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University of British Columbia
Pharmaceutical Sciences
PHAR 341

(1) Local Anesthetics 1. Discuss the pain pathway and name its priniciple components  cortex > thalamus > brainstem > trigeminal ganglion > trigeminal nerve  Cause loss of function: temperature/pain > touch > proprioception > motor control 2. Describe the mechanism of actions of local anaesthetics  thinner and unmyelinated nerves get desensitized first because their nodes are closer together  to block conduction, several nodes need to be affected  can block the channel protein on TTX receptor from the outside so can’t depolarize 3. Recognize the general chemical structure of amide and ester local anesthetics and explain the importance of different structural components to the activity of these drugs  lipophilic group (usually aromatic ring) with a hydrophilic group (primary, secondary or tertiary but NOT quaternary amine) diffuse through membrane and block channel from inside so can’t depolarize – determined by injection into axon 4. Discuss how factors such as local pH and blood flow as well as metabolism affect the onset and duration of local anesthesia  esters are broken down by plasma esterases, amides in liver  anything that helps the anesthetic get across membrane makes it more potent  block length is determined by redistribution of systemic circulation, not by metabolism  lowering the pH (make more acidic) decreases amount of uncharged drug, so can’t get across membrane as easy  co-injected vasoconstrictors can lengthen block duration b/c delays redistribution 5. List the generic names of commonly used local anesthetics and differentiate them based on their therapeutic and chemical attributes 6. Describe the various routes of administration and therapeutic applications of local anesthetics  topical/surface  infiltration (injected or ring block/injected around the area)  nerve block (injected around nerve)  spinal - subarachnoid (injected into cereberospinal fluid so faster) or epidural 7. Discuss systemic and local toxicity as well as calculate the max safe dose of a local anesthetic  systemic o CNS – dizzy, nervous, blurred vision, tremors > drowsy, convulsions, unconscious, respiratory arrest o cardiovascular – hypotension, cardiovascular collapse, bradycardia, cardiac arrest  local o hypersensitivity o prolonged anesthesia (several weeks) (2) Physiology, Pharmacology of NM Transmission 1. Describe normal neuromuscular function  presynaptic cleft release a vesicle of acetylcholine into NMJ  acetylcholine activate nicotinic receptors of postsynaptic cleft the activated depolarization  AChEase breaks down ACh in cleft so choline can be transported back into presynaptic cleft to be recycled 2. Illustrate how acetylcholine is released and recycled at the NMJ and describe where and how natural toxins and drugs act at the NMJ  botulinum prevent release of vesicle  AChEase inhibitors prevent rapid breakdown of Ach, increase/prolong effect of ACh – *drug of choice of myasthenia gravis  hemicholinium prevent reuptake of choline  vesamicol prevent reformation of Ach vesicles 3. Discuss the pharmacological mechanism and describe the therapeutic uses of botulinum toxin A and 4- aminopyridine  botulinum toxin A o cosmetic o ophthalmic – strabismus (imbalance of eye muscle strength so can’t focus both eyes on same target) or bepharospasm (involuntary contraction of eye lid muscle, wink) o face and neck muscle spasms – hemifacial spasm or cervical dystonia (unusual tone in neck) o hyperhidrosis – excess sweating (lasts 4-12 months at least) o pain – migraine, lower back, myofascial (trigger point) pain o **long term use can alter muscle fiber size  4-AP prolongs AP o MS (autoimmune disease – demyelinated nerve fibres to brain) o myasthenia gravis (weak muscles) o spinal cord injury 4. Describe the mechanism of action and the therapeutic uses of non-depolarizing and depolarizing neuromuscular blockers  non-depolarizing o binds to receptor but no response (competitive, so can overcome with high concentration ACh) o paralysis: eyelid > tongue > pharynx > jaw muscle > diaphragm > limbs > trunk musculature  