Adrenergic Receptors & Neurotransmitters PDF

# Pharmacology For Medical Students Volume I ## Sympathetic division of ANS (Adrenergic system) - Adrenergic neurotransmitters (endogenous catecholamines): - Noradrenaline (NA) mainly present in adrenergic nerve endings - Adrenaline (Ad) mainly present in adrenal medulla - Dopamine (DA...

# Pharmacology For Medical Students Volume I ## Sympathetic division of ANS (Adrenergic system) - Adrenergic neurotransmitters (endogenous catecholamines): - Noradrenaline (NA) mainly present in adrenergic nerve endings - Adrenaline (Ad) mainly present in adrenal medulla - Dopamine (DA) mainly present in CNS (extrapyramidal, basal ganglia, limbic system) & in peripheral. ### Synthesis of catecholamines - Phenylalanine is an aromatic amino acid actively absorbed from gut & converted to L- tyrosine in presence of hepatic phenylalanine hydroxylase & then L- tyrosine is taken up actively by the adrenergic neurons. | | | |---|---| | Tyrosine | DOPA (dihydroxyphenylalanine) | | | Tyrosine hydroxylase | | | | | DOPA | Dopamine | | | Dopa decarboxylase | | | | | Dopamine | NA (in vesicles) | | | ẞ hydroxylase | | | | | NA | Adrenaline (only in adrenal medulla) | | | phenylethanolamineN- Methyl transeferase | **Note:** Tyrosine hydroxylase is the rate limiting step in this synthesis. ### Storage - NA is stored in synaptic vesicles at the adrenergic neve terminals. - It is stored in the vesicles as a reversible complex with ATP & a protein chromogranin A which are release with NA in exocytosis. ### Release of NA: 1. Nerve impulse arrive, lead to depolarization of nerve terminal membrane & open the voltage gated Ca channels. 2. Calcium influx into the nerve terminal leads to increase in intracellular level of Ca which interacts with special protein associated with vesicular membrane → destabilization of vesicles → vesicles approach neuronal membrane. 3. Fusion of vesicular membrane with neuronal membrane resulting in the expulsion of vesicular contents into the synaptic cleft (exocytosis). The transmitter then activates a & ẞ adrenergic receptors in the membrane of postsynaptic cells that causes physiological action. ### Uptake of catecholamines: 1. **Neuronal uptake (Ul):** It is the main mechanism of terminating the action of NA on the post synaptic receptors. Neuronal uptake takes place in two steps: - Axonal uptake involves a Na /K activated ATPase that can be blocked by tricyclic antidepressants & cocaine. - Vesicular uptake: Via the amine transporter system which blocked by reserpine. 2. **Extraneuronal uptake (U2):** Uptake by other tissues e.g cardiac muscle, smooth muscles, and endothelial cells of blood vessels for NA, Ad, & DA then metabolized (not stored). * U2 is blocked by glucocorticoids & phenoxybenzamine. ### Enzymatic destruction - Circulating Adrenaline & NA are degraded by MAO (monoamine oxidase) & COMT (catechol- O- methyl transeferase). **MAO:** is associated with the outer surface of mitochondria. It is responsible for metabolism of NA in nerve endings. It is also present in liver, brain, intestine, kidney, blood, lungs & neurons. **COMT:** particularly in liver, responsible for metabolism of circulating catecholamines. The main metabolite of catecholamines is VMA (vanillyl mandelic acid) which can be measured in urine & blood. It is important indicator in case of pheochromocytoma. ## Drugs affecting adrenergic neurotransmitters 1. Metyrosine inhibits transmitter synthesis. 2. Reserpine inhibits transmitter storage. 3. Tyramine & amphetamine enhance transmitter release. 