is a poor substrate for COMT &MAO(half life about 4 hrs .)
3:- I has excellent absorption orally .
4:- It penetrates into the CNS producing stimulation .
Therapeutic uses :-
1:- As a presser agent to raise blood pressure .(both systolic &diastolic blood pr .)2:- As a nasal decongestant .
3:- As a mydriatic agent .
4:- Chronic treatment of asthma ,it produces bronchodilation (beta 2 ) .
5:- Stress incontinence ,it constricts the neck of the urinary bladder (alpha action ).
6:- Heart block ( beta 1 action ).
7:- Myasthenia gravis ; Ephedrine improve motor function because of its anti curare action .
Adverse effects :-
1:- Tachycardia .2:- cardiac arrhythmia .
3:- Worsening angina .
4:- Hypertension .
5:- Hyperglycemia .
6:- Tremor .
Metaraminol :- mixed action adrenergic drug with action similar to noradrenaline ,this agent has been used in the treatment of shock and to treat acute hypotension .
Amphetamine :-
It is an indirect acting sympathomimetic drug that releases intracellular stores of catecholamines ;it also blocks MAO.Pharmacological actions :-
1:-CNS:-
It has a marked CNS stimulatory action ,this lead to increase alertness ,euphoria ,decrease fatigue ,depress appetite and insomnia ,it can also cause weakness, tremor, dizziness, delirium , panic states and suicidal tendencies ,in high doses convulsion can occur ; chronic use produces a state of psychosis that resembles an acute schizophrenic attack .2:- Sympathetic nervous system :-
It act indirectly through noradrenaline release and causes hypertension(α action on vasculature & β effects on the heart )., cardiac arrhythmias , anginal pain , headache .and excessive sweating .
Therapeutic uses :-
Therapeutic uses of Amphetamine is limited due to psychological and physical dependence .1:- Attention deficit syndrome :- young children with hyperkinetic and lack the ability to be involved in any one activity for longer than few minutes .
2:- Narcolepsy :- it is a disorder marked by an uncontrollable desire for sleep .
3:- Anorexiant :- to control or suppress appetite .
4:- Depression :- used as a psychostimulant .
Adrenoceptor agonist drugs :-
β – agonists :-1:- Non –selective agonists :- Adrenaline , Isoprenaline , Ephedrine .
2:- Selective agonists β1 and β2 agonists .
β 1 – agonists :-
1:- Dobutamine .
2:- Xamoterol; which is partial agonist at β 1 adrenoceptors .it act as agonist or antagonist according to level of sympathetic autonomic activity .it increase the heart rate and contractility by its agonist action at low level of sympathetic activity .
β2 agonists :-
1:- Vasodilators :- they are used in peripheral vascular diseases e.g. Isoxsuprine ,Nylidrine .
2:- Uterine relaxants :- they relax the pregnant uterus and are used in premature labour e.g. Ritodrine .
3:- Bronchodilators :- they are used in bronchial asthma e.g. Salbutamol and Terbutaline (half life =3hrs.); Fenoterol(half life =12 hrs. ) ,they are administered orally (chronic treatment ) or by the inhalation route (acute attacks),or I.V. (status asthmaticus ) .other Albuterol, Salmeterol .
Side effects :- headache , anxiety , tremor , tachycardia , and hypotension .
α- agonists:-
1:- Non- selective α –agonists e.g. Adrenaline and Noradrenaline .2:- Selective α –agonists are :-
A)α 1- agonists :- mainly used as vasoconstrictors ;include Phenylephrine and Methoxamine .
Therapeutic uses :-
1:- Nasal decongestants ;they are used topically as a nasal drop .2:- I.V. in case of shock ; wither hypovolemic, or following spinal anesthesia .
3:- Phenylephrine used in treatment open angle glaucoma by reduced production of aqueous humor through vasoconstriction of cilliary body blood vessels .
4:- Mydriatic agent for ophthalmological examination of the eye .
5:- Supra ventricular tachycardia ;because it causes marked vasoconstriction & lead to a rise in blood pre. Lead to a reflex vagal discharge is evoked that may convert the arrhythmia to sinus rhythm .
Oral preparations of nasal decongestants are different types :-
a)Short acting (2-3 hrs.) , e.g. Phenylephrine .
b)Intermediate acting (6 hrs.) e.g. Pseudoephedrine .
c) Long acting (8-12 hrs.) e.g. Xylometazoline ; Oxymetazoline ,and others like Imidazoline e.g. Naphazoline .
