autonomic pharmacology -2 (1).pdf

Autonomic pharmacology By Dr/Ali khames abd el twab Lecturer of pharmacology and toxicology Faculty of pharmacy  Cholinergic antagonists They are classified into 3 categories according to  cholinergic receptors involved Antimuscarinic drugs Drugs that block muscarinic (M)recept...

Autonomic pharmacology By Dr/Ali khames abd el twab Lecturer of pharmacology and toxicology Faculty of pharmacy  Cholinergic antagonists They are classified into 3 categories according to  cholinergic receptors involved Antimuscarinic drugs Drugs that block muscarinic (M)receptors in periphery and sweat and salivary glands.these drugs have no effect on nicotinic receptors Natural agents Atropine (hyoscyamine) Natural alkaloid from atropa belladonna  Pharmacokinetics : tertiary amines lipohillic drugs has CNS actions and good oral absorption and distribution  Mechanism of action : competitive antagonist at muscarinic receptors centrally(tertiary amine) and peripherally  Pharmacological actions : CNS stimulant Inhibits all muscarinic action in GIT  constipation ,antispasmodic Inhibits all muscarinic action in urinary bladder urinary retension ,prevents urinary incontinence Pharmacological actions of atropine  Inhibits all secretions generalised dryness (dry mouth ,dry eye)  Inhibits ocular sympathetic miosis passive mydriasiscycloplegia and IOP  CVS effects : atropine has biphasic effect on heart at small dose decrease heart rate (due to blocking of presynaptic M1 receptors ) at high dose block also cardiac M2 receptors causing tachycardia Anticholinergic pharmacological effects Indications it is limited in clinical use due to non selectivity ( blocking of all muscarinic receptors).it can be used in the following Eye examination through passive mydraisis Atropine is not preffered in Eye examination due to prolonged cycloplegia 7- 14 daysshort acting alternatives such as tropicamide and cyclopentolate (6- 24 hrs) are used Pre-anaesthetic medications to inhibit respiratory secretions Treatment of organophosphorus poisoning Brady cardia and AV block Adverse effects of atropine dry mouth – blurred vision – tachy cardia- urinary retension –constipation Contraindications : BPH – glaucoma  Scopolamine (hyoscine) Atropine VS hyoscine Atropine Hyoscine CNS effects Excitatory At low dose it is inhibitory (sedation and amnesia) And excitatory at large dose Duration of action Long Short effect More effective at More antiemetic cardiac muscle effect in motion sickness (blocking of vomiting center) Hyoscine patches for motion sickness Synthetic antimuscarinic drugs anti asthma drugs (selective for bronchial muscarinic receptors ) They are quaternary ammonium compounds (have permanent positive charge  permanently ionized  poor distribution in CNS and tissues) these drugs are limited to use as inhalation in respiratory conditions such as COPD and asthma as it is not able to diffuse into blood they are divided into two categories long acting (tiotropium and glycopyrrolate) and short acting (ipratropium and aclidinium) antimuscarincs for urinary incontinence and overactive bladder ( selective for bladder muscarinic M3 receptors ) oxybutynin- tolterodine- solifenacin- trospium Solifenacin is more selective than oxybutynin- tolterodine anti parkinsonism antimuscarinics Benztropine and Trihexphenidyl Block muscarinic recetors in brain preventing parkinsonism symptoms. Ganglionic blockers Site of action of ganglionic blockers  All ganglionic blockers are experimental drugs ,not used clinically ??? due to non selectivity they block autonomic outflow both sympathetic and parasympathetic except nicotine that is used as gum or lozenges for smoking cessation Nicotine Mechanism of action : nicotine binds and stimulates nicotinic receptors in sympathetic ganglia causing increased noradrenaline outflow (sympathetic stimulation) increased HR,BP and in parasympathetic ganglia causing increased acetylcholine(parasympathetic stimulation) increased GIT,bladder motility and bronchospasm also stimulate adrenaline release from drenal gland trough stimulation of nicotinic receptors in adrenal gland this occurs at small nicotine