Pharm Exam 1 PDF

Regulation of biological process Hormones Neurotransmitters Histamine Prostaglandins Organization: Afferent (sensory) neurons -> PNS -> Efferent motor (motor neurons) -> Autonomic nervous system (homeostasis) {parasympathetic, sympathetic, or enteric} or somatic nervous system (skeletal muscle) Thor...

Regulation of biological process Hormones Neurotransmitters Histamine Prostaglandins Organization: Afferent (sensory) neurons -> PNS -> Efferent motor (motor neurons) -> Autonomic nervous system (homeostasis) {parasympathetic, sympathetic, or enteric} or somatic nervous system (skeletal muscle) Thoracic has the most spinal nerves Autonomic Nervous System Typically, a two-neuron structure is found in the autonomic nervous system The preganglionic neuron has its cell body in the central nervous system and its axon in an autonomic ganglion where it synapses with one or more postganglionic neurons The preganglionic neuron originates in the CNS with its cell body in the lantern horn of the gray matter of the spinal cord or in the brainstem (Acetylcholine) Sympathetic ○ Preganglionic neuron in thoracic and lumbar spinal cord (thoracolumbar division) ○ Designed to produce widespread physiological activity ○ (3-neuron trajectory) Parasympathetic ○ Preganglionic neuron in brainstem (CN III, VII, IX, X) and sacral spinal cord (craniosacral division) ○ Designed to produce response on an organ basis Neurotransmitter Sympathetic neuron = norepinephrine (3-neuron trajectory) Cholinergic neuron = acetylcholine Neurotransmission 1. Preganglionic synapse 2. Postganglionic synapse 3. Somatic motor end plates Post ganglionic innervation One way transmission Promotes a response in post-synaptic target Effector receptors Innervation ○ Most effector organs receive dual innervation ○ Both working in opposition (balanced) the one exerting the greater function will prevail Specific effects 1. Blood vessels a. Mainly innervated by sympathetic system, maintain smooth muscle tone 2. Heart a. Sympathetic system i. Positive chronotropic (heart rate) ii. Positive inotropic (force of contraction) iii. Positive dromotropic (conductivity) b. Parasympathetic system i. Negative inotropic ii. Negative dromotropic 3. Cardiovascular reflex a. Mainly due to stretch receptors (carotid body) effects on cardiovascular center at medulla oblongata 4. Eye a. Sympathetic system (mydriasis) i. Dilator pupillae (radial fibers) b. Parasympathetic system (miosis) i. Constrictor papillae (circular fibers) ii. At rest the suspensory ligaments of ciliary body exerts tension flattening the lens iii. Under parasympathetic stimuli the ciliary body contracts decreasing tension on the lens thickening the lens due to elasticity accommodating for near vision 5. Lung a. Bronchial tree is dually innervated b. Sympathetic system: bronchodilation c. Parasympathetic system: bronchoconstriction 6. GI tract a. Dual effects but act on local neural regulators i. Enkephalins ii. Substance P iii. Vasoactive intestinal peptide 7. Salivary glands a. Dual stimulation produce secretion with different characteristics b. Sympathetic stimuli i. Thick and mucous c. Parasympathetic stimuli i. Watery 8. Adrenal medulla a. Behaves as a sympathetic ganglion producing primarily epinephrine, then norepinephrine Adrenergic Agonist Agents Act on receptors stimulated by epinephrine and norepinephrine Indirect action: drug enhances release of norepinephrine from vesicles ○ Work through increasing NE accumulation by inhibiting the COMT enzymes, MAO enzymes, the NE uptake transporters (NERT) ○ Tyramine - an AA Not a clinically useful drug Found in cheese and chianti wine ○ Cocaine: Local anesthetic that blocks Na/K pump required for reuptake of norepinephrine enhancing its sympathetic activity ○ Amphetamines: (“ups”) Causes release of norepinephrine from presynaptic terminals and increases NE release Central stimulation Increase BP and heart rate Mixed action: drug acts both directly and indirectly ○ Induce NE release from presynaptic terminals and activate adrenergic receptors in postsynaptic membranes ○ Bind to adrenergic receptors and increase