PCOL- Manor- Notes - Module 4 Phle PDF

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!!!!PHARMACOLOGY! study of drugs! articles used in the prevention, diagnosis, mitigation, treatment and cure of diseases in men and other animals! - Division :! ! a. Pharmacodynamics! ! b. Pharmacokinetics! ! c. Pharmacotherapeutics - study of! ! rational use of drugs in the!! ! management of diseas...

Description

Module 4 Pharmacology 3. Antimitotics (Chemo Drugs)! ! a. Taxanes! • Paclitaxel! • Docetaxel! ! • Cabazitaxel! ! b. Vinca Alkaloids! • Vincristine! • Vinblastine! • Vinorelbine! • Vindesine! ! c. Estramastine!

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! !Basic Principles of Pharmacology !

PHARMACOLOGY! • study of drugs! • articles used in the prevention, diagnosis, mitigation, treatment and cure of diseases in men and other animals! • Division :! ! a. Pharmacodynamics ! ! b. Pharmacokinetics! ! c. Pharmacotherapeutics - study of ! ! rational use of drugs in the ! ! ! management of diseases.!

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B. Regulatory Proteins! • regulate cell activity or function! ! CHANNELS (Voltage-gated)! • conduct changes in electrical signals! • present in all cells!

! ! studyPHARMACODYNAMICS of physiologic and biochemical effects •

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Cells at rest are (-) or polarized, once excited, cell becomes less negative or (+) it will become depolarized and repolarizes (-) to reach equilibrium! Hyperpolarization of cells renders the cell more negative (-) or less excitable!

of drugs in living systems and the mechanisms by which these are produces!

TYPES OF MECHANISM OF DRUG ACTION! I. Target Protein Mediated! • biologic site of action, “action site” or “active site”! target a physiologic protein! •

Dominant anions/cations:! PISO (K, Na)! MICO (Mg, Ca)! PIChO (PO4-, Cl-)!

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A. Structural Proteins! ex. microtubules - made of alpha and beta units of tubulin. ! function: keep organelles in place (in eukaryotic cells)! ! chemotaxis - cell movement via chemical stimulus! ! axonal release of neurotransmitters! ! mitosis/cell division (metaphase)!

Importances of Ions:! Na, Cl - for tonicity! Ca - structural component in bones, muscle contraction, release of neurotransmitters from the pre-synapse! Mg or MgSO4 (Epsom salt) - natural CCB, used for eclampsia (IV/IM: anticonvulsant, PO: cathartic) competes with Ca at binding sites

! DRUGS THAT INHIBIT MICROTUBULES! !1. Griseofulvin !

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• • • • •

1. Voltage-gated Na-channels! ! Inhibitors: !

antifungal! management of dermatomycosis 1! arrest fungal mitosis! enzyme inducer! increased absorption with fatty food!

2. Colchicine! • 1st line for acute gout and acute gouty attcks! • inhibits chemotaxis of immune cells that causes inflammation!

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infection of skin and appendages

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• Class IA - prolong action potential (AP)! • Class IB - shorten AP! • Class IC - no effect on AP!

• exception: Aripiprazole which is an atypical antipsychotic!

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1. Eicosanoid Pathway:! • Phospholipase A2 (PLA2)! • Inhibitors: corticosteroids (eg. Prednisone)! • Cyclooxygenase (COX)! • 5-lipoxygenase (5-LOX)! • Inhibitor: Zileuton (anti-asthma)!

• Ester-containg : short acting! • Amide-containg : long acting!

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• Some anti-convulsants! Phenytoin! Carbamazepine!

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!2. Voltage-gated K-channels!

Phospholipids - precursor for Arachidonic acid, in turn giving Prostaglandin and Leukotriene (eicosanoids) with the action of COX and LOX respectively! Prostaglandin - cytoprotection, pain and inflammation! Leukotrienes - bronchoconstriction

• Class III Antiarrhythmics (Amiodarone)! • Insulin Secretagogues (Sulfonylureas: Glimeperide)!

!3. Calcium-Channel Blockers

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(CCB)!

• Dihydropyridines “-dipines” (eg. Nicardipine) - vasoselective (arteries)! • Non-DHP class IV antiarrhythmics ! • Verapamil - cardioselective tx for arrhythmia ! • Diltiazem - heart and blood vessels (intermediate effect)! • contraindicated sa px with heart failure 2!