dose. Nicotine causes complex stimultion of neurotransmitters release ,but at large nicotine dose the nicotinic receptors are blocked inhibiting autonomic response and results in respiratory failure and death Nicotine addiction (ciggarette smoking ) is treated by nicotine replacement therapy and bupropion. Nicotine pharmacological effects Adrenergic receptors agonists (sympathomimetics) Synthesis of norepinephrine N.B : In most postganglionic sympathetic neurons norepinephrine is the final synthesis product of tyrosine cascade while in the adrenal medulla and certain brain areas epinephrine is formed from norepinephrine, cascade terminates at dopamine step in dopaminergic neurons. Inhibition of NE storage Vesicular monoamine transporter (VMAT) is a membrane- embedded protein that transports monoamine neurotransmitter molecules into intraneuronal storage vesicles to allow subsequent release into the synapse it is inhibited by reserpine Inhibition of Norepinephrine transport Norepinephrine transporter (NET) transports norepinephrine from the synapse into presynaptic neurons where it can be restored or metabolized by MAO so terminating sympathetic response. it is inhibited by cocaine and tricyclic antidepressants. There are dopamine transporters, serotonin transporters, and other neurotransmitters Inhibition of NE release Release of NE from granules is inhibited by guanethidine Norepinephrine action at synapses is terminated either by reuptake into vesicles or metabolized by catechol –o methyltransferase (COMT ) and monoamine oxidase (MAO) Function of adrenergic receptors clinical tips alpha receptors are present in different subdivisions like α1A α1B α1C, α2A α2B.this explain the selectivity of some drugs as tamsulosin (α1A antagonist in the prostate gland and bladder not causes significant V.D where α1B is present in blood vessels) Molecular mechanism of epinephrine and norepinephrine Selectivity of agonists to alpha and beta receptors Isopretenol is the most selective for beta receptors due to bulky group substituent on the amino group. Epinephrine is more selective than norepinephrine on beta 2 receptors , while they are the same in selectivity on beta 1 receptors Sympathomimetic drugs They are drugs that can stimulate alpha or beta-adrenergic receptors sympathomimetic drugs are classified into catecholamine (contain catechol nucleus) and none catecholamine compounds Catecholamine sympathomimetics such as epinephrine, norepinephrine, dopamine and isoproterenol, these drugs are rapidly metabolized and inactivated by COMT and MAO enzymes so they have a short duration of action and because of their high polarity (two OH groups, their BBB permeability is limited) by contrast, noncatecholamines such as ephedrine and amphetamines are of longer duration and have CNS actions. The chemistry of the sympathomimetic determines its pharmacokinetics and dynamics :   pharmacokinetics is determined by the number of hydroxyl groups on benzene rings two hydroxyl groups (catechol) means polar nonabsorbable, less penetrating drugs and short duration due to COMT degradation e.g all catecholamines  one or no hydroxyl group on the benzene ring means decreased polarity and increased duration of action ?? pharmacodynamics : alpha-receptor activity: the potency of the sympathomimetic drugs depends on the number of hydroxyl groups on benzene rings  two hydroxyl groups (catechol) means more potent effect at alpha and beta receptors one hydroxyl group on the benzene ring means less activity at alpha receptors e.g phenylephrine less potent than epinephrine as an alpha agonist  absence of hydroxyl group on the benzene ring means no activity at alpha and beta receptors, but still similar in structure to catecholamines and can compete for reuptake and storage (indirect sympathomimetic action) e.g cocaine and amphetamine activity at beta receptors is dependent on substitution on amino nitrogen  as the substituent bulk increased the beta receptors activity increase while alpha receptors activity decreases e.g epinephrine (methyl group on amino nitrogen) is more active than norepinephrine at beta receptors, also isoproterenol ((isopropyl group on