4. Cocaine & TCA drugs inhibit uptake after release. ## Adrenoceptor subtypes & their distribution: (Table 2-5 ) | Organ | Receptor | Action | |---|---|---| | Eye | | | Iris radial muscle | Alphal | Contracts | | Ciliary muscle | Beta | Relaxs | | Heart | | | SAN | Beta 1 | Accelerates | | Ectopic pacemakers | Accelerates | | Contractility | Increases | | Blood vessels | | | Skin, splanchic vessels | Alpha | Contracts | | Skeletal muscle vessels | Beta 2 | Relaxes | | Bronchial smooth muscle | | | Alpha | Contracts | | Beta 2 | Relaxes | | GIT | | | Smooth muscle walls | Alpha 2, Beta2 | Relaxes | | Sphincters | Alpha 1 | Contracts | | Genitourinary s.muscle | | | Bladder wall | Beta 2 | Relaxes | | Sphincter | Alpha 1 | Contracts | | Uterus, pregnant | Beta 2 | Relaxes | | Penis, seminal vesicles | Alpha | Contracts | | Alpha | Ejaculation | | Skin | | | Pilomotor smoothmuscle | Alpha | Contracts | | Sweat glands | Muscarinic | Increases | | Thermoregulatory | Alpha | Increases | | Apocrine (stress) | Increases | | Metabolic functions | | | Liver | Beta 2, Alpha | Gluconeogenesis | | Liver | Beta 2 Alpha | Glycogenolysis | | Fat cells | Beta 3 | Lipolysis | | Kidney | Betal | Rennin release. | ## Sympathomimetics: - They are drugs which produce effects similar or resemble those of sympathetic nerve stimulation. ### Classification of adrenergic agonists: - **According to their chemical structures:** - Catecholamines (Adrenaline, noradrenaline, isoproterenol, dopamine, fenoldopam). - **Properteis:** - Rapid onset of action. - Breif duration of action. - Not administered orally. - Don't penetrate BBB. - Non catecholamines (Methoxamine, clonidine, metaproterenol, terbutaline, salmeterol, formoterol, amphetamine & ephedrine). - **Properties:** - Long duration of action. - All can be administered orally. - **According to their action on adrenergic receptors:** - Direct acting sympathomimetics (on receptors). - Indirect acting sympathmimetics. - Mixed action sympathomimetics. ### i- Direct acting sympathomimetics 1. **α & β-agonists:** Adrenaline & noradrenaline 2. **a- adrenergic receptor agonists:** - *α1 agonist:* Methoxamine, phenylephrine, naphzoline - *α2-agonists:* a-methyl dopa, clonidine (note: that they inhibit sympathetic activity since they release of NA) 3. **ẞ- adrenergic receptor agonists:** - *β1& B2- agonists (non-selective):* Isoprenaline, oxyfedrine & ethylnoradrenaline. - *Selective ẞ1-agonists:* Dobutamine &dopamine - *Selective ẞ2-agonists:* Terbutaline, salbutamol, salmetrol, ritodrine & isoxsuprine - *Selective ẞ3-agonists:* (BRL37344 & AD9677). ### ii- Indirect acting sympathomimetics: - Amphetamine, tyramine & cocaine ### iii- Mixed action sympathomimetics - Ephedrine ## Adrenergic agonists | | | | | | |---|---|---|---|---| | | **Direct agonists** | **Nonselective** | **Releasing agents** | **Reuptake I inhibitor** | **MAO inhibitor** | | | **Selective** | | | | | | | phenylephrine (a1) | isoproterenol (β, β2) | amphetamine | cocaine | pargyline | | | clonidine (a2) | oxymetazoline (a1, a2) | tyramine | | | | | dobutamine (B₁) | | | | | | | terbutaline (B2) | | | | | | | **Indirect agonists** | | | | | ## Directly acting sympathomimetics: ### Adrenaline (potent stimulator of both a & β) **Pharmacokinetics:** - It is ineffective after oral administration, because it is inactivated in GIT &liver. - Subcutanous absorption occurs slowly because of local vasoconstriction. - It is rapidly inactivated in the body by COMT & MAO. **Pharmacological actions (table 2-5):** 1. **On heart: (B1)** - It ↑ heart rate (HR) → tachycardia (+ve chronotropic) - It ↑ force of contraction → +ve inotropic - It enhances automaticity & causes arrhythmias. 2. **On BP:** It has dual effect depending on the dose - High dose ↑ systolic pressure (β₁) & diastolic pressure (αι). - Low dose ↑ systolic pressure (ẞ₁) but ↓ diastolic pressure by its action on ẞ→VD of skeletal blood vessels. This is because; ẞ2-receptors are more sensitive to adrenaline than a₁- receptors in blood vessels of skeletal muscle. 3. **On blood vessels:** Contraction of arteriols of skin & mucosa (al) & ↓ blood flow. It↑ blood flow to skeletal muscle (ẞ2). 4. **On GIT:** Relaxation of GIT (α & β), Contraction of sphincter (αι). 5. **On uterus:** Relaxation in the last month of pregnancy (ẞ2). 