depolarizing (succinylcholine) o binds and activates receptor  depolarization  fasiculating muscle contraction > maintained depolarization > muscle relaxation > desensitization of nicotinic receptor (channel block)  for surgical muscle relaxation  for electroconvulsive therapy (for depression)  for mechanical respiration 5. Describe the mechanism of action of dantrolene, its therapeutic effects and dosing, side effects and toxicity  Mechanism: o reduce release of Ca from sarcoplasmic reticulum so muscle relaxes  prevent muscle contraction o doesn’t block neuromuscular transmission  Dose: orally  Therapeutic uses: o malignant hyperthermia – continuous iv push until symptoms subside or max of 10mg/kg reached o spasticity – from spinal cord injury, stroke, MS, cerebral palsy, etc  Side effects: generalized milkd muscle weakness, transient drowsiness  toxicity: idiosynchratic fatal hepatitis (3) Myasthenia Gravis 1. Define myasthenia gravis  autoimmune disease characterized by severe muscle weakness, where antibodies are produced against the nicotinic receptor 2. Describe the symptoms, etiology, diagnosis and drug treatment of myasthenia gravis  symptoms o muscle weakness  progressively worse throughout day  commonly affects cranial muscles – oculomotor, elevator of upper eyelids, oropharyngeal, facial, trunk and limb  etiology o seropositive myasthenia gravis  circulating serum antibodies act on the nicotinic receptors  can remove circulating antibodies  can be passed from mom to new born  most likely to have abnormality of thymus glad, maybe even tumour o seronegative myasthenia gravis  antibodies against muscle-specific kinase (MuSK) – membrane signlaing element  can be congenital b/c of an inherited deficiency in nicotinic receptor  can result in mutation in another membrane signalling protein (rapsyn)  diagnosis: o *antibody titre – Best! detect circulating ab to AChR and other proteins like MuSK and rapsyn o muscle power tests o edrophonium test – fast acting, short lasting AChEase 10mg iv  positive test: increase in muscle strength within 1min  only identifies defect in NM transmission  makes cholinergic crisis worse, but improves myasthenic crisis o measure ACh receptor density from muscle biopsy using radiolabelled α-bungarotoxin  drug treatment: AChEase inhibitors 3. Differentiate between a “cholinergic crisis” and a “myasthenic crisis”  cholinergic crisis = drug therapy effect (from too much ACh) o Diarrhea o Urination o Miosis o Muscle weakness o Bronchospasm o Excitation o Lacrimation o Seizures o Sweating o Salivation  myasthenic crisis = disease effect o danger: breathing will be affected (4) The Autonomic Nervous System 1. Explain the function of ANS: homeostasis 2. Discuss how the parasympathetic and sympathetic divisions alter the activity of smooth muscle, cardiac muscle, and glands given in the examples Effector Stimulation Effect of Sympathetic Effect of Effects are: Parasympathetic (Heart) Sinus rate acceleration slowing Opposed Ventricular contractile increase (No direct effect) unopposed force Bronchioles Dilation Constriction Opposed Eye (pupil) Constriction Dilation Opposed (GIT) Secretion Increased secretion Unopposed Muscle wall Relaxation Contraction Opposed Sphincters Contraction Relaxation Opposed (Urinary Bladder) Fundus Relaxation Contraction Opposed Sphincter Contraction Relaxation Opposed (Glands) *Salivary Secretion (mucous) Secretion (watery) *parallel Sweat Secretion unopposed Piloerectors Contraction Unopposed Spleen Contraction Unopposed Blood vessels Constriction (dilate in Unopposed skeletal muscle) 3. Describe the anatomy of the ANS and discuss the major anatomical differences between the parasympathetic and sympathetic divisions  parasympathetic: o conservation and restoration of body energy stores o discrete and localized activation of certain target organs - *NO MASS ACTIVATION o ganglia usually near or in organs o less pre-ganglionic fibers than post-fibers  sympathetic o respond to stress (prepare fight or flight) – mass sympathetic discharge o ganglia are some distance away from target organ o a pre-ganglionic can synapse with many post-ganglionics o