Cyclooxygenase (COX) - lahat daw ng NSAID COX-inhibitor! ! Inhibitor:! ! NSAIDS! • ASA (Aspirin)! • Ibuprofen! • Naproxen! 3. Angiotensin Converting Enzyme (ACE)! • aka “Kinase II” or “dipeptidyl decarboxypeptidase”! ! Inhibitor:! • ACE-inhibitors “-prils”!

CARRIER MOLECULES! • cell membrane proteins with specific binding sites that undergo conformational change! 1. • • • ! !

ENZMYES!

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!4. Monoamine Oxidase (MAO A, MAO B)!

Na/K-ATPase Pump! found in the cardiac myocytes! responsible for Ca extrusion! activation of NCX is dependent on NKAP activation! Inhibitor:! Cardiac Glycosides! • Digoxin (from Digitalis lanata) inotropic! • Digitoxin (from D. purpurea)!

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Inhibitors:!

!2. H/K-ATPase Pump or Proton Pump!

• mediates release of gastric acid! • ACh, gastrin, histamine in the parietal cells of the stomach (triggers the release of HCl)! ! Inhibitor:! ! Proton Pump Inhibitor (PPI)! • “-prazoles” eg. Omeprazole! • most effective during hyperacidity! 2

inefficient force of contraction of the heart

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aka serotonin

• MAO A - metabolizes, NE, EPI, 5-HT 3! • MAO B - metabolizes dopamine! • Clinical Depression - serotonin and norepinephrine are deficient! • Parkinsonism - low dopamine!

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5. Catechol-O-methyltransferase (COMT)! ! Inhibitors:! • COMTIs “-capones”! • Tolcapone! • Entacapone!

! I.

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Serotonin blockers: -setron (Ondansetron) tx for cancer-induced nausea!

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2. Type II or Metabotropic Receptors! • G-protein linked, coupled receptors! • 7-transmembrane spanning receptors! • location: cell membrane! • increase or decrease of secondary messengers! • onset: secs!

Drug-Target Protein Mediated Mechanism of Action!

RECEPTORS! • functional macromolecular cell components with specific stereochemical configuration with which a ligand interacts, usually in a lock and key fashion!

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1. Type I or Ionotropic Receptors! • associated with ion channels (ligandgated ion channels)! • location: cell membrane! • onset: ms! GABA receptor complex - associated with Cl- channels! ! receptors! GABA A receptor! • Stimulators: BZDs, Barbiurates! • Barbiturates prolongs duration of Cl • channel opening! • C Benzodiazepenes - increases the frequency of Cl channel opening !

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Secondary Messengers:! a. cAMP (cyclic adenosine monophosphate)! b. cGMP (cyclic guanosine monophosphate)! • aforementioned secondary messengers utilizes same signalling cascades.! • intestinal mucosa & blood vessels! c. IP3 (inositol triphosphate)! d. DAG (diacylglycerol)!

! ! ! ! ! ! ! Nicotinic Receptors - associated with Na-

Barbiturates and benzodiazepenes enhances GABAa receptor binding with GABA. Hence, opening of Cl channels, influx of Cl, resulting to hyperpolarization of the cell. (CNS Depression)

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Types of G-proteins:! a. Gs - stimulates adenylyl cyaclase (AC)! • ex. Beta-receptors! • stimulators: Epi, NE! • Blockers: Beta-blockers (-olols)! b. Gi - inhibits adenylyl cyclase (decrease cAMP)! • ex. Pre-synaptic Alpha2 receptors! • stimulators: Clonidine, Methyldopa, Guanfacine, Guanabenz! ex M2 receptors! • c. Gq - stimulates Phospholipase C (PLC)! • PLC stimulates the formation of IP3 & DAG from PIP2. (increased intracellular Calcium ions = contraction)! • ex. Alpha1! • blockers: -zosin (Alprazosin)! • ex. M1, M3! • ex. Post-aynaptic Alpha2!

channels! • Nn (neural/neuronal)! • Nm (neuromuscular) - skeletal m. ! ! Stimulators:! • Nicotine! • Lobeline! • Varenicline! ! Inhibitors:! • Nm blockers (skeletal muscle relaxants):! • Tubocurarine! • Succinlycholine! • Atracurium “-curium”! • Pancuronium! • Rocuronium “-curonium”!