6. **On bronchial s. muscle:** Powerfull bronchodilation (B2). 7. **Metabolic effects:** - ↑glycogenolysis (a₁ & ẞ2) & ↓ in insulin release (a2) → hyperglycemia - ↑ free fatty acids in blood, because it stimulates (ẞ1 & ẞ3) in adipocytes. 8. **On genitourinary tract:** The bladder base, urethral sphincter & prostat contain a receptors that mediate contraction & promote urinary continence. **Notes about pharmacological actions of sympathomimetics:** - **On eye:** a agonists cause mydriasis & ↑ the outflow of aqueous humor from the eye & ↓ IOP. - **On GIT:** Contraction of sphincter by drugs selective to (a1). a2-selective agonists ↓ muscle activity indirectly by resynaptically ↓ the release of ACh, they also may ↓ salt & water flux into the lumen of the intestine. - **On CNS:** The action of sympathomimetics varies depending on their ability to cross BBB. These actions vary from mild alerting, improved attention, and elevation of mood, insomnia, euphoria & anorexia to full- blown psychotic behavior. - **On exocrine glands:** The apocrine sweat glands, located on the palms of the hands & a few other areas, respond to adrenoceptor stimulants with ↑ sweat production(these nonthermoregulatory glands are associated with psychological stress). The thermoregulatory eccrine sweat glands are regulated by sympathetic cholinergic postganglionic nerves that activate M receptors. **Clinical uses:** (Uses of adrenaline are due to VC, cardiac stimulation & bronchodilation actions). 1. **Anaphylactic shock (I.M):** It is DOC for rapid relief of hypersensitivity reactions. It produces bronchdiiation, VC effects & mast cell stabilization, therefore, it acts as physiological antagonist to histamine that causes bronchoconstriction & VD. 2. **Bronchial asthma.** 3. **Cardiac arrest to restore cardiac rhythm (it is given intracardiac).** 4. **With local anesthetics, because it causes VC →:** - ↓ absorption of local anaesthetic. - ↑ duration of their action. - their systemic toxicity. - ↓ bleeding. 5. **Topical haemostatic on bleeding surfaces (such as epistaxis), it is used locally in a piece of cotton.** 6. **Glaucoma, because it ↓ IOP by ↓ the production of aqueous humor (VC in the ciliary body).** ### Side effects: 1. Anxiety, restlessness & throbbing headache (on CNS). 2. Tremors (on sk.m) 3. Pallor (VC) 4. Palpitation & arrhythmia (on heart). ### Contraindications: 1. Hypertension. 2. Diabetic patients. 3. Hyperthyroidism (thyroxine increases cardiovascular actions & ↑ sensitivity of BV receptors to adrenaline). 4. Psychological diseases. ## Noradrenaline: - Potent agonist on a1, a2 & β₁ adrenoceptors (little action on ẞ2). ### Pharmacological actions: 1. **CVS:** - It ↑ systolic & diastolic blood pressure (it doesn't produce reduction in peripheral resistance at low doses). - It stimulates cardiac function, but this stimulation is antagonized by reflex vagal stimulation (bradycardia) & ↓ in CO as a reflex of hypertension. 2. **Smooth muscle:** - It has no effect on bronchial muscle. - It ↓ motiltity of GIT. ### Therapeutic uses: - Treatment of acute hypotensive states due to septic shock, while fluids or blood being administered to preserve cerebral & coronary blood flow. It is given by slow I.V infusion, not given I.M or S.C due to severe vasospasm → necrosis.* In cardiogenic shock, dopamine is preferable drug since it produces renal VD via D₁- receptors & prevents renal failure during cardiogenic shock. ## Isoprenaline (β₁ & ẞ2- agonist) - It is a synthetic catecholamine. - It can be absorbed from sublingual mucosa through inhalation & by I.M route. - It is metabolized by COMT, its half life = 2 hrs. ### Pharmacological actions: 1. **Heart:** It stimulates all properties of heart. 2. **Blood vessels:** It causes VD. 3. **Bronchial muscles:** It is very potent bronchodilator, prominent when bronchi constricted, no important effect in normal person. ### Therapeutic uses: 1. Acute attack of bronchial asthma. 