stimulation of adrenal medulla releases adrenaline or epinephrine to affect many organs 4. Identify the neurotransmitters released by ganglion neurons, parasympathetic effector neurons and sympathetic effector neurons and the receptors they act on Sympathetic Effector Neuron Effector Organ Neurotransmitter Receptor Neurotransmitter Receptor Organ ACh nicotinic Noradrenaline Adrenergic heart ACh nicotinic ACh Muscarinic Sweat gland ACh nicotinic dopamine D1 (dopamine Kidney receptor) Parasympathetic ACh nicotinic ACh Muscarinic Salivary gland Somatic Motor ACh nicotinic Skeletal muscle 5. Predict the likely effect of a sympathomimetic (activates sympathetic division) or parasympathomimetic (activates parasympathetic division) drug on smooth muscle, cardiac muscle or glands given in the examples. (5) Cholinergic Pharmacy 1. Using ACh as a prototype, explain the effects of direct acting cholinergic agonists on major organ systems  can activate nicotinic (high dose) and muscarinic receptors (low dose) - **nicotinic effects occur only with high doses of ACh or if a muscarinic blocker is co-administered  administered iv, quickly metabolized by cholinesterases in blood  muscarinic actions of ACh: CNS Doesn’t cross BBB Cardiovascular -Vasodilation; decrease inotropy & chronotropy (force of contraction and heart rate) -slowed conduction (hypotension and reflex tachycardia when given iv) Respiratory Bronchoconstriction, increase secretion GI Increase motility and secretion (usually not observed when given iv) Urinary Potention increase in voiding pressure (usually not observed when given iv) Glands Sweating and salivation  cholinergic agonist – activated ACh receptors  Cholinergic antagonist – blocks ACh receptors  Parasympathomimetic – activates actions of parasympathetic system  Parasympatholytic – blocks actions of the parasympathetic system 2. Discuss the therapeutic uses and side effects of direct-acting cholinergic agonists  open angle glaucoma – lowers intraocular pressure 3. List the 5 subtypes of the muscarinic receptor, identify the organs in which they are found and discuss how activation of the specific receptor subtype affects the organ M1,3,5 = postsynaptic & stimulatory M2,4= presynaptic & inhibit neurotransmitter release Type Location Function M1 Parasympathetic ganglia Increase parasympathetic tone Salivary gland Increase saliva Stomach Acid release M2 Heart Decrease HR (directly in atria) Decrease force of contraction (indirectly in ventricles) GI smooth muscle Oppose symp-mediated relaxation Bladder smooth muscle Oppose symp-mediated relaxation CNS Analgesia? M3 Airway s.m. Bronchoconstriction GI s.m. Contract Eye Constrict pupil Contract ciliary muscle (len shape) Bladder smooth muscle Contract trabecular meshwork Contract bladder Glands Salivation [a]fter [1] [V]odka [P]at [P]uked [P]rofusely [B]ehind [H]omeDepot Alpha 1 vascular smooth muscle Vodka papillary dilatory muscle Pat prostate Puked bladder sphincter Behind heart homedepot Alpha 2 Adrenergic & cholinergic Friendly Asian Vancouver Girl Beta 2 Rhode a Pony to South vancouver Beta 3 Hooked-on Face book M1 M2 M3 Alpha 2: [F]riendly [A]sian [V]ancouver [G]irl Beta 2: [R]ode a [P]ony to [S]outh [V]ancouver Beta 3: [H]ooked-on [F]ace [B]ook M1: [P]olitely [S]ay [S]orry M2: [H]uge [G]eese in [B]ritish [C]olumbia M3: [A]sian [G]irls [E]nvision [B]ig [H]unky [G]uys 4. Describe the mechanism of action and discuss the therapeutic usefulness and toxicity of indirect-acting cholinergic agonists  mechanism: increase the effect of synaptically released ACh by blocking the breakdown of acetylcholine at neuromuscular, autonomic ganglion, and parasympathetic effector synapses. Basically, acetylcholinesterase inhibitors.  