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Glycine blocker: strychnine!

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“KISS KICK” Gq Gi Gs Gs (alpha and beta), Gq Gi ! Gq (M-receptors)!

• Chelating Agents ! ! ex. British Anti-Lewisite (BAL) or dimercaprol (IM) for Hg & As toxicity (peanut oil as vehicle)! • Penicillamine (Cuprimine) for Cu Wison’s disease! Deferoxamine (Desferal) for Fe ! •

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In what body fluid is prostaglandin derived?! Answer: Semen

3. Type III or Enzyme-linked Receptors! • location: cell membrane! • insulin receptor - tyrosine kinase linked! • onset: minutes! • effects: stimulation of glucokinase (glycolysis)! • translocation of glucose transporters (GLUT2, GLUT4) into the cell membrane! • ex. Insulin receptors, Platelet-derived Growth factor, epidermal growth factor!

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C. Counterfeit or Incorporation Mechanism! • ex: Antimetabolites! • purine and pyrimadine base analogues (also used as anti-cancer drugs)! • e.g. 5-fluorouracil!

! ! ! DRUG-RECEPTOR !I. Characteristics!INTERACTION

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! Affinity - ability to bind to receptor! ! Intrinsic activity - ability of a ligand to evoke an active response.constitutive activity/ effect; (+)effect even in the absence of ligand!

4. Type IV / Gene Transcription-linked Receptor / Nuclear Receptors / Intracellular Receptor (DNA to RNA)! • location: intracellular (cytoplasm, nucleus)! onset: hours! • modulate gene transcription! • DRUGS: sex hormones, thyroid • hormones, Vit D, steroidal hormones (corticosteroids)! ! II. Non-Target Protein Mediated Mechanism!

!II. Types of Ligands!

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A. Colligative Mechanism / Mass Effect! • Colligative properties - dependent on the number of solute particles! ! ex. VP lowering, BP elevation, FP ! ! depression, Osmotic pressure!

A. Agonist - has affinity and intrinsic ! activity [increase intrinsic activity (IA)]! B. Antagonist - no effect on IA! C. Inverse Agonist - decrease IA!

!Mannitol - osmotic diuretic/aquaretic!

MOA (IV Infusion): inhibits water reabsorption in the water permeable regions in the renal tubules (descending limb of loop of Henle) by increasing the osmotic pressure.! MOA (PO) : osmotic diarrhetic!

III. Types of Agonist! ! A. Full Agonist - produces all of the effects of receptor (ex. Morphine - mu receptor) IA=1! ! B. Partial Agonist - produces some of the effects of the receptor; has a mixed agonist and antagonist action. (IA > 0 but < 1)! ! ex. Nalbuphine - mixed agonistantagonist; acts as a full antagonist in the presence of a full agonist (morphine)! ! Tamoxifen - management of estrogen receptor in breast CA; partial agonist

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B. Chemical Antagonism / Direct Chamical Interaction! • Local Antacids - neutralization reaction! ! ex. Mg(OH)2, Al(OH)3! • Systemic Antacids - NaHCO3 for metabolic acidosis! • Protamine sulfate for heparin toxicity (neutralization din yielding ionized 4 heparin)!

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when a drug is ionized, it is rather excreted than absorbed

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Based on the Type of Interaction! 1. Reversible Antagonism! • temporary (duration of interaction stomach! The small intestine’s surface area is 120 sq. m making it the main site of drug absorption. The small intestine has vili & microvilli that increases its SA.

4. Degree of Perfusion ! ! SI > stomach! • local anesthetics / vasoconstrictors (epinephrine)! • to minimize systemic absorption! • to minimize systemic toxicity! • prolong duration of action of local ones! • minimize bleeding! 5. Gastric Emptying Time (GET) - time ! it takes the stomach to empty ! its contents into the small ! ! intestine! normal: 2-3 hours! • Faster emptying, faster absorption, • lower GET.! • you need gastric emptying because the stomach has a small surface area, degree of perfusion and thick mucous membrane making it inefficient for absorbing drugs! !

Factors increasing GET (slower absorption)! • high fat / protein meal, heavy meal! • stress! • strenuous exercise (heavy)! • gastric ulcers! • lying on the left side! • drugs decreasing GI motility ! • (anticholiner gics, opioids, m or phine, nalbuphine)!