2. Heart block (to increase ventricular rate), in emergency as temporary drug. 3. Cardiac arrest (cardiac stimulant). ## Dopamine: - It is a precursor of NA. It is important neurotransmitter in the brain. - It acts on dopaminergic receptors D₁ (renal, mesenteric, cerebral &coronary vessels), D2 (in CNS) - It acts also on adrenoceptors (β₁ & α₁). ### Pharmacological actions: - Its hemodynamic effects depend on the dose: - At low concentration (1-5 Microgram/Kg/min) given I.V. It acts on vascular D1- receptors → renal, cerebral & coronary VD. - At moderate dose it acts on ẞ1- receptors in the heart, producing +ve inotropic & chronotropic effect (less than that produced by adrenaline) - At higher doses it acts on al- receptors & causes VC &↑ BP. ### Therapeutic uses: 1. Shock especially when associated with compromised renal function such as cardiogenic & hypovolemic shock. It is used in low dose by infusion to avoid activation of al-adrenoceptors which counteracts the VD in renal blood vessels, it produces less tachycardia than adrenaline. 2. Acute heart failure. ### Side effects: 1. Arrhythmia (serious). 2. Nausea & vomiting because it acts on CTZ. 3. Hypertension (only for few minutes). ## Fenoldopam (selective on D receptors): -It is used I.V for treatment of hypertension. ## Dobutamine (selective ẞ₁- agonist): - It is related to dopamine chemically, but it does not act on D- receptors. - It has short duration of action (2 min), it is used by I.V infusion. - It is used in congestive heart failure. - It is less arrhythmiogenic than dopamine. ## Salbutamol (selective ẞ2- agonist): - It acts mainly on bronchial muscles (relaxation). - Relaxation of pregnant uterus. ### Therapeutic uses: 1. Acute attack of bronchial asthma, it is used by inhalation, parentrally &orally (tablets & syrup). 2. Premature labor (uterus contraction). ### Side effects: 1. Tachycardia. 2. Tremor (effect on sk. m) ## Other selective ẞ2- agonists: - Salmetrol: It is similar to salbutamol but has long duration of action. - Terbutaline: It is like salbutamol, but it is only given as inhaler or SC. - Ritodrine: It is only used in premature labor. - Isoxusurpine: It is used in treatment of Raynaud's phenomenon to produce peripheral vasodilation. - BRL37344 & AD 9677 (selective ẞ3-agonists): They might prove as the potential targets for the new antiobesity drugs. ## Clonidine (a₂- selective agonist It decreases release of NA from adrenergic nerve ending and inhbits sympathetic activity, therefore it is sometimes classified as adrenergic neuron blocker. ### Pharmacological actions: 1. Centrally, it activates a 2-receptors in the brain stem ↓ central sympathetic outflow (it is lipid soluble that can pass BBB). 2. Peripherally, it activates peripheral a2- receptors; also it ↓ plasma concentration of renin & aldosterone in hypertensive patient. 3. It has other effects that are unrelated to adrenergic receptors, such as on I1, I2 imidazoline receptors. ### Therapeutic uses: 1. Hypertension 2. Morphine withdrawal in addicted patients. 3. Migraine prophylaxis. ### Side effects: 1. Bradycardia (it activates parasympathetic outflow & ↑vagal tone). 2. Sedation. 3. Dry mouth 4. Rebound hypertension when withdraw suddenly because of increase in sympathetic outflow, this can be treated by using labetalol. ## Dexmedetomidine (a₂- selective agonist): It is centrally acting, used for sedation of initially intubated & mechanically ventilated patients during treatment in intensive care setting. ## Apraclonidine & brimonidine (a₂- selective agonists): They are mainly used for treatment of glaucoma. ## a- Methyl dopa: - It is pro-drug; it is metabolized in the brain to methyl-noradrenaline which stimulates a2- adrenergic receptors in the brain stem, inhibiting sympathetic discharge. Unlike NA, a- methyl NA is more potent on a₂- receptors sites than al-adrenoceptor sites. With chronic administration of methyl dopa, endogenous NA is replaced by a- methyl NA in the peripherals & CNS, where it is released & acts as a false neurotransmitter. ### Pharmacological actions: 1. It vascular resistant → ↓ BP. 2. It has no effect on renal blood flow. 3. It has no effect on HR. ### Side effects: 1. Sedation, dry mouth, nasal stuffiness, headache. 