sympathomimmetics
TRANSCRIPT
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Adrenergic Agonists and Antagonists (for MD Pharmacology)
Dr. Advaitha
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CATECHOLAMINES
• These are compounds containing a catecholmoiety
(a benzene ring with two adjacent hydroxyl groups and an amine side chain.)
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Dopamine :
• It is the metabolic precursor of noradrenalineand adrenaline.
• Main neurotransmitter in the Brain.
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• Noradrenaline (norepinephrine) : a transmitter released by sympathetic nerve terminals.
• Adrenaline (epinephrine): a hormone secreted by the adrenal medulla
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Synthesis, Storage, Release, andRemoval of Norepinephrine
In Noradrenergic Neuron
• It starts with the amino acid tyrosine (from diet)
• It enters the Noradrenergic neuron by active transport.
In the neuronal cytosol….
• Tyrosine is converted by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (dopa).
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Drug :
• Tyrosine hydroxylase enzyme inhibitor :
“α-Methyl-p-tyrosine”
• Can be Used to control the discharge of NE and E in surgical removal of adrenal tumor.
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• DOPA is converted to dopamine by the enzyme L–amino acid decarboxylase or DOPA decarboxylase
• The dopamine is actively transported into storage vesicles.
In storage vesicles…..
• It is in here, Dopamine, is converted to Norepinephrine by dopamine –beta-hydroxylase (exclusively present in synaptic vesicles)
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In the adrenal medulla..
• The synthesis is carried one step further.
• The enzyme phenyl-ethanolamine N-methyltransferase converts norepinephrine to epinephrine.
• The human adrenal medulla contains approximately 80% epinephrine and 20%norepinephrine.
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• NE is stored in the synaptic vesicles.
• Noradrenergic transmitter is released during action potentials through exocytosis.
Action Potential causes : Na+, Ca2+ and Cl- enter while K+ efflux…
Ca2+ entry causes disruption of Vesicles to release NE
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Drugs :
• Release of NE is inhibited by bretylium and guanethidene.
• Can be used in HTN (now obsolete)
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• So.. after Action Potential and effect…..
• There is removal of norepinephrine from Synapse.
Three processes contribute :
1. Transport back into the noradrenergic neuron (uptake1)
• For vesicular storage or enzymatic inactivation
by mitochondrial MAO.
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About , Monoamine Oxidase (MAO) and Catecholamine-O-Methyltransferase (COMT) :
• Both enzymes inactivates NE and E.
• Both are widely distributed (Liver, Intestine, Kidney, Brain)
• However, COMT is absent In ADRENERGIC Neuron.
• So it is only MAO which metabolises NE, intraneuronally…
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2.Diffusion from the synapse into the circulation
For ultimate enzymatic destruction in the liver ( by COMT and MAO ) and renal excretion
3. Active transport of the released transmitter into effector cells (extraneuronal uptake or uptake2)
followed by enzymatic Inactivation by COMT
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Drugs :
• Neuronal reuptake (uptake1) inhibitors :
Cocaine and Tricyclic antidepressants.
-potentiates effect of NE and E
• Vesicular reuptake inhibitors : Reserpine
(used in HTN, obsolete)
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• Inhibitors of MAO-A (present in Adrenergic neuron, intestine, liver, Kidney and Placenta) :
Clorgyline and Meclobemide ( rarely used in depression)
• Inhibitors of MAO-B (present in Dopaminergicneuron, brain, Platelets and Iiver) :
Selegeline ( used in parkinson’s disease)
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Termination of NE, E
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Termination of Dopamine
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Adrenergic Receptors
• The liberated NE at Synaptic junction stimulates postsynaptic adrenoreceptors---
Alpha1, Alpha2. Beta1, Beta2, Beta3
to elicit end organ response.
So what are the end organ responses of each receptor ????
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• All belong to the superfamily of G-protein-coupled receptors
• α1 receptors activate phospholipase C, producing
inositol trisphosphate and diacylglycerol as second messengers
• α2 receptors inhibit adenylyl cyclase, decreasing
cAMP formation
• All types of β receptor stimulate adenylyl cyclase
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• All receptors Are mostly present Postsynapticallyexcept α2 which is in Presynaptic region.