NE accumulation ○ Pseudoephedrine: medications for runny nose, cold symptoms ○ Ephedrine: Enhance contractility and improve motor function in myasthenia gravis ○ Metaraminol: Alternative drug for shock treatment May be used to treat acute hypotension Direct action: drug directly activates receptor (act like EPI or NE) ○ Endogenous/Natural Occurring Epinephrine Interacts with alpha and beta receptors Low dose/levels ○ Higher affinity for beta receptors ○ Beta receptor activity predominates (vasodilation by beta 2 receptor activity) High dose levels ○ Higher affinity for alpha receptors ○ Alpha receptor predominates (vasoconstrictor by alpha 1 receptor activity) Pharmacokinetics ○ Rapid onset but brief duration: IV, SC ○ Orally ineffective ○ Metabolites excreted in urine (metanephrine and vanillylmandelic acid) ○ Interactions: hyperthyroidism and cocaine ○ Adverse effects CNS disturbances intracerebral Hemorrhage cardiac arrhythmias (digitalis) Pulmonary edema Cardiovascular system ○ (+) inotropic and chronotropic (B1) ○ Peripheral vasoconstriction with decreased renal blood flow (A1) ○ Peripheral vasodilation (B2) Actions on: ○ Respiratory system - bronchodilation (B2) ○ Liver - glycogenolysis (B2) ○ Pancreas - lowers insulin (A2) ○ Adipose tissue - lipolysis (B3) Therapeutic use: ○ Bronchospasms (SC) ○ Anaphylactic shock Type I hypersensitivity reactions (anaphylaxis) ○ Glaucoma open angle (2% sol) - lowers IOP by increasing uveoscleral outflow ○ Anesthetics - increased duration of local anesthetic effect due to vasoconstriction Norepinephrine Affects mostly alpha receptors Actions ○ Cardiovascular - vasoconstriction Endogenous NE is reduced with baroreceptor reflex (stretching of baroreceptors due to increased BP which cause decrease in sympathetic flow and thus NE levels) Therapeutic use: ○ Acute hypotension in a hemodynamically unstable patient ○ It can be used as atropine pre-treatment for acute hypotension (if given after atropine it will cause tachycardia) ○ Cardiac arrest (adjunct tx) Dopamine: A1 and B1 receptors activity D receptors activity ○ Dopamine 1 receptors subserve vasodilation, especially in the renal, coronary, mesenteric, and cerebral vascular beds ○ ○ Dopamine 2 receptors have been located at the endings of postganglionic sympathetic nerves; upon activation inhibits norepinephrine release Actions ○ Cardiovascular - (+) inotropic (+) chronotropic (B1), vasoconstriction (A) ○ Vasodilation of dilation of renal and splanchnic beds Therapeutic use - primarily used for cardiogenic shock and acute HR Adverse effects - short-lived arrhythmias and nausea Synthetic Dobutamine Isoproterenol (below) Major effects mediated by alpha receptors Alpha 1: works through the phospholipase C pathway (increases IP3 and DAG) increases intracellular Ca++ in smooth muscle cells -> contraction ○ Vasoconstriction ○ Increase peripheral resistance ○ Increased blood pressure ○ Mydriasis ○ Increased closure of internal urinary bladder sphincter ○ Phenylephrine Go off of video notes ○ Oxymetazoline Nasal decongestant Ophthalmic (Upneeq) Alpha 2: works through the adenylate cyclase pathway (inhibits cAMP) - decreases release of neurotransmitters and hormones -> decreases secretion ○ Alpha 2 activity in the iris induces relaxation of the dilator muscle ○ inhibition of norepinephrine release ○ inhibition of insulin release by the pancreas ○ Fenoldopam: D1 and A2 Rapid vasodilation for severe hypertension in hospitalized patients ○ Clonidine Essential hypertension due to CNS action (diminish central adrenergic outflow) Major effects mediated by beta receptors Beta 1+2: ○ Isoproterenol: non-selective B1 and B2 agonist Actions: Cardiovascular - (+) inotropic (+) chronotropic -> decrease peripheral resistance Pulmonary - bronchodilation Therapeutic use: bronchial asthma, heart block, or cardiac arrest Adverse effects: tachycardia Beta 1: works through stimulation of the adenylate cyclase pathway on the cardiac muscle (increases cAMP) -> increases intracellular Ca++ -> contraction of cardiac muscle ○ Tachycardia ○ Increased myocardial contractility ○ Increased lipolysis ○ Dobutamine: (+) inotropic