2. Depression & Parkinsonism. 3. Bradycardia in large doses 4. Sexual dysfunction. 5. Salt & water retention. 6. Hepatitis. 7. Positive Coomb's test, haemolytic anemia. ## Phenylephrine (a₁- selective agonist): - It is not a catecholamine; it is not inactivated by COMT. ### Pharmacological actions: 1. VC→↑PR→↑ mean arterial pressure with reflex bradycardia, so it is used in paroxysmal supraventriculr tachycardia. 2. Active mydriasis (contraction of radial smooth muscles of iris). ### Therapeutic uses: 1. Hypotension states (during spinal anesthesia). 2. Nasal decongestant with antihistamine (topically). 3. Mydriatic before ophthalmic examination (as drops). 4. Paroxysmal supraventricular tachycardia. ### Side effects: 1. Rebound congestion (it causes ischemia that lead to swelling on continuous use). 2. ↑ BP & dizziness. ## Methoxamine (a₁- selective agonist): - It is used to maintain BP during anesthesia. ## Naphazoline (a₁- selective agonist): - It is used in ophthalmology as a mydriatic & also used as nasal decongestant.. ## Indirectly acting sympathomimetics: - Amphetamine, tyramine & cocaine - They act either by releasing noradrenaline from the adrenergic nerve terminal which in turn stimulates the adrenoceptors (amphetamine & tyramine) or by inhibiting reuptake of noradrenaline at noradrenergic synapses which results in accumulation of noradrenaline at adrenoceptors (cocaine). ### Amphetamine & its substitutions (phenmetrazine, methylphenidate): - They discharge NA, dopamine& 5-HT stored in nerve ending centrally & peripherally resulting in powerfull CNS stimulation & peripheral a & ẞ actions. ### Pharmacological actions: 1. ↑ BP with reflex bradycardia. 2. CNS stimulation leads to: - Wakefulness, alertness& ↓ sense of fatigue. - Mood elevation & self confidence. - Depression of appetite. - ↑ motor & speech activity & euphoria. ### Therapeutic uses: 1. Narcolepsy (sleep occurring in fits). 2. Attention deficit hyperactivity disorder in children ADHD: (paradoxical effect), this disorder is characterized by excessive motor activity, difficulty in sustaining attention, learning problems & impulsiveness. Amphetamine, at low dose, dramatically calms some patients by unknown mechanism. 3. Obesity (not used now because of abuse liability). * It is abused by students, athlets, drivers & women. ### Side effects: 1. CNS effects: Psychological dependence, restlessness, tremor, weakness, insomnia, fatigue, depression & schizophrenia like syndrome. 2. CVS effects: Palpitation, anginal pain, arrhythmias & increase in BP. 3. GIT effects: Anorexia, nausea, vomiting & diarrhea. ### Treatment of toxicity: 1. Acidification of urine. 2. Chlorapromazine. 3. a- adronoceptor blockers. ## Modafinil: - is a new amphetamine substitute that approved for use in narcolepsy & in ADHD. It has a fewer side effects. ## Tyramine (not used clinically): - It acts on peripheral neurons to release NA from nerve terminals. It is metabolized by MAO in the GIT wall & liver before reaching systemic circulation. It is found in high concentration in fermented foods & beverages such as cheese, beer & wine. - **Cheese reaction:** Ingestion of tyramine rich foods in patient taking non-selective MAOIs causes hypertensive crisis, because MAOIs inhibit metabolism of tyramine, which releases NA that causes increase in BP. *Therefore fermented food should be not taken by patient receiving non-selective MAOIS ## Cocaine: - It is uptake 1- inhibitor. - It is a powerful CNS stimulant & local anesthetic agent. - It is highly abused drug. ## Mixed action sympathomimetics: - Ephedrine & pseudoephedrine (direct & indirect effects): These drugs act directly on adrenoceptors as well as indirectly by releasing endogenous NA. ### Pharmacological actions: 1. VC→↑ BP. 2. Bronchodilation. 