Pharm Exam 2 PDF

Parasympathetic System Cholinergic Agonists Acetylcholine, neurotransmitter of parasympathetic system Cholinergic neuron Acetylcholine (Ach) synthesis Storage release Binding to receptor degradation Recycling Muscarinic receptors Found primarily in the neuro-effector junction of the parasympathetic...

Parasympathetic System Cholinergic Agonists Acetylcholine, neurotransmitter of parasympathetic system Cholinergic neuron Acetylcholine (Ach) synthesis Storage release Binding to receptor degradation Recycling Muscarinic receptors Found primarily in the neuro-effector junction of the parasympathetic nervous system M1: brain, exocrine glands and autonomic ganglia and stomach (gastric parietal cells) M2: heart, brain, autonomic ganglia and smooth muscle M3: exocrine glands & smooth muscle, brain and endothelial cells M4: basal ganglia, amygdala, hippocampus (areas involved in mood, emotions, limbic system) M5: substantia nigra (midbrain) function unclear As a group found in: ○ Ganglia of PNS ○ Autonomic effector organs ○ Heart ○ Smooth muscle ○ Brain Nicotinic receptors Weak muscarinic activity CNS Adrenal medulla Autonomic ganglia Neuromuscular junction Ach is dependent on nicotinic receptors Acetylcholine signal transduction Activation of 2nd messenger (protein G) Increased intracellular [Ca] May stimulate or inhibit a secondary enzyme M2 in the heart stimulates protein G which inhibits adenyl cyclase thus increasing K conductance with decreased heart rate and force of contraction Direct acting agents Acetylcholine ○ Therapeutically of no importance ○ Has muscarinic and nicotinic actions: decreased heart rate (vagal stimulation) decrease blood pressure (vasodilation) increase salivary secretions and motility in the eye causes contraction of ciliary muscles with miosis (constriction of pupil) Bethanechol ○ Structurally related to acetylcholine but not destroyed by acetylcholinesterase ○ No nicotinic action ○ Strong muscarinic action ○ Actions: Increased intestinal motility and tone Stimulate detrusor muscle of bladder promoting urination ○ Applications: Urology (stimulation of bladder tone) ○ Adverse effects: Generalized cholinergic stimulation: sweating Decreased blood BP Nause Abdominal pain/diarrhea Bronchospasm Carbachol ○ Muscarinic and nicotinic actions may last up to 1 hr ○ Actions: Systemic use cause profound effect on cardiovascular and GI systems Promotes release of epinephrine from adrenal medulla On available for ophthalmic use to reduce IOP Pilocarpine ○ Stable to hydrolysis by acetylcholinesterase ○ Actions: Ocularly produces miosis and enhances accommodation (Vuity) Stimulates sweat, tears, and saliva production ○ Therapeutic use: POAG Acute angle closure Pigmentary glaucoma Sjogren’s syndrome (oral admin) - xerostomia/xerophthalmia Adverse reactions: potent stimulator of secretion of sweat glands (body odor) Indirect-acting agents: Acetylcholinesterase Inhibitors Inhibits acetylcholinesterase - enzyme responsible for the breakdown of used acetylcholine By interfering with the metabolism of acetylcholine, they indirectly stimulate both nicotinic and muscarinic receptors due to the consequential increase in available acetylcholine at the synapses site Reversible inhibitors Physostigmine ○ Actions: wide range of actions; stimulates muscarinic and nicotinic receptors with duration of 2-4 hrs ○ Therapeutic use: Atony of intestines and bladder, it promotes motility Decrease IOP (topical) Overdose: atropine, phenothiazine, tricyclic antidepressants ○ Adverse effects: convulsions bradycardia Pyridostigmine and Ambenonium ○ Use in myasthenia gravis (active 3-6 hrs) and (4-8 hrs) Neostigmine ○ Doesn’t cross BBB, but has greater effect in skeletal muscle ○ Used in myasthenia gravis tx and antidote for tubocurarine and neuromuscular blockers Demecarium ○ Similar action as neostigmine ○ Old drug to tx POAG Edrophonium ○ Like neostigmine but shorter duration ○ Use IV in the dx of myasthenia gravis Tacrine, Donepezil, Rivastigmine and Galantamine ○ Used in the tx of Alzheimer's disease (loss of Ach dumping for thinking is not there) Irreversible inhibitors Synthetic organophosphate compounds most extremely toxic and developed by the military as nerve gases Related agents are used as insecticides (parathion, malathion) Echothiophate: ○ Covalently binds to active site of acetylcholinesterase and permanently inactivates it ○ Generalized cholinergic stimulation, paralysis of motor function, convulsions and miosis ○ Therapeutic use: ophthalmic ointment for chronic treatment of open-angle glaucoma Pralidoxime: ○ Used for organo-phosphate poisoning ○ Reactivation of acetylcholinesterase Muscarinic agonists' side effects Diarrhea, Diaphoresis, Miosis, Nausea, Urinary urgency, transient myopia, brow pain Cholinergic Antagonists Atropine ○ Antimuscarinic receptor ○ Derived from Belladonna alkaloid ○ Central and peripheral activity ○ Actions: Eye: mydriasis (remember: dilator constricts, sphincter relaxes) and cycloplegia GI: antispasmodic (relieve spasm of involuntary muscle) Urinary system: enuresis (inhibits urination) CV: tachycardia Endocrine (secretory): xerostomia, xerophthalmia (dry mouth, dry eye) ○ Use: Eye: cyclo refraction, uveitis, antispasmodic Antidote: organophosphate intoxication (insecticides) ○ Pharmacokinetics: Readily absorbed, partially metabolized in liver and eliminated in urine T ½ life of 4 hrs ○ Adverse effects: Dry mouth, blurred vision, tachycardia, constipation, confusion, hallucinations and delirium Scopolamine ○ Belladonna alkaloid with similar to atropine but molecularly 10x stronger than atropine ○ Action in CNS is longer ○ Effective anti-motion sickness/sedation ○ Cycloplegic refraction, uveitis Ipratropium/Tiotropium ○ Quaternary derivative of atropine used by inhalation for in asthma and COPD (decreases smooth muscle contraction of bronchi) Tropicamide (6 hrs) and cyclopentolate (24 hrs) ○ Ophthalmic solutions producing similar effects to atropine Benztropine ○ Centrally acting antimuscarinic agent ○ Employed as adjuvant tx in Parkinson Disease ○ Also used to minimize dystonia in tx with antipsychotic medications Darifenacin/Fesoterodine/Oxybutyin/Solifenacin/Tolterodine ○ Synthetic atropine-like meds employed in tx for overreactive bladder (Only Oxybutyin and Tolterodine) ○ Increase capacity by lowering intravesical pressure ○ Side effects: Dry mouth Constipation Blurred vision Cholinergic Antagonists Side Effects: Blurred vision, confusion, mydriasis, constipation (because of the decreased motility) Ganglionic blockers Act specifically on nicotinic receptors Non-selective for para- or sympathetic ganglia Ineffective as neuromuscular antagonist Block entire output of ANS Rarely used therapeutically Nicotine ○ Depolarize ganglia ANS and striated muscle ○ Low dose increases BP, HR, peristalsis, and secretions ○ High dose decrease BP and diminishes muscular activity Trimethaphan ○ Short-acting competitive nicotinic ganglion blocker ○ Use IV in emergency lowering of BP (e.g. pulmonary edema) Mecamylamine ○ Competitive nicotinic ganglion blocker ○ One dose lasts up to 10 hrs ○ Active orally ○ Clinically useful for moderate to severe arterial hypertension Neurochemical effects of nicotine Dopamine: pleasure, appetite suppression Norepinephrine: arousal, appetite suppression Acetylcholine: arousal, cognitive enhancement Glutamate: learning, memory enhancement Serotonin: mood modulation, appetite suppression Beta-endorphin: reduction of anxiety and tension GABA: reduction of anxiety and tension Neuromuscular blocking drugs Block cholinergic transmission between nerve endings and nicotinic receptors at neuromuscular end-plate Non-depolarizing - competes with acetylcholine for receptors Depolarizing - cause prolonged stimulation and subsequent desensitization of the receptors Clinically useful during surgery producing complete muscle relaxation decreasing anesthetic doses Also used in mechanical ventilation Non-depolarizing (competitive) blockers Curane (d-Tobocurarine, 1st drug) ○ Skeletal neuromuscular junction blocker ○ Low dose - prevents binding of acetylcholine ○ High dose - blocks Na+ ion channels of end plate ○ Actions: Muscle paralysis Small muscles of face, eyes, fingers, limbs, neck and trunk muscles The last one affected is the diaphragm ○ Therapeutic use - adjuvant in anesthesia ○ Pharmacokinetics: Used IV As a group, does not cross BBB ○ Benefits: Decrease concentration of general anesthetic drugs by achieving adequate muscle relaxation **vecuronium rocuronium - others: Rocuronium is a vecuronium analog used to facilitate tracheal intubation and to relax skeletal muscles during surgery Drug interactions ○ Cholinesterase inhibitors (neostigmine, etc.) Overcome depolarizing action at low dose ○ Aminoglycosides (Gentamycin or Tobramycin) Inhibit acetylcholine release from neuromuscular junction - potentiates the effect of blockers ○ Calcium channel blockers Increase neuromuscular block of tubocurarine and other competitive blockers Depolarizing blockers Succinylcholine ○ Attaches to nicotinic receptor acting like acetylcholine depolarizing the neuromuscular junction persisting in cleft at [higher] for longer time followed by an altered repolarization ○ 2 phases: twitch/flaccid paralysis during depolarization & desensitization during repolarization flaccid paralysis ○ Actions: Paralyzing process similar as non-depolarizing agents ending in respiratory muscles ○ Therapeutic use: Rapid endotracheal intubation during induction of anesthesia to avoid gastric aspiration ○ Pharmacokinetics: ○ ○ Rapid onset of short duration (minutes) due to hydrolysis by plasma cholinesterase Administered by IV continuous infusion Adverse effects: Hyperthermia In conjunction with halothane may cause malignant hyperthermia in genetically susceptible persons Apnea: In genetically deficient patients of plasma cholinesterase Miscellaneous Muscle Relaxants Neural acting ○ Benzodiazepines Enhance or facilitate the action of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter Diazepam (Valium) - anxiety med. Use for muscle spasms ○ Baclofen Binds to GABAb receptors Upon binding causes an influx of potassium into the neuron, leading to hyperpolarization of the neuronal membrane and decreased calcium influx at presynaptic nerve terminals Others ○ Dantrolene directly inhibits Ca++ release from sarcoplasmic reticulum ○ Orphenadrine Methyl derivative of diphenhydramine (a commonly used antihistamine), but its mechanism of action in causing analgesia and skeletal muscle relaxation