Use in congestive heart failure to increase cardiac output Adverse effects: tachycardia, exacerbates angina Beta 2: ○ Vasodilation ○ Slight decrease in peripheral resistance ○ Bronchodilation ○ Increased glycogenolysis (liver and muscle) ○ Increased glucagon release ○ Relaxation of uterine smooth muscle ○ Albuterol (short-acting) Short-acting beta 2 agonist (SABA) Acute treatment for asthma and COPD Indicated in hyperkalemia since we want excess K to shift into the cell ○ Metaproterenol ○ Pirbuterol ○ Salmeterol and Formoterol Long-acting beta 2 agonist (LABA) Chronic treatment of COPD and/or asthma ○ Terbutaline Short-acting beta 2 agonist (48 hrs) Better used in severe asthma Also for tocolysis (bronchodilator to decrease uterine contractions in premature labor - delays labor) Alpha + Beta Agonists Norepinephrine (alpha > beta) Epinephrine + Dopamine (beta > alpha) Adrenergic Agonists SE: Arrhythmias, headache, hyperactivity Insomnia, nausea, tremors Adrenergic Antagonist Decrease sympathetic tone of blood vessels Results in decrease in TPR May provoke reflex tachycardia Phenoxybenzamine (preferred) (noncompetitive antagonist) An haloalkylamine Binds irreversibly to alpha-adrenergic receptors Leads muscle relaxation and a widening of the blood vessels Vasodilation results in ○ Lowering BP (alpha 1 receptors are blocked thus inhibiting vasoconstriction) ○ Increased blood flow to the skin, mucosa and abdominal viscera Used to control of episodes of HTN in pheochromocytoma (tumor of the adrenal medulla that produces large amounts of epinephrine and NE - they bind to alpha 1 and beta 2 receptors and increase BP to a great extent) prior to sx Phentolamine Competitive reversible antagonist of alpha-1 (duration of 4 hrs) Induces vasodilation of vascular smooth muscle Used as adjunct tx for pheochromocytomaectomy IV/IM (pre-op 1-2 hrs) Also used for HTN crisis q 10 min Also competitively inhibits the inhibitory activity of alpha-2 adrenergic receptors Block alpha-1 adrenergic receptors of iris dilator, thus reduces diameter of the pupil (miosis) Ryzumvi 0.75% ophthalmic solution to reverse mydriasis induced by muscarinic antagonists Quinzaoline - based drugs Primarily use for BPH and HTN ○ Prazosin ○ Tamsulosin Linked to intraoperative floppy iris syndrome (IFIS), a risk factor for complications during cataract surgery, interferes with pupillary dilation ○ Terazosin ○ Doxazosin Facilitates passage of kidney stones (ureterolithiasis) - off label First dose phenomenon - orthostatic hypotension, dizziness reflex, tachycardia effect Compounds made up of two fused six-member simple aromatic rings Display hypotensive and anticancer activity Alpha 1-AR blockers Relaxation of smooth muscle of peripheral vasculature results in hypotensive effect by decreased TPR Relaxation of smooth muscle in the prostate and bladder sphincter; decreases resistance to urinary flow, reduces discomfort associated with BPH Some studies have found to have antitumor efficacy through the induction of apoptosis in benign and malignant prostate cells - to reduce tumor growth Drugs affecting neurotransmitter release Reserpine ○ Anti-hypertensive effect is by blocking the transport and storage of biogenic amines (dopamine, serotonin, NE) causing depletion of NE from central and peripheral synapses ○ Also been used for relief of psychotic symptoms by reducing dopamine levels in the brain Guanethidine ○ Blocks release of storage NE ○ Mechanism: depletes the nerve ending of NE in the PNS ○ Main effects: decrease in PVR and decrease in HR -> decrease in BP ○ Adverse effects: orthostatic hypotension, Na+ and water retention; no CNS effects ○ Pharmacokinetics: poorly absorbed from the GI; onset slow (1-2 weeks). Metabolites excreted in urine ○ Not used anymore; severe side effects Classification ○ Nonselective (1st gen) Some with intrinsic sympathomimetic activity (ISA) ○ Cardioselective (beta-1 selective, 2nd gen) ○ Hybrid antihypertensive drugs (beta and alpha blocking CV actions) (3rd gen) Proposed mechanisms ○ Block cardiac beta-1 receptors -> lower HR -> lower CO ○ Block renal beta-1 receptors -> lower renin, lower