3. Mild stimulation of CNS (alertness, ↓ fatigue& sleep). 4. ↑ heart rate & dilate coronary vessels. 5. ↑tone of skeletal muscle. ### Therapeutic uses: 1. Bronchial asthma. 2. Nasal decongestants. ## Clinical uses of sympathomimetics: ### A-Cardiac uses: 1. Acute heart failure. Dopamine &dobutamine. 2. Cardiogenic shock. Dopamine &dobutamine. 3. Heart block. Isoprenaline. 4. Cardiac arrest. Adrenaline. 5. Paroxysmal atrial tachycardia. Phenylephrine & methoxamine. ### B- Vascular uses: 1. Hypotension. Phenylephrine & methoxamine. 2. Hypertension. Clonidine & methyl dopa. 3. Nasal decongestant. Phenylephrine, ephedrine & naphazoline. 4. To arrest local bleeding from skin or mucous membranes e.g epistaxis (adrenaline applied locally at site of bleeding). 5. Raynaud, s phenomenon. Isoxusuprine. 6. Along with local anesthetics. Adrenaline. ### C- Allergic disorders - such as anaphylactic shock. Adrenaline ### D- Smooth muscle uses: 1. Bronchial asthma. Salbutamol, terbutaline, salmeterol & adrenaline. 2. Premature labor. Salbutamol & ritodrine. 3. Mydriatic agent to facilitate examination of retina e.g. Phenylephrine, apraclonidine & brimonidine. ### E- Central uses: 1. Narcolepsy. Amphetamine & its derivatives. 2. ADHD. Amphetamine & its derivatives. 3. Antiobesity. BRL 37344 & AD9677 ## Adrenoceptor antagonists (blockers): ### Classification: 1. **a- adrenceptor antagonists** 2. **B-adrenoceptor antagonists.** 3. **a & ẞ- antagonists** ### I- a- adrenoceptor antagonists: - **A- Non selective (al & a2) antagonists:** **Phenoxybenzamine:** - It binds covalently with receptors. It has long duration of action (48 hrs). **Pharmacological actions:** 1. Blocking al receptors →VD →↓ PR → JBP & reflex tachycardia. 2. Blocking a2-receptors →↑ NA→ tachycardia. - It causes postural hypotension due inability redistribute blood following change in posture from supine to standing because of loss the vasoconstrictor tone that causes decrease in blood supply to brain. ### Therapeutic uses: 1. Treatment of phaeochromacytoma before & during surgery to ↓ BP (it is a tumor of adrenal medulla → excessive secretion of Ad & NA characterized by severe hypertension & cardiac arrhythmias). ### Notes: - a- blockers are given in phaeochromocytoma to tachycardia, however they should not be given before a- blockers because unopposed a- receptors cause more vasoconstriction & more elevation in blood pressure which may result in cerebral hemorrhage. - Phenoxybenzamine is not used to control chronic hypertension because of tachycardia & sometimes cardiac output. 2. It is also used in Raynaud's phenomenon. ### Side effects: 1. Postural hypotension with reflex tachycardia. 2. Flushing & nasal congestion. 3. Inhibition of ejaculation in male 4. Miosis 5. adrenergic sweating. ## Phentolamine: - It is similar to phenoxybenzamine but it is reversible & has short duration of action. - It is also used locally to prevent dermal necrosis after extravasation of a adrenergic agonists. ### B- Selective al- antagonists: - Prazosin, terazosin, tamsulosin - They are selective for (a 1) receptors, but they have no affinity for (ᾳ 2) receptors, so they allow NA to act on presynaptic a2 receptors & less NA release & less activation of ẞ1 that cause less tachycardia, so they can be used for treatment of chronic hypertension. ### Therapeutic uses of prazosin: 1. Hypertension. 2. Raynaud's phenomenon (vasospam in peripheral circulation). 3. Benign prostatic hyperplasia (BPH). It relaxes bladder neck & prostatic muscle relieving urinary obstruction. *Tamsulosin is the preferable drug in this case since it is selective a 1A antagonist & produces less effect on arterial blood presuure (see below). ### Side effects: 1. First dose phenomenon. It is marked postural hypotension & syncope seen 30-90 min after an initial dose due to: - Rapid development of both venous & arterial dilation without compensatory tachycardia. - Reduction of sympathetic outflow centrally. 