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α1 Receptors
• When activated produces Excitatory effects on in most organs.
• E.g, Vascular smooth muscle, Salivary glands, Bronchi, Uterus, Radial muscle of iris etc.
• Except in intestine where they produce Relaxation.
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α2 Receptors• Present Presynaptically in Post ganglionic
Adrenergic and Cholinergic (gut) Neuron.
• When activated by NE in synaptic cleft-
it inhibits further release of NE from presynaptic Adrenergic neuron.
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They also inhibit Ach in cholinergic neuron (in gut)
• They are also present Postsynaptically in blood vessels etc. where it behaves like α 1 (vasoconstriction)
In Brain, whether Pre or Post synaptically present it decreases sympathetic outflow.
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β1 receptors
• located Postsynaptically.
• found in heart.
- Produce Positive ionotropic and Chronotropic effects.
• found in Kidney
- Promotes Renin release.
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β2 Receptors
• Their action causes smooth muscle relaxation (Except in Myocardium)
• It is present in Bronchi, Blood vessels supplying Skeletal Muscles, coronary artery, uterus , GIT, Heart smooth muscle.
• There are also some presynaptic β2. these facilitates NE release unlike α2.
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• Uterus
Non pregnant Contraction α1
Pregnant Relaxation β2
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Classification of SympathomimeticDrugs
Classified as :
• Direct-acting,
• Indirect-acting,
• Mixed-acting sympathomimetics.
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• Direct-acting sympathomimetic drugs act directly on one or more of the adrenergic receptors.
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• Indirect-acting drugs are those increase the availability of norepinephrine (NE) or epinephrine to stimulate adrenergic receptors.
By releasing or displacing NE from vesicles of sympathetic nerve varicosities
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or by blocking the transport of NE into sympathetic neurons
or by blocking the metabolizing enzymes, (MAO ,COMT)
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Epinehrine or Adrenaline• Acts on β2 > β1= α1= α2, and weak β3 action
• Cardiac Effects : β1, β2 effects
• Final effect : increase in SBP
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Vascular Effects :
• Constricton of arterioles in skin,mucousmembrane, viscera and renal beds-- α1 effect
• Dilation predominates in skeletal muscle, liver and coronaries– β2 effect. Decrease in peripheral vascular resistance
• So the cumulative effect decease in DBP
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• What happens when adrenaline is given after pretreatment of α Blocker ?
ANS : Hypotension
( Dale’s vasomotor reversal phenomenon ) predominant β2 effect.
• What happens when adrenaline is given after pretreatment of β Blocker ?
ANS : Accentuated Hypertensive effect.
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• Effects on smooth muscle :
• Bronchial :
bronchodilation- β2 effect.
Decrease in bronchial secretion α1 effect
• GIT :
• Constriction on sphincters α1 effect
• Gut relaxation α2 and β effect
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Uses of AdrenalineAnaphylactic Shock :
• Relieves Bronchospasm and Angioneuroticedema of larynx
• Prevents release of histamine from mast cell.
• Dose : 0.3 – 0.5 ml IM. 1: 1000 solution IM or SC
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• Bronchial Asthama : Rarely used.
• Cardiac resusitation : Intracardiac route to reverse sudden cardiac arrest in drowning and electrocution
(Absolute Containdication in Ventricular Fibrillation)
• To prolong duration of loacal Anaesthetic agents.
• To control Epistaxis : Rarely
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Adverse effects• Cerebral Haemorrage
• Angina
• Palpitation
• Arrhythmias
• CNS side effects : Anxiety, tremors and headache.
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Contraindications/ interactions
• Angina and Hypertension
• Hyperthyroidism ( upregulation of receptors)
• Concomitant use of MAO
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Noradrenaline• Acts on α1=α2>β1, β3.
• Poor β2 action.
Cardiovascular effects :
• Raises both SBP and DBP. (because β1-SBP,α1-DBP )
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Uses
• Cardiogenic Shock
• Hypotensive states in Surgical shock and MI ( it increases peripheral vascular resistance)
• Dose : 0.5 to 1 ml per minute. IV infusion.
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Facts :
• Should be careful of renal shut down. So Dopamine is preferred.