PVR ○ Oppose action of NE released (ISA) Beta-adrenergic blocking agents Clinical uses: ○ Hypertension - reduce cardiac output and renin secretion ○ Angina pectoris - Propranolol, Nadolol and other beta blockers reduce heart rate and force of contraction ○ Glaucoma - Timolol and other beta blockers reduce secretion of aqueous humor ○ Migraine - Propranolol provides prophylactic effect ○ Thyrotoxicosis - Propranolol reduces cardiac rate and potential for arrhythmias ○ Arrhythmia prophylaxis after a myocardial infarction and tx of supraventricular tachycardias Propranolol, Metoprolol, Esmolol, Acebutolol and Timolol Block beta-1 receptors in the heart -> reduce the sympathetic effect on the heart causing: ○ Decrease automaticity of SA node and ectopic pacemakers ○ Prolong refractory period (slow conduction) of the AV node 1st gen non-selective ○ Propranolol ○ Timolol ○ Pindolol ○ Penbutolol ○ Carteolol 2nd gen beta-1 selective ○ Metoprolol ○ Acebutolol ○ Atenolol ○ Betaxolol ○ Bisoprolol ○ Diabetics on insulin and asthmatics 3rd gen (hybrids) ○ Labetalol (alpha and beta) A combined alpha-1, beta-1, and beta-2 blocker. Beta-blocking action is more prominent. It also has some ISA property Can be given IV for hypertensive emergencies ○ Carvedilol (alpha and beta) Nonselective beta-blocker and alpha-1 blocker BB of choice in the treatment of CHF Beta-adrenergic blocking agents SE: Arrhythmias, Bronchoconstriction, Sexual dysfunction Ocular Adrenergic Agonist and Antagonist drugs Efferent (motor) and afferent (sensory) Efferent in the eye ○ Includes the sympathetic and parasympathetic ○ 3 synapses in the sympathetic system (central, pre- and post-gnaglionic) Afferent in the eye is ONLY parasympathetic Look at efferent oculosympathetic pathway (3rd order neuron) & oculo-sumpathetic pathway Sympathetic neurotransmitters 1. The neurotransmitter in the central and pre-ganglionic synapse is acetylcholine 2. For the sympathetic post-ganglionic synapse, the neurotransmitter is norepinephrine * adrenergic action 3. In some post-ganglionic site the neurotransmitter is still acetylcholine Physiologic efferent pupillary (motor) response 1. Iris sphincter a. Constricts the pupil via parasympathetic innervation b. The action is cholinergic (acetylcholine) 2. Iris dilator a. Dilates the pupil via sympathetic innervation b. The action is adrenergic (norepinephrine) Post-ganglionic receptors and effector structure ○ Beta 2 receptors - increase secretion in aqueous humor production (NPECB) ○ Alpha 1 receptors Dilation by dilator muscle contraction Lid elevation by Mueller muscle contraction Contraction of SM conjunctival arteriole ○ Alpha 2 receptors Inhibitory response Relaxation of dilator muscle - miosis Decrease active secretion in aqueous (NPECB) humor production Direct sympathomimetics ○ Epinephrine Endogenous EPI is the counterpart of NE Medulla of the adrenal gland Hormone-like, aka ADRENALINE Mixed-agonist Inactivated almost immediately Conjunctival vasoconstriction Hypotensive effect - 1% (Eppy) for tx POAG; increases uveal scleral outflow Dx of Horner’s syndrome - postganglionic Topical SE: Burning, HA’s, paradoxical conj. hyperemia Ocular SE: Maculopathy - 20-30% of aphakic patients; reversible Madarosis - reversible Pigment deposit on tarsal conjunctive (oxidized EPI), mostly seen in elderly pts Allergic rxns. Not indicated in patients with narrow angles ○ Phenylephrine Synthetic, structurally similar to EPI Virtually an alpha 1 agonist Sodium Bisulfite (0.12%, 2.5%, 10.0%) Dilation, Mueller’s, conjunctival arterioles Variable hypotensive effect Partial dilation 2.5% and 10% 45-60 min., 6-7 hrs. No clinical cycloplegia MEC 5% (no difference between 2.5% and 10% in dark eyes) Clinical use: Posterior synechiae (10%), Pupllary cysts (2.5%) Conjunctival hyperemia (0.125%); caution w/ pts that have narrow angles Horner’s ptosis (0.125%) Dx Horner’s (1%) Ocular SE: Lacrimation due to irritative effect Pain, keratitis Allergic dermatitis Iris pigment drop out Rebound miosis Decrease in conjunctival and iris PO2 with chronic use ○ Vasoconstriction of conjunctival and iris vasculature ○ Blood flow reducition ○ Hypoxia Systemic SE: Episodes of rise in BP have been seen (10%) ○ Age factor, DMI, HTN, no prolonged contact time Ventricular tachycardia, reflex bradycardia, sub-arachnoid hemorrhage Drug interaction 10%: Tricyclic antidepressants and MAO inhibitors enhances its cardiovascular effect Guanethedine Methyldope potentiates the effect on adrenergic receptors Atropine Contraindications 10%: Idiopathic hypotension Parkinson’s History of hyper-reaction Malignant hypertension Aneurysm Indirect adrenergic agonists ○ Hydroxyamphetamine 1% conc., paredrine Mode of action - liberates norepinephrine from the pre-synaptic vesivle at the neuromuscular junction Very little effect on accommodation Clinical uses Partial dilation - 1% sol. Paremyd (combo w/ 0.25% tropicamide) Differentiate between central/2nd and 3rd neuron in horner’s syndrome Ocular SE: moderate irritation Systemic SE: Rare (little use as a mydriatic in comparison with phenylephrine) Some cases of rise in BP (characterized as tachyphylaxis) Contraindication similar to phenylephrine ○ Cocaine Anesthetic action and blocks the reuptake of norepinephrine Not comercially available in ophthalmic solution Salt form (HCL) is diluted in aqueous solution for 1%,4%,10% for ophthalmic use Clinical uses: force duction test, Dacryocystorhynostomy, Horner’s syndrome Adverse effects Ocular ○ Grayish irregular depressions of corneal epithelium ○ Epithelial corneal erosion Systemic ○ Restlessness, anxiety ○ Nausea, vomiting, abdominal pain ○ Rapid irregular pulse ○ Respirator failure > death Drug interaction Monoaminoxidase inhibitors Tricyclic antidepressant Methyldope Selective adrenergic agonist ○ Aproclonidine Iopidine 0.5% Mainly alpha 2 agonist 1% concentration pre and post-operatively in anterior segment laser procedures Mode of action - decreases aqueous humor production, may have some effect in the uveoscleral outflow Exhibits tachyphylaxis - primarily used as short term therapy on patients awaiting on glaucoma surgery Minimal side effects ○ Brimonidine tartrate Alphagan P 0.2% Alpha 2 agonist primarily Mode of action - decreases aqueous production Mode therapy - BID IOP reduction similar to Timoptic Side effects: May cause increased BP in some patients Blanching test before prescribing Lumify - OTC For the treatment of conjunctival hyperemia 1 drop in affected eye every 6-8 hours Ophthalmic adrenergic antagonists ○ ○ ○ ○ ○ ○ ○ Reversible blockage of beta receptors at NPECB Ocular hypertensive effect by decreased active secretion in aqueous humor production -IOP 20-22% IOP reduction, ~10% on the fellow eye Dapiprazole (mydriolytic agent) Rev-eyes 0.5% Effect on mydriasis Reversibly blocks alpha 1 receptors on dilator muscle Almost complete reversal on phenylephrine Partial reversal on tropicamide Contraindicated in inflammatory processes Side effects Transient hyperemia Superficial punctate keratitis (stability for 3 weeks) Ptosis Non-selective Timolol Maleate Timoptic 0.25, 0.5; XE 0.5%, ocudose PF; Betimol 0.5% New mode of therapy - 0.25% qd AM Maximum effect in 3 weeks Washout period 1-2 months Liposoluble substance Cosopt Levobunolol Betagan 0.25%, 0.5% Same indications as Timoptic More effective in some patients More side effects in some patients Carteolol Ocupress 1% Mode of tx - BID Equally as effective and Timoptic Less effective than Betagan in some patients Hydrosoluble substance (less SE) Increases the ratio of high density lipids to total cholesterol Cardio-selective Betaxolol Betoptic S 0.25% suspension Beta-1 blocker (safer in asthmatic patients) Mode of tx - qd AM Calcium channel blocker activity Careful with sulfa allergies Systemic SE: Mask of hypoglycemic effects in patients under diabetic tx Bronchial asthma (non-selective) Bradycardia (hypotension) Mental depression (except ocupress) ○ Ocular SE: Allergic conjunctivitis Transient burning and irritation Corneal hypesthesia causing dry eye Ocular myasthenia Superficial punctate keratitis (SPK) ○ Contraindications: COPD Broncial asthma CHF Bradycardia Hypotension Combo alpha agonist/beta blocker: Combigan (Brimonidine tartrate/Timolol Maleate)