Therapeutic usefulness Edrophonium -Reverse paralysis of non-depolarizing NM blockers -myasthenia gravis diagnostic agent Neostigmine -postoperative ileus -postoperative urinary retention Pyridostigmine -myasthenia gravis (DOC) (Insecticides) -some related compounds are notorious toxic nerve gas agents (Tabun, Parathion Sarin) Diazinon -propoxur is a possible treatment option for bedbug epidemic Malathion Propoxur  Toxicity (DUMMBELSSS) CNS -if can cross the BBB, cause anxiety, headache, tremors, confusion, coma Eye -lacrimation, miosis, blurred vision CVS Bradcardia (hyper- or hypotension) Respiratory Bronchial constriction, increased secretions GIT Nausea, vomiting, diarrhea, abdominal cramps Bladder Increased urinary urgency, involuntary micturation Glands Increased salivation and sweating Skeletal Initial spasms leading to muscle weakness, respiratory paralysis muscle (5.2) Cholinergic Pharmacy – Anticholinergics 1. Describe the pharmacological actions of cholinergic antagonists including muscarinic receptor subtype selective antagonists 2. discuss the therapeutic uses and side effects of non-selective cholinergic antagonists 3. discuss the therapeutic uses and side effects of muscarinic receptor subtype selective antagonists (5.3) Ganglion Blockers 1. Describe the pharmacological actions of ganglion blockers 2. Discuss the therapeutic uses and side effects of autonomic ganglion blockers (6.1) Adrenergic Pharmacology 1. Using epinephrine as a prototype, explain the effects of direct acting non-selective adrenergic agonists on major organ systems ****need to find out where epinephrine acts…on the B2 receptor? 2. Discuss the therapeutic uses and side effects of adrenergic agonists Epinephrine Norepinephrine 3. List the 5 subtypes of the adrenergic receptors, identify the organs in which they are found and discuss how activation of the specific receptor subtype affects the organ (MEMORIZE******) α1 Vascular smooth muscle Contract Papillary dilator muscle Contract (pupil dilate) Prostate Contract Bladder sphincter Contract α2 Adrenergic & cholinergic Inhibit transmitter release nerve terminals (inhibit adrenergic responses) β1 Heart Positive chronotrope & inotrope β2 Respiratory Relax Vascular smooth muscle Relax (dilate) β3 Fat cells Activate lipolysis Bladder Relax 4. Describe the mechanism of action and discuss the therapeutic usefulness and toxicity of indirect-acting adrenergic agonists  Dopamine o D1 receptor: relax vascular smooth muscle (stimulate adenylyl cyclase (just like β receptors) to increase Ca influx to cause contraction) o D1 receptor: suppress norepinephrine release (like a negative feedback loop?)  Dobutamine  for hypotensive emergencies to keep cerebral and corony blood flow going  … (6.2) Alpha receptor antagonists 1. Recognize the names of the α blockers given in the lessons  Prazosin (competitive)  Phenoxybenzmine  Phentolamine (non-selective, competitive)  Phenoxybenzamine (irreversible, a1 selective) 2. Describe the pharmacological effects and discuss the therapeutic uses of α adrenergic antagonists Drug Effects SE Therapeutic Uses Prazosin -lower peripheral vascular -postural -relax arterial & venous smooth muscle (competitive, a1 resistant and BP hypotension (esp. -hypertension selective) -postural hypotension and 1 dose for elderly) -mild benign prostatic hyperplasia reflex tachycardia = dizziness Phenoxybenzmine -miosis & nasal stuffiness (irreversible) -decreased bladder sphincter tone Phentolamine (non- -inhibits responses to Severe tachycardia Pheochromocytoma (tumour in adrenal selective, serotonin medulla releases epinephrine & competitive) -agonist @ muscarinic, H1 & norephinephrine) H2 histmaine receptors -intermittent or sustained hypertension Phenoxybenzamine -inhibits reuptake of -postural -palpitaions (irreversible, a1 norepinephrine, blocks hypotension & -headaches (from hypertension) selective) histamine, ACh, & serotonin tachycardia -increased sweating receptors Tamulosin -relax prostate smooth -little on BP Mild benign prostatic hyperplasia (competitive, a1A & muscle (more than vascular -a lot of dizziness a1D selective) smooth muscle) 3. Recognize and predict potential side effects of this drug class (6.3) Beta receptor antagonists 1. Recognize the names of the β blockers given in the lessons 2. Describe the pharmacological effects and discuss the therapeutic uses of β adrenergic antagonists Drug Effects SE Therapeutic Uses Propanolol (non selective) -extensive first pass -Fatigue, Dizziness, -hypertension, angina, metabolism by liver Depression, Nightmares, migraine (prophylaxis), bradycardia essential