• As it is a powerful vasoconstrictor, if given undiluted via SC or IM causes, Necrosis.
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Dopamine• Acts on D1, D2, β1, little α action
• No β2 and β3 action.
• Does not enter the BBB when given Parentrally.
• Effects :
It is dose dependent.
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Uses
• Cardiogenic Shock
• CCF, liver and renal failure
• Hypotensive states (after correcting hypovolemia)
• Dose is 5mcg-10mcg/kg/min IV
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Adverse effects
• Nausea vomitting
• Tachycardia
• Hypertension
• Ectopic beats
• Arrhythmias
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Dobutamine
• Synthetic Catecholamie.
• Racemic Mixture of -
L-form (α1 agonist )
D- form (α1 antagonist and β1 agonist)
• So it is relatively selective β1 agonist.
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Effects :
• More selective ionotropic and chronotropiceffects.
Uses :
• Heart failure : it increases CO and stroke Volume without increasing Heart rate.
Adverse effects :
• Sharp rise in BP in HTN patients
• Angina can be aggravated
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Dopexamine• Synthetic Catecholamie.• Acts on D1, D2, and β2 receptors
• Effects : Peripheral Vasodilation, increase Cardiac output and increased renal blood flow.
• Uses : To provide Haemodynamic suppport in CCF and Shock
Adverse Effects :• Tachycardia and Hypotension
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Fenoldapam• Synthetic. Selective D1 agonist
Effects :
• vasodilation in peripheral arteriole, coronary, Renal and Mesentric vessels
Uses :
• Short term management of Severe Hypertension in Patients with severe Renal impairement.
• Adverse Effects : Reflex Tachycardia, Headache.
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“ α1 Selective agonists ”
Phenylephrine
• Non Catecholamine
• So not metabolized by MAO or COMT
• Effects : α1 stimulation increases Peripheral vascular resistance and BP ( associated with reflex Bradycardia)
Uses :
• Nasal decongestant
• Mydriatic
• Hypotension (rarely)
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Other similar drugs are :
• Oxymetaxoline
• Xylometazoline
• Midodrine
• Naphazoline
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α 2 Selective Agonist
ClonidineUses with MOA :
1) Moderate Hypertension
Mechanism : Not properly elucidated.
• stimulates central α 2 receptors to decrease sympathetic outflow.
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• Stimulates presynaptic α2 on postganglionic sympathetic neuron to supress NE release.
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• When given I.V there is transient rise in BP ( post syaptic α2 effect which causes vasoconstriction) and then Decrease.
• However when given oral, there is only hypotensive effects
• 100 % bioavailability.
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• Dose :100-300 mcg BD.
• Also available as Transdermal Patch.
• Major limitation is Rebound Hypertension.
2) In the Prophylaxis of migraine
• It reduces cerebral blood flow
3) Management of opiate, alcohol and Nicotine Withdrawl
• It reduces sympathetic effects associated with withdrawl
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4) Preanaesthetic Medication:
• For its slightly sedative, anxiolytic and analgesic effect
5)Menopausal Hot flushes :
• For counteracting symptoms
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6) To control diarrhoea in diabetic patients with autonomic neuropathy
α2 in GIT decreases sodium,water retention and reduces motility by inhibiting Ach
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Adverse Effects :
• Dry mouth
• Sedation
• Nasal stuffiness
• Constipation
• Impotence
• Contact dermatitis (in patch usage)
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Newer congeners of clonidine
• Moxonidine
• Rilmenidine
In these rebound hypertension is less frequent
longer acting than Clonidine
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• Apraclonidine
• Brimonidine
Used in Glaucoma (reduces Aqueous Humor by α2 action in cilliary muscles)
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β2 selective Agonists
Salbutamol
Effect : Produce relaxant effect on bronchi, uterus.
• Has minimal cardiac stimulant property.
• Half life : 4hr
Uses :
• Immediate relief of Asthama
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• Dose : 100mcg in Metered dose inhaler
• or 2-4 mg PO TDS
• To arrest uncomplicated premature labour(inbetween 24 to 34 weks of gestation) by slow IV injection
Adverse effects :
• Tremors in hands, Palpitations, hypokalemia
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• Terbutaline
• Salmetrol and Formetrol ( longer acting 12hr)
• Pirbuterol
• Clenbuterol ( anabolic strength on skeletal muscle, illicit use in sports)
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Indirectly acting drugsTyramine
• Not used clinically
• It is found in cheese, beef, wine, beer, yoghurt yeast.