2. Headache, nausea, dizziness & drowsiness. ## Tamsulosin: - It is a new drug selective for a1-A in smooth muscle of prostate, urinary bladder, neck & urethera, so it is used in BPH without postural hypotension, since in blood vessels a 1-B receptors subtype are mainly present. ### C- Selective a2- antagonists: - Yohimbine: (not used clinically) ## Other a- adrenoceptor antagonists: - Ergot alkaloids (ergotamine & ergometrine): - They are produced by claviceps purpurea a fungus that infects grain under damp growing or storage conditions. - They have a- adrenergic blocking activity with partial agonistic activity; they also have antagonist activity to dopamine & serotonin. They are used for their direct VC & oxytocic actions, rather than as adrenergic blocking agents. - *Ergotamine (B.V) → used in migraine.* - *Ergometrine (uterus) → used in bleeding* - Alfuzosin is al - antagonist used in BPH. - Urapidil is al- antagonist is used as antihypertensive agent & for BPH. - Trazodon is al- antagonist used as antidepressant agent. ## Clinical uses of a- adrenoceptor antagonists: 1. **Hypertension:** - Chronic hypertension: Prazosin &terazosin. - Hypertensive emergencies (excess circulating concentration of a-gonists).Phentolamine, prazosin &terazosin 2. **Phaeochromocytoma:** - For management: Phenoxybenzamine (with ẞ-blocker). - For diagnosis: Phentolamine (patients with this tumor often manifest a greater than average drop in BP in response to a-blockers). If after giving 5 mg of phentolamine (I.V), the blood pressure falls by 25-35 mmHg, it is a potential case of phaeochromacytoma & if less, it is a case of essential hypertension. 3. **Urinary obstruction (benign prostatic hyperplasia). Tamsulosin** 4. **Raynaud, s phenomenon. Phentolamine, tolazoline or phenoxybenzamine (Ca- antagonists may be preferable).** 5. **Local vasoconstrictor excess: Phentolamine (local infiltration into the ischaemic tissues).** 6. **Migraine (acute attacks). Ergotamine** 7. **Uterine bleeding. Ergometrine** ### Adverse effects: - As mentioned before for phenoxybenzamine. ## II- ẞ-adrenergic receptor blockers (BB): ### Classification: 1. **Accoding to selectivity:** - **a- Non-selective (β₁ & ẞ2) blockers:** - (Propranolol, timolol, pindolol, nadolol) - **b- Selective (β₁, cardioselective) blockers:** - (Atenolol, esmolol, acebutalol, metoprolol) - **c- Selective ẞ2-agonist:** - Butoxamine (not used clinically, but only for research purposes). - **d- Vasodilators** - Carvedilol (non-selective ẞ & a-blocker), celiprolol (β₁- blocker & β2 -agonist). - **e- a & ẞ blockers** - Labetalol 2. **According to solubility** - **a- Lipid soluble (propranolol & timolol).** - **b- Intermediate soluble (pindolol & acebutalol).** - **c- Water soluble (atenolol & nadolol).** ### Pharmacological actions of ẞ- blockers: 1. **CVS:** They ↓ BP because, - **a- They ↓ H.R & C.O.** - **b- They block β receptors in juxtaglomerular apparatus →↓ in renin secretion & Ang II (Ang II is a potent VC & ↑ aldosterone & H2O & Na retention).** - **c- They block presynaptic β receptors & ↓ release of NA..** 2. **Bronchial smooth muscle: They cause bronchospasm.** 3. **Metabolic effect:** They inhibit glycogenolysis & ↓ glucose (they potentiate hypoglycemic effects of insulin & delay recovery from hypoglycemia); they also mask the manifestation of hypoglycemia (tachycardia &tremor). They inhibit lipolysis & ↓ FFA in blood. 4. **Eye:** They production of aqueous humor. 5. **CNS: They tremors & anxiety.