amino nitrogen)is the most potent at beta receptors, in the same time isoproterenol is the leas potent at alpha receptors  Mechanism of action of sympathomimetics Direct-acting sympathomimetics : NE It is given by the I.V route and can not be given orally, to avoid degradation by COMT and MAO in the gut wall receptor selectivity: α>β and has no effect on β2 released from postganglionic sympathetic nerves and a small percentage from the adrenal medulla pharmacological actions of NE  In a normal therapeutic dose, it affects mainly alpha receptors  α1 stimulation  generalized vasoconstriction of blood vessels  increased B.P  α2 stimulation  NE release  weak β1 stimulation  increase cardiac contraction and HR, but the net result of NE on HR is no effect ?? due to baroreceptor stimulation by increased BP that activates vagal response causing bradycardia. Pharmacodynamics of NE Indications: Not used due to serious side effects on BP except in some emergency cases of shock e.g septic shock as a vasopressor. Adverse effects: Central effects e.g tremors and anxiety. Cardiac effects e.g arrhythmia. Cutaneous (at the site of injection) dermal sloughing due to severe vasoconstriction.  Contraindications of NE digoxin (arrhythmia) diabetes General anaethesia hyperthyroidism  Epinephrine  Pharmacokinetics : Rapid onset and short duration of action (minutes) Route of administration depends on the situation, in anaphylaxis it is given I.M while in ICU emergency it is given I.V also it can be given SC or by inhalation Receptor selectivity : β > α 80 % of epinephrine is released from the adrenal medulla after methylation of NE Pharmacological actions of epinephrine The affinity of epinephrine to β receptors is more than to α receptors meaning that the presence of a small dose of epinephrine will stimulate β receptors but a higher dose stimulates α receptors CVS effects : Cardiac: epinephrine stimulates β1 receptors in the heart causing positive inotropic and chronotropic effects Vascular: epinephrine stimulates β2 receptors in the vascular endothelium of the liver and skeletal muscles leading to vasodilatation so decreased diastolic blood pressure Pharmacological actions of epinephrine cont. Epinephrine stimulates α 1 receptors in the vascular endothelium of the viscera including kidney and skin CNS effects: anxiety and tremors Respiratory: stimulation of β2 induces bronchodilatation Pharmacological actions of epinephrine cont.  Metabolic:  1- Epinephrine increases blood glucose level through stimulation of β2 induces glucagon secretion and hepatic glycogenolysis  stimulation of α 2 inhibits insulin secretion  2-Increases lipolysis (lipids degradation to free fatty acids ) through stimulation of β3 in fat tissues  Indications of epinephrine With lidocaine in dental epistaxis procedures anaphylaxis Intracardiac injection incase of cardiac arrest Adverse effects: Central effects e.g tremors and anxiety. Cardiac effects e.g arrhythmia. Contraindications: withhyperthyroidism (( beta receptors sensitivity), with diabetes With digoxin (arrhythmia), inhalational anesthetics ( beta receptors sensitivity)  Isoproterenol synthetic nonselective beta-agonist pharmacokinetics: As other catecholamines  pharmacological actions Itsactions are similar to epinephrine on beta receptors  CVS effects :  Cardiac: stimulate β1 receptors causing positive inotropic and chronotropic effect systolic blood pressure  Vascular: stimulate β2 receptors in skeletal muscle blood vessels causing a decrease in peripheral resistance and diastolic blood pressure  Respiratory: stimulation of β2 induces bronchodilatation  Adverse effects: as epinephrine on beta receptors   Dopamine  Natural catecholamine released from basal ganglia and acts as a neurotransmitter  Pharmacokinetics: as previous catecholamines  Pharmacological actions : stimulates β1 in the heart  increase cardiac output stimulates D1 in the kidney  renal vasodilatation stimulates α1 in the heart  vasoconstriction Indications : shock: increase blood pressure through increased heart rate (β1 ) and peripheral resistance (α1) heart failure: increase cardiac output acute renal failure cases Adverse effects: hypertension, nausea, vomiting, and flushing Dobutamine Synthetic catecholamine with a short half-life Pharmacological actions : It stimulates mainly β1 in the heart  increase cardiac output It has a weak agonist effect on β2, α1 Indications : Treatment of heart failure Noncatecholamine sympathomimetic drugs alpha-receptor agonists : Phenylephrine : synthetic α1 agonist Pharmacological actions: α1 agonist  vasoconstriction increased BP  Reflex bradycardia (if given parenterally) Indications: nasal decongestant (vasoconstriction of nasal blood vessels, treatment of hypotension in hospital, ophthalmic mydriasis  Oxymetazoline and xylometazoline :  synthetic α1 agonist  Indications:  nasal decongestant  Adverse effects:  anxiety, nervousness, hypertension  Midodrine synthetic α1 agonist in blood vessels causing vasoconstriction  Indication:  treatment of hypotension clinical tips: the drug must stop 4 hours before sleeping to avoid supine hypertension  Clonidine syntheticα2 agonist in presynaptic neurons inhibiting sympathetic outflow to the periphery Indications: Opoid ithdrawal ADHD Nicotine ithdrawal treatment of hypertension adverse effects:  sedation, xerostomia, and constipation    Beta receptors agonists  Bronchodilators:  short-acting β2 agonists ( bronchodilators) lasting 4-6 hrs (more hydrophilic, rapidly excreted)  salbutamol ( albuterol ) ,terbutaline  used for relief of acute asthmatic attacks Beta-2 agonists in the egyptian market  long-acting β2 agonists ( bronchodilators) lasting 12 hrs (more lipophilic, slowly excreted)  salmeterol , formeterol  used for the prevention of asthmatic attacks (not treatment of acute cases), combined with corticosteroids.  β2 agonist drugs causing bronchial muscle relaxation  Indications:  treatment of bronchial asthma and COPD  Adverse effects :  Hyperglycemia, hyperkalemia, tachycardia, and tremors Mirabegron  β3 agonist in bladder detrusor muscle causing delaying urination  Indications:  overactive bladder  Contraindications:  with hypertension ( BP)  with digoxin ( level of digoxin) indirect-acting sympathomimetics  Drugs that increase the actions of epinephrine and norepinephrine through the increasing release of epinephrine and norepinephrine or through inhibiting either reuptake or degradation of these neurotransmitters. Cocaine (natural alkaloid )  Mechanism of action :  Cocaine acts as:  a-indirect sympathomimetic through inhibiting neuronal uptake of norepinephrine so causes accumulation and profound sympathomimetic effect.  b- local anesthetic through block sensory nerve conduction (prevent the spread of action potential from the site of pain to the brain) through blocking nerve cell sodium channel and stopping action potential propagation. Indications: - local anesthetic ( from which available local anesthetics are derived).it is used as a recreational drug Adverse effects : - Mood disturbances. CVS: hypertension-arrhythmia CNS :stroke –seizures- addiction GIT: abdominal discomfort Chronic inflamed running nose due to repeated snorting. N.B Atomoxetine (used in ADHD ), reboxetine (used in depression), sibutramine (appetite suppressant), and tricyclic antidepressants act by inhibiting NE reuptake. Amphetamine (strong CNS stimulant)  Mechanism of action : Increases the sympathetic activity in the body through increasing the release of norepinephrine and dopamine from nerve endings (after displacement of these neurotransmitters in vesicles) and inhibiting the reuptake of these catecholamines through competition with NE on uptake through NET. Uses of amphetamine derivatives  Indications: treatment of narcolepsy –ADHD-anorexic drug Tyramine ( tyrosine derivative monoamine)  - Not a drug but it is Present in fermented foods  e.g fermented food  - Tyramine increases the sympathetic activity in the body by increasing the release of norepinephrine and dopamine from nerve endings Clinical tips  taking tyramine with MAOIs results in serious life- threatening interaction  MAO is the enzyme that can degrade tyramine but using MAOIs expose the body to a high dose of tyramine ( from fermented foods) resulting in hypertensive crisis Mixed action sympathomimetics Ephedrine and pseudoephedrine : Mechanism of action: - Has direct agonist effect on alpha and beta receptors (weaker than epinephrine, but longer duration??) - indirect action by increasing the levels of norepinephrine at the nerve terminals through displacement in vesicles. Indications of ephedrine Anesthesia-related hypotension Nasal decongestant In some cough medications as a bronchodilator Weight loss It is CNS and physical stimulant so, it is banned in sports Ephedrine cont.  