Adverse effects :-
1:- Rebound congestion with hypertrophy of nasal mucous membrane .2:- Local ischemia and mucous membrane is likely to be damage with long time using 3:- Allergy (with prolong use) .
4:- Lipoid pneumonia ; oily drops may enter the lungs .
5:- Interaction with anti hypertensive drugs leading to failure of therapy .
6:- Interaction with MAO inhibitors (anti depressant drugs ), may cause hypertension
7:- Hypotension with Imidazoline especially Naphazoline ( act on α 2 in CNS, suppressing sympathetic outflow ) ,so should never used in children .
α 2 agonists :-
They have an important ability to decrease blood pressure through actions in the CNS e.g. Clonidine & Methyldopa are useful in the treatment of hypertension .Clonidine :-
Is a potent anti hypertensive agent acts centrally by reducing noradrenaline outflow from adrenergic neurons ,it causes growth hormone stimulation centrally and this useful in dwarfism .Side effects :-
1:- Sedation .
2:- Dry mouth ,it act on salivary glands centrally .
3:- Constipation .
4:- Sever bradycardia .
5:- Rebound hypertension ,if patient withdrawal the drug .
α-methyldopa :-
Antihypertensive drug ,act by 2 ways :-a)Stimulate α2 receptors centrally ,leading to reduce noradrenaline secretion .
b) Entering the pathway of noradrenaline synthesis ;because it is similar to l-dopa ,leading to produce a false neurotransmitter .
Side effects :-
1:- Impotence .
2:- Galactorhea .
3:- Diarrhea .due to GIT irritation .
4:- Sedation and even some times depression .
5:- False positive Coombs test .
6:- Hepatitis ,auto immune reaction producing destruction of liver cells .
Adrenoceptor blocking drugs :-
1:- Alpha adrenoceptor antagonist drugs :-1:- Non –selective α-blockers e.g. Phentolamine ,and Phenoxybenzamine .
Block α 1 lead to decrease blood pressure ,while block α 2,result in increase blood pressure . Phentolamine has histamine like action ,Phenoxybenzamine has carcinogenic effect in experimental animals .2:- Selective α-adrenoceptors antagonists :-
A)Selective α 1-antagonisrt drugs :-
include Prazosin , Terazosin , and doxazosin →treatment of hypertension .Tamsulosin and Alfuozosin → treatment of benign prostatic hyperplasia, (B.P.H.).
Therapeutic uses of α 1 – blockers :-
1:- Peripheral vascular disease; individual with Reynaud's phenomenon and other conditions involving vasospasm in the peripheral circulation do benefit from alpha-blockers .
2:- Urinary obstruction ; alpha receptor blockade was found to be helpful in benign prostatic hyperplasia (B.P.H.) . Tamsulosin is more potent inhibitor of the alpha 1 A receptor found on smooth muscle of the prostate .
3:- treatment of Hypertension .
4:- Local use to overcome vasoconstriction caused by local anesthesia .
Side effects :-
1:- Hypotension and postural hypotension (Prazosin has what's called first dose effect ,the first dose may cause brisk hypotension sufficient to cause loss of consciousness ,initiate dose should be low dose and on going to bed .2:- Peripheral edema ,(α 1 dilates both arterioles and venues lead to decrease venous return → decrease stroke volume→ decrease C.O.P. →decrease systolic blood pre. );evoked if there is heart failure .
3:- Reflex tachycardia .
4:- Flushing .
5:- Headache .
6:- miosis .
7:- urine incontinence .
8:- In the male ,failure of ejaculation .
Alpha 2 antagonists :-
Yohimbine is a weak alpha 2 adrenoceptor blocking agent ,it works at the level of CNS to increase sympathetic outflow to the periphery .Therapeutic uses:-
1:- autonomic insufficiency .
2:- Type 2 diabetes (α 2 receptors inhibit insulin secretion ).
3:- Psychiatric depression .
4:- Improve male sexual derive
5:- Improve symptoms in patients with painful diabetic neuropathies .
Beta-adrenoceptors blocking drugs :-
All beta –blockers are competitive antagonists ,the effects depend on the amount of sympathetic tone present e.g. exercise .Classification of beta –blockers :-
1:- According to the pharmacokinetic properties into :-a)Lipid soluble :-
Are extensively metabolized by the liver ,they are subject to extensive hepatic first pass metabolism after oral administration .