!! ! ! ! ! ! !! ! ! ! ! ! ! ! ! !Bioequivalence is the similarity of BA of

2. Regional Blood Flow - fraction of the cardiac output that reaches a specific organ or tissue (direct with D.)! • 100% lungs! • 25% liver! • 25% kidney! • 5 mcg/kg/min: A1 activation! • Uses:! • management of Septic Shock! • management of cardiogenic shock! • management of AHF 8, complicated by oliguria or anuria!

III. Centrally Acting! • CNS! • Habit-forming!

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DIRECT ACTING! • Non-selective - stimulate more than one type of receptor (alpha, beta, dopa)! • Selective - stimulate only one type of receptor !

! Non-Selective (alpha, beta, dopamine)! !1. Natural Catecholamines - NE, Epi, DA! !Pharmacodynamics:!

! ! ! ! !Adverse Effects:!

Oliguria: < 500 mL/day! Anuria: < 50 mL/day!

• higher affinity at Beta Receptors than Alpha (mas madikit sa beta kesa alpha)! • low dose: Beta effect! • high dose: alpha effect may manifest! • Epinephrine: B1 = B2 > A1! • Norepinephrine: B1 > A1! • Dopamine: D1 > B1 > A1!

• Alpha1 Overstimulation: digital necrosis! • Beta1 Overstimulation: tachyarrhythmias!

! Selective (alpha, or beta, or dopa)! !

1. Non-selective B Agonist ! • ex. Isoproterenol/Isoprenaline! • uses: ! • alternative during shock states! • management of AHF (pwedeng Beta1 agonist)! • historically used for the management of bronchial asthma (can cause tachyphylaxis 9 leading to ventricular tachyarrhythmias)!

!Pharmacokinetics:!

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• undergo extensive first pass effect (decreased oral BA)! • Routes: IV, SQ, inhalation! • Metabolism by MAO & COMT: (degradation products)! • NE & Epi! • 3-methoxy-4-hydroxy-mandelic acid! • aka vanillyl mandelic acid (VMA)!

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2. Beta1-selective Agonist ! • cardioselective! • eg. Dobutamine! • uses:! • 1st line for cardiogenic shock! • management of AHF ([+]inotrope)! • pharmacologic stress test!

• Dopamine! • Homovanillic acid!

!Clinical Uses:!

a. Epinephrine or Adrenaline! • 1st line cardiac stimulant! • 1st line for anaphylaxis & anaphylactic shock! • local vasocinstrictor! 8

acute heart failure

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rapid development of tolerance to B2 effects

• management of glaucoma (Dipivefrin: pivalic ester of Epi)!

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3. Beta2-selective Agonist! • SABA (short-acting beta agonists)! • Albuterol/Salbutamol! • Terbutaline!

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5. Alpha2-selective Agonists! • Clonidine! • Methyldopa! • Guanfacine! • Guanabenz! • effect: autoregulation!

• LABA (long-acting)! • Salmeterol - slow onset of action! • Formoterol - fast onset of action! • Bambuterol! • Indacaterol!

!Clonidine:!

• Phases of Effects:! • Initial: Vasoconstriction (post-synaptic alpha2 activation), transient! • Final: Vasodilation (pre-synaptic), lasting effect! • uses:! • alternative for HTN! • alternative for ADHD! • management of Clonidine withdrawal induced HTN (alt. Captopril, Labetelol)!

• Tocolytics! • Ritodrine! • Isoxsuprine - most common! • Terbutaline (SQ) - off-label! • Uses:! • management of bronchial asthma & COPD! • management of pre-term labor! • adjuncts in the management of hyperkalemia (hypokalemic kasi ang B2)! Terbutaline - used in the management • of symptomatic bradycardia, promotes (+) chronotropic effect, enhances baroreceptive reflex (increase sympathetic tone)!

!Methyldopa:!

4. Alpha1-selective Agonists! • Phenylephrine (decongestant)! • Methoxamine! • Propyhexedrine! • Tetrahydrozoline! • Oxymerazoline! • Nafazoline! • Uses:! • management of hypotension! • management of nasal congestion! • local vasocinstrictors! • Adverse Effects (local intranasal)! • rhinitis medicamentosa - rebound congestion (remedy: do not use decongestant for more than 3 days)! Adverse Effects (systemic)! • exacerbation of hypertension! • urinary retention (BPH 10 px)! • tolerance (increases the risk of toxicity) • remedy: use A1 agonist for nmt 5 days!