** 6. **Cell membrane stabilization:** Propranolol has local anesthetic action (↓ Na influx through the membrane), but it is not used for this purpose because of its irritation &its effect doesn,t appear only when using high dose which lead to many systemic side effects. * Pindolol is a partial agonist & has intrinsic sympathomimetic activity (ISA), it is less likely to cause bradycardia & withdrawal syndrome at sudden stop of the drug.. * **Advantages of selective β1-blockers drugs:** - Less liable to produce bronchospasm. - Less likely to delay recovery from hypoglycemia. - Less liable to induce Raynaud,s phenomenon. * However, it should be noted, as mentioned above, that the selectivity of β-antagonists is relative (not absolute) and decreases when higher doses are used. Consequently these drugs should generally be avoided in patients with bronchial asthma, diabetes mellitus & Raynaud,s phenomenon. ### Pharmacokinetic properties of BB: - Most of them are well absorbed after oral administration, peak concentration occur 1-3 hrs after ingestion. Bioavailability is limited to varying degrees (30-50%), except pindolol (90%), this is because of first pass metabolism. - Propranolol & timolol are lipophilic; easily pass BBB, so more CNS side effects, while atenolol is hydrophilic, less CNS side effects. ### Therapeutic uses of BB: 1. **Hypertension:** Alone or combined with other drugs (e.g vasodilators) to prevent the reflex tachycardia caused by these drugs, they are not useful in hypertensive crisis. Labetalol only is used in hypertensive emergency. 2. **Angina pectoris:** They ↓ frequency of attacks & prevent acute attack of stable angina only, not used in variant angina, because the coronary spasm may increase by unopposed a 1 actions, coronary artery contain a 1 & ẞ2-receptors, α 1(VC), β 2 (VD). 3. **Myocardial infarction:** They ↓ infarct size when given I.V because they ↓ myocardial O2 demand & cause redistribution of myocardial blood flow. 4. **Supraventricular & ventricular arrhythmias: (propranolol, esmolol & sotalol).** 5. **Hyperthyroidism:** Propranolol inhibits overactivity of sympathetic nervous system. It also inhibits conversion of T4 to T3. 6. **Glaucoma: Timolol as eye drop.** 7. **Prophylaxis of migraine:** \incidence & severity of attack. 8. **Phaeochromacytoma:** To protect heart from tachycardia (with a-blockers). 9. **Relieve anxiety symptoms:** By inhibiting overactivity of SNS. (↓ tremors & tachycardia). 10. **Alcohol withdrawal:** To control symptoms of alcohol withdrawal such as tremors, anxiety, palpitations ......etc. ### Adverse effects: 1. They can cause heart failure or block, should be administered with caution in patient have cardiac disorders. 2. Potentiate insulin action in diabetics & mask tachycardia & tremors associated with hypoglycemia. Also they may delay recovery from hypoglycemia. 3. Abrupt withdrawal of agents increases risk of angina & arrhythmias (upregulation of receptors) especially with short acting agents that lead to tachycardia & nervousness. 4. Bronchospasm (CI in bronchial asthma). 5. Cold extremities & Raynaud,s phenomenon. 6. CNS disorders: Sedation, depression & nightmares with propranolol. 7. Fatigue due to ↓ in blood flow to skeletal muscle & CO. ### Contraindications: 1. Heart failure. 2. Heart block. 3. Bronchial asthma (non selective). 4. Diabetes. 5. Hypotesion. 6. Peripheral vascular disease. 7. Varient angina. 8. Hepatic diseases (e.g propranolol is highly metabolized by liver & may lead to toxicity). ### Drug-drug interactions: 1. Not used with Ca channels blockers (verapamil) → heart block. 2. Enzyme inducer (phenytoin, rifampin) ↓ activity of BB. 3. Enzyme inhibitors (cimetidine) ↑ activity of BB. ## Adrenergic neuron blockers: - They are drugs that interrupt the sympathetic function by preventing the synthesis, release or depleting NA stores in adrenergic nerve endings, leaving the receptors free from neurotransmitter. ### 1- Reserpine: - It is a natural drug (alkaloid) extracted from the root of Indian plant Rauwolfia Serpentina. - It deplets NA, DA & 5-HT from the brain & peripheral nerves by inhibiting their uptake into storage vesicles. - It has antihypertensive effect, but rarely