• Metabolized by MAO.
• Significance : If patient on MAO inhibitor, it can trigger hypertensive crisis
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Amphetamine
• Powerful CNS stimulant .
CNS effects :
Stimulation of
• cortical region
• Reticular activating system.
• Medullary respiratory centre.
Causes
• Wakefullness
• Alertness
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• Decreased sense of fatigue
• The performance of simple task increases but errors increase
• Physical performance improves
![Page 81: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/81.jpg)
CVS effects :
• Increases SBP and DBP
• Tachycardia followed by bradycardia
Other effects
• Suppression of appetite by depressing lateral hypothalamic centre
![Page 82: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/82.jpg)
Uses :
• Narcolepsy : prevents attacks of daytime time sleep
• ADHD (excitability, impulsiveness, difficulty in sustaining attention) : Paradoxically improves with low dose
• Weight reduction
![Page 83: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/83.jpg)
Other Analogues…
• Methylphenidate : more prominent action on mental function.
• Methamphetamine : High potential of abuse
• Pemoline : minimal CVS effects and longer plasma half life. Used in ADHD
![Page 84: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/84.jpg)
Mixed Action drugs Ephedrine
• Non catecholamine alkaloid
• Has direct action on α and β. Also enhance NE release.
• CNS : powerful stimulant
• CVS: increase in BP, CO, HR.
• RS : Bronchodilation.
![Page 85: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/85.jpg)
Uses : Very restricted.
• Hypotension following Spinal Anaesthesia
• Chronic asthma.
Adverse effects :
• HTN,
• Insomnia,
• Tachyphylaxis.
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Pseudoephedrine :
• Stereoisomer of ephedrine used as nasal decongestant.
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Adrenergic Antagonists
![Page 88: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/88.jpg)
![Page 89: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/89.jpg)
Phenoxybenzamine
• Irreversible, nonselective, Non competitive Antagonist at α1,α2
• Also inhibits reuptake of NE by adrenergic nerve terminal.
• Crosses BBB.
Effects :
• Vasodilation
• Decrease Peripheral vascular Resistance
![Page 90: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/90.jpg)
• Hypotension ( this triggers baroreceptorscausing sympathetic discharge)
• Tachycardia (sympathetic discharge action on β 1 )
![Page 91: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/91.jpg)
Uses :
Treatment Phaeochromocytoma :
• Controls episodes of severe hypertensionduring surgical manipulation .
• Dose : 1mg /kg , slow IV infusion
In Raynaud’s syndrome and
Frostbite.
Dose 10mg TDS PO
![Page 92: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/92.jpg)
Adverse effects :
• Marked Postural Hypotension with initial doses.
• Tolerance develops later.
• Inhibition of ejaculation
• Salt and water retention
• Sedation
• Fatigue
• Nausea
![Page 93: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/93.jpg)
Phentolamine and Tolazoline
• Competitive, Reversible antagonist of α1, α2.
Effects :
• Vasodilation
• Decrease Peripheral vascular Resistance
![Page 94: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/94.jpg)
• Hypotension ( this triggers baroreceptorscausing sympathetic discharge)
• Tachycardia (sympathetic discharge action on β 1 )
![Page 95: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/95.jpg)
Other effects
• Nasal stufiness
• Miosis (loss of tone of radial muscles)
• Failure of ejaculation
• Nausea vomitting diarrhoea
( inhibition of inhibitory sympathetic influence of GIT and agonist action on H2 receptors, Tolazoline)
![Page 96: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/96.jpg)
Uses
• Treatment Phaeochromocytoma.
• In peripheral vascular disease
• To prevent dermal necrosis ( after incidental extravasation of NE after IV infusion)
• To treat hypertensive crisis
![Page 97: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/97.jpg)
α1 selective blockers Prazosin
Effects :
• Peripheral vasodilation
• Fall in arterial pressure
• Lesser tachycardia
Because of lack α 2 blocking no promotion of NE release, so no β1 stimulation.