Adverse effects :  CVS: Tachycardia-hypertension-arrhythmia  CNS : seizures ,irritability,stroke  Ephedrine and pseudoephedrine can be used orally and has a longer duration of action than catecholamines  Pseudoephedrine is used illegally in the synthesis of amphetamines  Sympatholytics  Anti-adrenergic drugs are classified into :  A- Alpha-receptors blockers  B- Beta-receptors blockers  C- Adrenergic neurons blockers : including 1-drugs that block NE release such as guanethidine and bretylium. 2- drugs that prevent NE storage such as reserpine A- Nonselective alpha-blockers :  1- Phenoxybenzamine  Pharmacokinetics :  low oral bioavailability (20- 30 %) ??? due to poor water solubility. It has longer duration of action due to covalent binding with receptors  Mechanism of action :Non selective irreversible α blocker (block α ,β ).by covalent bond leading to relaxation of blood vessels and decreasing blood pressure Pharmacological actions  CVS : α1 block →→→ relaxation of blood vessels → ↓ BP →reflex tachy cardia ( stimulation of heart to raise blood pressure)+ ↑ NE by α2 blocking  Urinary : block α1 receptors in trigone and sphictor → ↑ urine flow  ↑ NE release  Miosis blocking α1 in radial muscles  It is an antagonist at histamine , acetylcholine and serotonin receptors Indications :  Treatment of pheocromocytoma where it alleviates symptoms of increased BP and sweating  Adverse effects :  Reflex tachycardia – postural hypotension – failure of ejaculation – nasal stuffiness- first dose syncope 2- Phentolamine  Nonselective competitive alpha-receptors blocker with similar actions to phenoxybenzamine but it has short half life  It is an agonist at histamine and acetylcholine receptors and blocker at serotonin receptors Indications of phentolamine  n the treatment of hypertension and hypertensive emergencies,  pheochromocytoma,  vasospasm of raynaud disease and frostbites  impotence (When injected into the penis (intracavernosal), it increases blood flow to the penis, which results in an erection) indications  Pheocromocytoma  Phentolamine can be given intra-cavernosal ( into penis) to induce erection  Phentolamine is used locally to reverse local anaesthesia (local anaesthesia is maintained by epinephrineand reversed by phentolamine) B- selective α1 blockers:  prazocin- terazocin –doxazocin  pharmacokinetics : all have poorbioavailability due to extensive first pass metabolism. Doxazocin t1/2 >terazocin > prazocin  mechanism of action : selective reversible blockers of α1 receptors  indications  hypertension – peripheral vascular disease –BPH  adverse effects : causes less cardiac side effects than none selective agents (especially tachycardia because of α2 negligible effects) C- selective α1A blockers:  tamsulosin –silodosin  it can treat BPH effectively and selectively with less adverse effects (postural hypotension) than other α1 blockers ?? due to higher selectivity at α1A (prostate) > α1B (blood vessels)  serious adverse effects oral tamsulosin + cataract surgery = ↑intraoperative floppy iris syndrome so patient must stop tamsulosin 4 weeks prior to surgery. D- Other α1 blockers:  Alfuzocin selective α1 blocker →↑QT prolongation  Indoramine ,urapidil selective α1 blockers  Labetalol and carvidilol are (mixed antagonists ) block both α1 and β receptors  Chloropromazine ,haloperidol ,trazodone and ergotamine have α blocking activity E- α 2 blockers :  yohimibine  mechanism of action : a natural alkaloid acts as α 2 blocker  pharmacological actions: it ↑NE release →↑ BP  indicatios :  it is used in veterinary medicine to reverse the sedating effect of xylazine (α 2 agonist)  it used previously as aphrodiasic agent but nowit is replaced by phosphodiestrase inhibitors. 