tremor, decrease -increase triglyceride levels sudden death after MI, a lot severe hyperthyroidism Metoprolol (B1 selective) -pure antagonist -fatigue, dizziness Hypertension, angina, after -bradycardia MI Acebutolol (B1 selective -weak membrane stabilizing -fatigue, dizziness Hypertension, angina antagonist, partial B1 activity -not so much bradycardia agonist properties) - -not so much alter to plasma lipids Labetalol (racemic mis of -hypotension -hypertension (hypertensive chiral isomers that are a1- -less tachycardia than with emergency & pregnancy) selective; one isomer is a-blockers non-selective B w/ some B2 agonist) 3. Recognize and predict potential side effects of these drug class (6) Postaglandins and Leukotrienes 1. Describe the synthesis of prostaglandins and leukotrienes  arachidonic acid is released from cell membrane phospholipids by phospholipase A2, phospholipase C, & diglyceride lipase  then lipoxygenases (LOX) converts it to leukotrienes  cyclooxygenases (COX) converts it to prostaglandins o COX is blocked by NSAIDs; NSAIDs may promote synthesis by LOX  corticosteroids block phospholipase A2, therefore, blocks all synthesis pathways of prostaglandin and leukotrienes 2. Recognize the names of common prostaglandins and leukotrienes and the receptor subtype(s) they affect Prostaglandin Receptor Effects PGE2 EP1 -Activate GI smooth muscle -Protects against NSAID ulceration in stomach EP2 -facilitates pain transmission -mediates joint inflammation EP3 -mediates fever generation -inhibits gastric acid secretion -protects against NSAID ulceration in intestine EP4 -sensitize nociceptors & neurons -pro-inflammatory in join -promotes mucus secretion in stomach PGD2 DP (1,2) -bronchoconstrictor -promotes sleep induction PGF2a FP A,B -vasoconstrictor -bronchoconstrictor -regulation of intraocular pressure PGI2 IP -uterine relaxation -sensitize nociceptors TXA2 TPAB -potent vasoconstrictor -potent bronchoconstrictor -promote platelet aggregation Leukotriene Receptor Effect LTB4 BT 1,2 -Chemoattractant (PMNs) -Activates inflammatory cells LTC4,D4,E4 CystLT 1,2 -Chemoattractant (eosinophils) -Potent bronchoconstrictor (induce bronchial inflammation) 3. Discuss specific physiological actions mediated by prostaglandin and leukotriene receptor subtypes Prostaglandin physiological actions Leukotriene physiological actions Analgesia PGE2 Dysmenorrhea Increased endometrial synthesis of PGE2 and PGF2 Patent Ductus Arteriosus PGE2 keeps the fetal ductus arteriosus open 4. Describe the therapeutic use and potential adverse effects of drugs that mimic, inhibit the synthesis or block select receptor activation of prostaglandins and leukotrienes PG Agonist Therapeutic uses SE Alprostadil (OGE1-analogue of PGE2) -maintain ductus arteriosus while -penile pain if intracavernosal – vasodilator waiting cardiac surgery injection -2 line tx for erectile dysfunction Dinoprostone (PGE1) -facilitate delivery -abdominal discomfort - promotes uterine contractions & -abortion (1 /2 trimester) -diarrhea cervical ripening Misoprostol (PGE1) -prevent NSAID-induced peptic ulcers -abdominal discomfort -inhibits gastric acid secretion (high -with antiprogestins for early abortion -diarrhea dose) PG Analogue Therapeutic uses SE Lubiprostone (metabolite of PGE1) -chronic constipation -vomiting --activate voltage-dependent chloride -nausea channels to increase chloride, to -abdominal cramping promote intestinal fluid secretionrapid transit Latanoprost (PGF2 derivative) -glaucoma (lowers IOP) Prostacyclin (PGI2) -pulmonary hypertension -powerful vasodilator, inhibitor of -porto-pulmonary hypertension platelet aggregation, role in vascular homeostasis TXA2 (aka Thromboxane) -agreggate platelets, vasoconstriction…for cardiovascular Therapeutic uses SE Zileuton -asthma -elevated liver enzymes -5-lipoxygenase enzyme inhibitors -indigestion, abdominal pain, nausea -alter metabolism of warfarin, theophylline, propanolol Monelukast -asthma Like placebo -competitive antagonist @ CystLT1 -allergic rhinitis receptor (7) Corticosteroids 1. Describe the HPA axis & its regulation  Hypothalamus Pituitary Adrenal axis  function: regulate steroid