![Page 98: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/98.jpg)
Also partly because it decreases sympathetic outflow from CNS
It decreases cardiac preload
• It is also potent phosphodiesterase inhibitor
this leads to rise in cAMP in smooth muscle
So vasodilating effect.
• It relaxes smooth muscle - in bladder neck
Prostate capsule
Prostatic urethra
![Page 99: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/99.jpg)
• So improves urine outflow in BPH
• Uses :
• In Hypertension : oral dose is 1mg bed time to avoid postural hypotension
• In BPH : 1-5 mg BD PO, however newer ones are preferred.
• In raynaud’s disease : rarely, because CCB are preferred.
![Page 100: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/100.jpg)
Adverse effects :
• Postural hypotension
• Impotence
• Nasal congestion
![Page 101: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/101.jpg)
Terazosin and doxazosin
• Longer duration of action
• Terazosin : 12 hr
• Doxazosin : 20hr..
• So OD dosing in HTN and BPH
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Bunazosin and Alfuzosin
• Similar to Prazosin profile
• Alfuxosin : to be cautiously used in hepatic impairement as it is metabolized there.
• Bunazosin : longer acting but no favourableprofile than Prazosin
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Tamsulosin and Silodosin
They are α 1A antagonist .
• α 1A is located on bladder neck and urethra
• α 1B is located in blood vessels
• It is more efficacious in BPH with little effect on BP unlike non-selective ones.
![Page 104: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/104.jpg)
• Better bioavailability
• Plasma Half life 8hr
Dose :
Tamsulosin 0.2 to 0.4mg OD, PO
Silodosin(longer acting analogue of Tamsulosin) 4-8mg , PO
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Adverse effects :
• Abnormal ejaculation
• Floppy iris syndrome – which creates problem in cataract surgery.
![Page 106: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/106.jpg)
Alpha2 Antagonists Yohimbine
• Natural alkaloid from Pausinystalia Yohimbe
• Other than Alpha2 blocking action, has 5HT antagonist action.
Uses are unestablished
• To teat male sexual dysfunction
• To treat diabetic neuropathy
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![Page 108: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/108.jpg)
Propranolol• Nonselective, Competitive blocker . acts on
beta1 and beta2.
• It is prototype drug in the group
( all features are characteristic except that its not used in glaucoma even though it does reduces IOP)
![Page 109: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/109.jpg)
• Cardiovascular effects :
The blockade of β1 causes
decrease of
heart rate,
myocardial contractility
conduction velocity
cardiac output
Automaticity ( suppression of SA Node)
This causes reduced myocardial oxygen demand
Consequent to all these BP falls
![Page 110: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/110.jpg)
Blockade of β 2
• Peripheral vascular resistance rises, because α1
adrenoreceptor is no longer opposed by β 2
• This reflex vasoconstriction is maintained.
So Postural hypotension is least troublesome.
• Patient show a gradual fall in BP after chronic use.
![Page 111: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/111.jpg)
Other minor mechanism to lower BP
• β1 blockade decrease release of renin.
(however pindolol which has no effect in renin is also effective antihypertensive)
• Blockade of facilitatory effect of presynaptic β 2
receptor on NE release.
• Chronic decrease in Cardiac output
![Page 112: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/112.jpg)
Other effects on circulation :
• Plasma lipid profile is worsened in long term intake.
• Total TG, LDL increase and HDL level falls.
![Page 113: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/113.jpg)
Respiratory effects
• Least affected in normal individuals
• In Asthmatic patients, it causes severe bronchoconstriction because of β 2 effect
![Page 114: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/114.jpg)
• Metabolic effects
• In normal persons , minimal effects on basal glucose level.
• Normally ,
In stress-induced hypoglycemia and insulin induced hypoglycemia in diabetics, there is protective adrenaline induced glycogenolysis ( β 2 effect in liver )
![Page 115: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/115.jpg)
This is protective mechanism to overcome hypoglycemia
Therefore Patients on Propranolol
blocking β 2 has adverse delay on recovery of hypoglycemia.