3- Beta blockers Pharmacokinetics of beta –receptor blockers:  Absorption: good absorption ,decreased bioavailability increased rate of first pass metabolism of most beta blockers especially propranolol ,exception are pindolol ,penbutolol ,sotalol and betaxolol  Distribution : propranolol and penbutolol are the highest lipophilic beta blockers so can easily pass BBB Pharmacokinetics of beta –receptor blockers Metabolism : propranolol and metoprolol are extensively  hepatically metabbolised so ,their use must be limited in hepatic patients or during enzyme inhibitors use Esmolol is the shortest half life  Nadolol has the longest half -life between beta blockers it  is excreted unchanged in urine so ,its use in renal impairment is limited Pharmacodynamics of beta –receptor blockers  Actions :  A- CVS :  Heart : blockade of β1 receptors →negative inotropic and chronotropic effects  Blood vessels : blockade of β2 receptors → prominent vasoconstriction due to unopposed α1 in blood vessels →C.I with peripheral vascular disease  ↑ peripheral resistance (acute effect ,chronic use can leads to decrease in peripheral resistance )  Kidney : ↓ renin release  Respiratory : blockade of β2 receptors → bronchoconstriction →avoid in asthmatics  Eye : ↓aqueous humor production →↓IOP→ treatment of glaucoma  Metabolism : carbohydrate → blockade of β2 receptors in liver →↓glycogenolysis→ hypoglycemia→ C.I with diabetics ( blocking β1 mask warning signs of hypoglycemia, blocking β2 prevent recovery from hypoglycemia by blocking hepatic glycgenolysis)   Lipid → blockade of β1,3 receptors in dipose tissues →↓lipolysis →↑triglyserides , ↑VLDL,↓HDL  Clinical tips : avoid concomitant use of beta-blockers with type 1 diabeteics ?? because blocking of β1 in the heart causes masking of hypoglycemia alerting signs (tachycardia) so the diabetic patient may enter hypoglycemic coma without attention  N.B at high doses some beta-blockers have a quinidine-like or local anesthetic membrane-stabilizing effect on the cardiac action potential. MSA (membrane stabilizing activity) Such as propranolol ,labetalol ,metoprolol ,pindolol and acebutolol.it adds to the toxic properties of these beta-blockers ( needs high doses).  Indications :  Hypertension- arrhythmia – heart failure –glaucoma thyrotoxicosis  Adverse effects :  CVS : bradycardia – fatigue  CNS : sedation –depression and vivid dreams  Clinical tips : in patients treated with beta-blockers and suffer from CNS effects you can shift to another hydrophilic drug as nadolol or atenolol  Respiratory : bronchoconstriction ,common even with selective β1 but at lower incidence rate  Cold extremities due toperipheral vasoconstriction ( blocing of β2 in extremities)  Hypoglycemia , so C.I with diabetics  Clinical tips : abrupt withdrawal of beta- blockers is alife- threatening case and can precipitate arrhythmia especially short acting agents as propranolol. -first generation Non-selective Blocker of beta-adrenergic receptors  propranolol :  Dose dependant bioavailability (hepatic metabolism saturation)  → C.I with asthmatics ,diabetic??  Indications :  Hypertension - thyrotoxicosis-hemangioma second generation selective beta1- blockers  atenolol ,bisoprolol ,betaxolol ,esmolol and metoprolol  Used referably in M.I patients with COPD  Can be used with diabetic patients Third generation beta-blockers with additive vasodilatory properties  nebivolol- carvidilol-labetalol  They have the ability to increase levels of NO so cause V.D and are highy effective in treatment of hypertension.Carvidilol (antioxidant) and labetalol are mixed antagonists (α,β blockers )  Nebivolol : the most selective β1 agonist – it causes V.D by endothelial NO roduction- it increases insulin sensitivity ophthalmic beta-blockers  Timolol and betaxolol used for treatment of glaucoma through decreasing IOP partial beta-agonists  pindolol.,penbutolol,acebutolol and carteolol  Used for treatment of hypertension and angina with less bradycardia than pure antagonists  N.B : partial agonist acts as pure antagonist in presence of an agonist  Butoxamine :selective β2 blocker used in research not clinically