hormone synthesis and secretion by adrenal gland  mechanism: hypothalamus release CRF (corticotropin-releasing factor)stimulate pituitary to secrete ACTH (adrenocorticotrophic hormone)act on adrenal gland to release glucocorticoids  elevated levels negatively feedback to hippocampus to suppress release of CRF 2. Discuss the activation of steroid hormone receptors and differentiate between genomic and non-genomic effects of glucocorticoids  hGRα&γ receptors in cytoplasm in complex with proteins o free glucocorticoid diffuses across cell membranebind glucocorticoid receptorfree it from complexactively transported into nucleusbind GREs (glucocorticoid-response elements) in promoter regions of responsive genes o regulates transcription of target genes  genomic effects: slow effects (mins to hours) related to expression of proteins o ligand-bound receptor interacts with other transcription factors to act on non-GRE-containing promoters to regulate transcription of genes  non-genomic effects: fast effects (sec to few minutes) – too fast to be mediated by protein synthesis o resistant to hGR & hMR inhibitors b/c don’t need to activate these receptors – don’t involve protein synthesis o –related to actions on neurons and affect behaviours o mechanism: activate kinase pathways increase voltage gated Ca channel activity in neurondecrease Ca influx 3. Discuss specific physiological actions mediated by activation of glucocorticoid and mineralcorticoid receptors  Effects of hGR activation: o fasting state- stimulate gluconeogenesis and glycogen synthesis o stimulate release of αα in muscle breakdown o insulin release – increase serum glucose levels and inhibit uptake of glucose by muscle cells o increase serum fats by lipolysis of hormone-sensitive lipase o fat deposition – increased insulin stimulates lipogenesis  Corticosteroid anti-inflammatory/immunosuppressive effects o ↓ concentration, distribution, function of peripheral leukocytes from vascular bed back to lymphoid tissue o ↓ resp0onse to Ag by inhibiting function of macrophages & other APC o ↓ synthesis and release of inflammatory mediators o ↓ COX-2 o ↓ histamine released by suppressing mast cell degranulation o large doses ↓ Ab production  actions of glucocorticoids o maintain enough glucose supply for brain during fasting o SE: decrease muscle mass, induce weakness, thin skin, osteoporosis, reduce growth in kids  cortisol (hydrocortisone) = major glucocorticoid o cortisone = inactive, activated to cortisol by type 1 β-hydroxysteroid dehydrogenase (β-HD)  mineralcorticoid action: o salt-retaining: angiotensin controls secretion of Aldosteron (major salt retaining hormone) o cells involved in mineralcorticoid effects have type 2 β-HDnegatively feedback by converting cortisol back into cortisone 4. Describe the pathophysiology of Addison’s and Cushing’s diseases and their treatments a. low cortisol: depression, impaired renal function, inability to excrete water normally Addison’s  chronic adrenocortical insufficiency  cause: adrenal cortex unable to make gluc- and mineralcorticoids  symptoms: weak, fatigue, weight loss, hypotension, hyperpigmentation (b/c ACTH level increase), inability to maintain blood glucose level during fasting  minor trauma, pain or infection can cause acute adrenal insufficiency (fluid & electrolyte abnormalities, medical emergency) circulatory shock or death  treatment: 20-30 mg hydrocortisone daily (b/c 20mg is body’s normal production of cortisol), increased during stress + supplement mineralcorticoid b. high cortisol: insomnia & euphora (initially)depression, maybe increase intracranial pressure, associated with peptic ulcers, increase visceral, facial, nuchal, and supreclavicular fat (moon face), increase # platelets and RBC i. chronic elevation: suppress pituitary release of ACTH, growth hormone, thyroid-stimulating hormone, luteinizing hormone Cushing’s  cause: o exogenous – taking large doses of glucocorticoids o endogenous  ACTH-secreting pituitary adenoma (a benign tumour)  ectopic ACTH production by tumours or local changes in function of the adrenal gland  symptoms: moon f
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