They readily cross cell membranes ,so have high volume of distribution VD.
They readily enter the CNS .
They have a short half life ( about 3 hrs.).
Examples :- Propranolol and Metoprolol .
b)Water soluble :-
They are less subject to hepatic first pass metabolism .These agents are less widely distributed (low VD).
Have lower incidence of effects to penetrate of the CNS.
They have a longer half life (about 9 hrs.)
Examples :- Atenolol and Nadolol .
2:- According to selectivity:-
1)Non –selective beta blockers ;act at both beta 1 and beta 2 receptors e.g. Propranolol, Pindolol, Oxprenolol , Timolol , Nadolol .2) Selective – beta 1 blockers ( cardio-selective ) :- have a higher affinity (50-100 times) for beta 1 than for beta 2 receptors ; e.g. Atenolol , Metoprolol, Acebutolol , Esmolol , Bisoprolol .
The clinical advantages of selective beta 1-blockers are :-
1:-In asthma ;there is less likelihood of causing bronchoconstriction .In peripheral vascular disease ;when cold extremities is a side effect . 2:-
3:- In diabetics ; where beta 2 receptors mediate the symptoms of hypoglycemia and counter-regulatory metabolic responses that reverse the hypoglycemia .
3:- According to non-blocking effects :-
1:-Partial agonist action (PAA)(Intrinsic sympathomimetic activity) (ISA):-Most beta –blockers are pure antagonists i.e. not cause activation of the receptors ;some are partial agonists ( cause partial activation of the receptors ), sometimes described as having intrinsic sympathomimetic activity (ISA) ;e.g. Pindolol and Acebutolol .
2:- Membrane stabilizing action(MSA) :-
It is a prominent effect of several beta –blockers ; this action is the result of typical local anesthetic blocked of sodium channels .e.g. Propranolol and Acebutolol .
Therapeutic uses of beta – receptor blocking drugs :-
A) Cardiovascular uses in:-1:- Angina pectoris ,by decrease cardiac work and oxygen demand .
2:- Hypertension , by reduction in cardiac output ,lowering of total peripheral resistance ,inhibition of rennin release .
3:- Cardiac tachyarrhythmias ;beta –blockers are class 2 antiarrhythmic ,they depress automaticity and increase the AV nodal refractory period ,they are especially effective for treatment of supraventricular arrhythmias .
Sotalol is a non selective beta blocker that has marked class 3 anti arrhythmic effect .
4:- Myocardial infarction ,by reduction in infracted size and protection against cardiac rupture .
5:- Hypertrophic obstructive cardiomyopathy by decrease outflow resistance and increase stroke volume .
B)Endocrine uses in :-
1:- Hyperthyroidism ,by reduce the unpleasant symptoms of sympathetic-over activity .
2:- Pheochromocytoma , beta blockers should not be employed prior to establishing effective alpha receptor blockade .
C)CNS uses :- anxiety ,tremor , migraine headache prophylaxis ; Propranolol show a beneficial effect in reducing the frequency and intensity of migraine headache .
D) Eye uses:- Glaucoma , by Timolol ,reduce I.O.P. by reduce production of aqueous humor by the cilliary body .
Adverse effects of β- blockers :-
1:- Brady cardia ,hypotension, enhancement heart failure .2:- Bronchoconstriction ,beta 2 blockade commonly worsening of preexisting asthma .
3:- Hypoglycemia ,by inhibition gluconeogenesis and glycogenolysis .
4:- Cold extremities , it is due to reduce peripheral blood flow especially with non- selective drugs .
5:- Withdrawal phenomenon ;abrupt withdrawal of therapy can be dangerous in angina pectoris and after M.I.
6:- Intrauterine growth retardation ,by decrease placental blood flow ,they also produce neonatal bradycardia and neonatal hypoglycemia .
7:- Hyperlipidemia , beta –blockers cause decrease of HDL/LDL ratio which is increase risk of IHD .
8:- impotence .
9:- Oculomucocutaneous syndrome .
10:- CNS side effects ;include sedation ,fatigue ,nightmares ,and depression .
Contraindications of β- blockers :-
1:- Heart failure .2:- Asthma .
3:- Diabetes.
4:- Peripheral vascular disease .
5:- Sick sinus syndrome or heart block .
6:- Bradycardia and hypotension .