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6. D1-selective Agonist! • Fenoldopam! • use: hypertension crisis!

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INDIRECT ACTING! a. Releasers! • Tyramine, Ephedrine*, Amphetamine! b. Reuptake Inhibitors! • TCAs, COCaine, Reboxetine!

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• prodrug! • alpha-methynorepinephrine! • false neurotransmitter! • alpha-2 agonist! use: management of hypertension in • pregnancy! • AE:! • sedation (most common)! • hepatotoxicity! • (+) Coomb’s test (hemolytic anemia)!

benign prostatic hyperplasia

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*Ephedrine has mixed action. DIrectly activates alpha, beta and dopamine receptors. Indirectly it increases the releases of norepinephrine from the presynapse.

Ephedrine! • management of hypotension! • local vasoconstriction! • Management of bronchial asthma! • Ephedra sinica (Ma Huang)! • S/E! • Exacerbation of HTN! • Urinary retention (BPH px)! • Ventricular tachyarrhythmias!

Pheochromocytoma! • tumor/hyperplasia in adrenal medulla due (causes hypersecretion of Epi < NE)! SSX:! • • agitation! • confusion! • tachycardia! • palpitation! • paroxysmal HTN! • Dx:! • VMA Assay (Vanillymandelic Acid) in serum/urine! • Imaging Studies (MRI, CT)! • Treatment:! • initial control: alpha, beta blockers! • surgical incision!

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CENTRALLY ACTING! • Phentermine, Phenmetrzine, Phenylpropanolamine (PPA), AMphetamine, Methylphenidate! • Uses:! • management of ADHD! • 1st line: Methylphenidate! • alt. : Amphetamine! • Anorexiants! • phentermine, phenmetrazine, PPA! • management of narcolepsy (Phentermine)! • S/E! • increased risk of addiction! • PPA - increases risk of hemorrhagic stroke! • Phentermine - increases risk of pulmonary hypertension!

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Carcinoid’s Syndrome! • neuroendocrine condition associated with malignancy affecting enterochromaffin cells (secretes 90% of 5-HT)!

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Raynaud’s Syndrome! • digital vasopressin in response to stress/cold environment (vasoconstriction causes necrosis)! Treatment: CCBs! •

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SYMPATHOLYTICS / ADRENERGIC ANTAGONISTS

Side Effects Associated with AlphaBlockers! • First dose Phenomenon! • selective alpha-1 blocker! • orthostatic hypotension & syncope ! • Triggers:! • initial dose! • big dose! • use of another anti-HTN! • Remedies:! • give 1st dose at bedtime! • give 1/2 or 1/4 of usual dose!

ALPHA BLOCKERS! a. Non-selective ! • Phenoxybenzamine - irreversible (antihistamine)! • Phentolamine - reversible! b. Selective!

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BETA BLOCKERS! a. Selective B-1 Blockers! • cardioselective B-blockers! • less likely to cause bronchospasm! • BEAM!! • Bisoprolol, Betaxolol! • Esmolol (shortest t1/2, given IV)! • Atenolol, Acebutolol! • Metoprolol! • Celiprolol!

• Clinical uses:! • management of hypertension (secondary to pheochromocytoma), nonselective, selective A1! in patients with BPH (selective A1)! • management of carcinoid syndrome • (phenoxybenzamine DOC)! • management of Raynaud’s syndrome (nonselective, selective A1)!

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• Nebivolol! • most cardioselective! • vasodilator! • increases NO or EDRF 11! • 1st line for HTN in px with hx of MI! • Management of Angina Pectoris! • management of stable heart failure (bisprolol, metoprolol, carvedilol)! • management of arrhythmia (Class II)! • management of glaucome (timolol, betaxolol)! • management of sympathetic symptoms of hyperthyroidism (Propranolol - inhibit the peripheral conversion of T4 to T3 [deiodination] enzyme: 5-deiodinase)! • anaphylaxis of migraine headache! • management of stage fright (Propranolol)! • AE:! • bradycardia, ...