• Also it blocks sympathetic manifestations like palpitations and sweating
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CNS effects
• It is lipid soluble . Enters BBB.
• Upto some extent decreases sympathetic outflow
• Produces sedation, lethargy and disturbances in sleep.
![Page 117: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/117.jpg)
• It supresses performance anxiety ( more of peripheral action rather central)
• At higher doses it has Antipsychotic effects
![Page 118: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/118.jpg)
Ocular effects
• It decreases formation of Aqueous Humor in glaucoma patients.
• But seldom used - low potency, Local Anesthetic action on cornea which is not desired
![Page 119: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/119.jpg)
Miscellaneous effects :
• It prevents platelet aggregation and promotes fibrinolysis
• It reduces portal vein pressure in cirrhotic patients
• increases synthesis and release of PGs
![Page 120: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/120.jpg)
Pharmacokinetics :
• Low bioavailability, extensively metabolized in liver.
• Plasma T ½ is 4-6 hrs.
• It has L and D forms.
• L is 100 times potent than D form
• D form has more membrane stabilizing property ,quinidine like effects.
• Commercial available is racemic mixture.
![Page 121: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/121.jpg)
Uses :
Essential Hypertension :
• Used alone or with a diuretic
• Dose : 20-40 mg TDS PO
or 80mg sustained release single dose.
![Page 122: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/122.jpg)
Congestive cardiac failure :
• It can worsen the condition.
• However now its established that it is beneficial in mild to moderate HF
• To be started with low dose and increased gradually.
![Page 123: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/123.jpg)
• It is said to retard progression of condition and prolong life
How ?
• In CCF, there is damaging hyperactivity of β1
which causes remodeling of myocardium
• So these prevent the hyperactivity, the remodeling.
![Page 124: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/124.jpg)
Angina Pectoris
• Used only in stable or effort-induced angina
• It decreases cardiac workload
• Decreases myocardial oxygen demand
• But absolute contraindicated in Prinzmetal’s angina
Because beta blocking will unmask Alpha receptor to cause coronary vasoconstriction
![Page 125: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/125.jpg)
Cardiac arrhythmias :
• It is effective in all supra ventricular arrhythmias.
• Effect is mainly due to increase in refractory period at AV node
![Page 126: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/126.jpg)
Myocardial infarction
• It will decrease the incidence , recurrence and mortality on long term use
• Prevent platelet aggregation
• Promotion of fibrinolysis
• Prevents ventricular fibrillation in the 2nd
attack of MI
![Page 127: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/127.jpg)
• Non cardiovascular uses :
Migraine
• Used in prophylaxis
• Mechanism is uncertain
• Dose : 10 to 20 mg BD or TDS
![Page 128: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/128.jpg)
Anxiety provoking situation
• It only blocks peripheral manifestation (palpitations, tremors and sweating)
• Dose : 10-20 mg TDS
no action in Parkinson’s tremors
![Page 129: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/129.jpg)
Hyperthyroidism
• Reduces sympathetic over activity
• It also inhibits conversion of T4 to T3 ( independent of beta action)
• Dose : 20mg BD
![Page 130: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/130.jpg)
Phaeochromocytoma
• Given in combination with alpha blockers to antagonize beta1 effects of catecholamines during surgery
• Dose : 20 mg TDS, 3 days before surgery
![Page 131: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/131.jpg)
Alcohol withdrawal
• To reduce sympathetic over activity
• Dose 20mg TDS
![Page 132: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/132.jpg)
Esophageal varices and Portal hypertension
• It induces splanchnic vasoconstriction (beta2 blocking and unopposed alpha1 action)
• This reduces bleeding and reduces portal pressure by 40%
![Page 133: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/133.jpg)
Adverse effects :
• Bronchoconstriction
• Bradycardia
• Cold extremities (loss of beta2,loss of cutaneous vasodilation)
• Hypoglycemia
• Fatigue , sleep disturbances.
• Rebound hypertension on withdrawal ( upregulation of beta receptors)
• Adverse lipid profile
![Page 134: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/134.jpg)
Other non selective 1st Gen
• Timolol
Main use :
wide angle glaucoma as eye drops 0.25%
![Page 135: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/135.jpg)
Sotalol
• Uses and side effects are similar to propranolol (less lipid soluble, less CNS side effects)
• It has additional K+ blocking property and this makes it class III anti arrhythmic drug
• Dose : 80- 320mg BD PO
![Page 136: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/136.jpg)
Nadolol
• Uses and side effects are similar to propranolol ( does not cross BBB)
• Longer plasma half life- 20 hrs
• Least first pass metabolism
![Page 137: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/137.jpg)
β1 selective blockers• At high doses it can even block beta2
Advantages
• Safer in Asthmatics
• Safer in hypoglycemic conditions ( glucose release is not inhibited )
• Safer in PVD ( no beta2 blockade)
• Less deleterious effect on lipid profile.
![Page 138: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/138.jpg)
Metoprolol :
• Uses are similar to Propranolol
• Dose : extended release 50-100 mg .
Atenolol :
• Uses are similar…
• Do not cross BBB
• Dose : 25-50 mg once daily
![Page 139: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/139.jpg)
• Nebivolol
• Highly selective antagonist
• Additional action : enhances NO production and release . Used in effective reduction of BP
• Dose : 5-10 mg OD
![Page 140: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/140.jpg)
Esmolol
• Ultra short acting selective antagonist
• Plasma half life 8-10min.
Uses :
• Only in emergency conditions/ during surgery/ critically ill patients as IV preparations
To treat SVT, AF etc
![Page 141: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/141.jpg)
Non selective β blocker with intrinsic sympathomometic Activity
Beneficial properties are
• Lesser bradycardia, myocardial depression
• Rebound hypertension after withdrawal is less likely. Because β agonist property of this group prevents upregulation of receptors
• Lipid profile is less worsened.
![Page 142: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/142.jpg)
• Disadvantages
• Cannot be used in migraine- intrinsic Beta2 agonistic action causes further dilation of cerebral vessels
• Less suitable for secondary prophylaxis MI
![Page 143: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/143.jpg)
Acebutolol :
• It is a prodrug , converted to ‘Diacetolol’
• T1/2 10-12 hrs
• Dose : 400 mg OD
Celiprolol :
• It has partial agonist action on β 2 as well
• Also causes direct vasodilation by releasing NO.
• Preferred in HTN+ bronchial asthma patients
• Dose : 200-400 mg OD
![Page 144: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/144.jpg)
• Drugs are : Pindolol and Oxprenolol
• Dose : Pindolol 10 mg OD
Oxyprenolol 20 mg BD or TID
![Page 145: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/145.jpg)
selective β1 blocker with intrinsic sympathomimetic Activity
• They offer all the advantages of “ non selective β1 blocker with intrinsic sympathomometic Activity “ group
with
• Membrane stabilizing Action ( however its of no clinical use as it appears to significant at higher doses)
• Drugs are : Acebutolol and Celiprolol
![Page 146: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/146.jpg)
Mixed(α+ β ) antagonist
• Labetolol and Carvedilol
• Labetolol
• It is racemic mixture of 4 diastereomers.
• Racemic mixture exhibits
selective blockade of α1 , β1
Partial agonist action on β2
![Page 147: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/147.jpg)
Effects :
• Fall in BP (α1 , β1 blockade)
• Also peripheral vasodilation and bronchodilation(β2 agonistic)
Main Uses :
• Hypertension in pregnant women
• In pheochromocytoma
• Rebound hypertension in clonidine withdrawl
Adverse effects :
• Postural hypotension, hepatotoxicity
![Page 148: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/148.jpg)
Carvedilol :
Actions :
• Has prominent β1 β 2 blockade , lesser α1
blockade.
• Inhibits free radical induced lipid peroxidation.
• Inhibits smooth muscle mitogenesis.
• It blocks L-type voltage gated Ca2+ channels.
• All these prove to be cardio protective In CCF
![Page 149: Sympathomimmetics](https://reader033.vdocuments.mx/reader033/viewer/2022060202/559cf66b1a28ab75438b47b6/html5/thumbnails/149.jpg)
Uses
• Hypertension/ angina : Dose is 6.25mg BD
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Reference • Sharma. Principles of Pharmacology.
• Goodman and Gilman
• Rang and Dale
THANK YOU