Exam 4 - All NEW drugs

Pediatric Concerns of Dextromethorphan

"Dexing", "Robodosing", "Robotripping" "Going pharming" -Estimated 1,000,000 aged 12-25 misuse dextromethorphan products each year -Estimated nonmedical misuse results in 6000 visits to emergency department each year (co-ingestion with ethanol common) -Inhibit NMDA receptors similar to ketamine and PCP -->Hallucinations, "out of body" sensation, dissociation -Higher doses -->Tachycardia, hypertension, diaphoresis

Milrinone

(Same as Inamrinone) *CLASS:* Phosphodiesterase inhibitors *MECHANISM OF ACTION:* -*Inhibit phosphodiesterase type 3 --> Increase cAMP* -*Increase contractility, vasodilation in venous and arterial circulation* *INDICATION:* -Short term management of severe heart failure *ADVERSE:* -Thrombocytopenia -*very arrhythmogenic* = *'Killrinone'* *PK:* *Route:* IV

Tolterodine

*CLASS:* Antimuscarinic *MECHANISM OF ACTION:* -Antimuscarinc with no apparent selectivity for different muscarinic receptor subtypes; however therapeutically seems to act somewhat selectively in bladder to decrease detrusor muscle contraction and increase bladder capacity *INDICATION:* -Overactive bladder *ADVERSE:* -Still causes typical anticholinergic effects, but incidence significantly lower than with previous antimuscarinic drugs

Dextromethorphan

*CLASS:* Antitussives *MECHANISM OF ACTION:* -*D-isomer of codeine analog methorphan but no activity at opioid receptors* -*NMDA receptor antagonist but also binds at other undetermined sites* *INDICATION:* -*Antitussive* *ADVERSE:* -Relatively safe drug at prescribed dosage -*At high doses (>2mg/kg): tachycardia, agitation, psychosis, seizure, ataxia, coma* -*FDA Recommendation: Use be prohibited in children younger than 6 years old* --Inhibit NMDA receptors similar to ketamine and PCP-->Hallucinations, "out of body" sensation, dissociation -Higher doses-->Tachycardia, hypertension, diaphoresis [See next slide]

Procainamide

*CLASS:* Anttiarrhythmics - Class Ia *MECHANISM OF ACTION:* -Block fast Na+ channels that open during phase 0 depolarization -Make threshold potential less negative (more difficult to reach threshold), and decrease slope of phase 4 depolarization (takes longer to reach threshold) -*The Na+ channel blockers bind when the Na+ channel is in the OPEN or INACTIVATED state. The drugs dissociate ('unbind') when the channel reverts to the RESTED state* -Slow conduction and create conditions favorable for conduction block -*Suppress abnormal automaticity*-decrease automaticity in Purkinje fibers (and decreased abnormal automaticity in atrial and ventricular myocytes) *Class Ia* -Intermediate Dissociation Rate -Moderate Blockage -Prolonged Repolarization *Other Effects:* - Slows conduction by decreasing slope of depolarization - ↑ AP length and ERF (effective refractory period) by blocking K+ channels. - Has anticholinergic effects: increases A-V conduction speed [Ach turns off SNS by reducing cAMP and opening K+ channels] *ANS:* muscarinic receptor blockade (but less than quinidine) *INDICATION:* -Supraventricular and ventricular arrhythmias -When treating atrial fibrillation/flutter combine w/ beta blockers or CCBs to abrogarte the anticholinergic effects of class Ia agents on AV conduction *ADVERSE:* -Nausea, vomiting -Hypersensitivity reactions -Lupus-like autoimmune syndrome -Proarrhythmia -torsade de pointes (caused by metabolite -NAPA) *PK:* *Route:* Oral or IV *Metabolism: hepatic, renal -Acetylated to N-acetyl procainamide (NAPA). *NAPA blocks K+ channels so it has class III drug properties* *Half-life:* 3-4 hours

Nifedipine

*CLASS:* Calcium channel blockers- Type II *MECHANISM OF ACTION:* -Improve oxygen delivery to ischemic myocardium by vasodilating coronary arteries -Reduce myocardial oxygen consumption by reducing afterload -Reduce myocardial oxygen consumption by reducing heart rate (increased time spent in diastole) and contractility -Decrease: PVR and increase HR (baroreceptor reflex) -No effect on SA node, AV node, Contractility *INDICATION:* -Treatment of ischemic heart disease *ADVERSE:* -Problems in ~20% of patients: -*Major:* Hypotension, Headache, Peripheral edema

Dobutamine

*CLASS:* Sympathomimetic amines *MECHANISM OF ACTION:* -Agonist at both beta1 and beta2 receptors -*Improve cardiac contractility and relaxation* *INDICATION:* -Short term management of severe heart failure (hypotension, renal failure) *ADVERSE:* -Increase heart rate -Arrhythmogenic *CONTRAINDICATION:* -Don't take with MAO-Inhibitor *PK:* *Route:* IV Only *Metabolism:* MAO/COMT *Half-life:* 2 mins

Timolol

*Class:* *Beta Blockers* *Mechanism of Action:* -Non-selective beta blocker -Decreases aqueous humor production in eye thus reducing intraocular pressure *Indications:* -Glaucoma (topical) -Hypertension -Angina (systemic) *Adverse:* -Sufficient doses can be absorbed from eye to cause serious adverse effects on heart and airways in susceptible individuals (e.g. patients with asthma, cardiac pacemaker, conduction pathway disease).

Neural Control of Vascular Smooth Muscle

*Excitatory:* -Sympathetic NS (NE through alpha receptor) *Inhibitory* -NO -VIP (vasoactive intestinal polypeptide)

Type II Calcium channel blockers

*Predominantly vascular effects* (good for vasodilation) -Nifedipine

Classification of antiarrhythmic drugs

*Vaughan Williams Classification* *Classified according what they predominantly block:* -Class I: Sodium channels -Class II: Beta adrenoreceptors -Class III: Potassium channels -Class IV: Calcium channels

Beta-adrenergic receptor blockers -Metoprolol

-Act on cardiac muscle cells

Organic nitrates

-Nitroglycerin -Isosorbide Dinitrate

Aldosterone Receptor Antagonists

-Spironolactone -Eplerenone

Conditions needed for Reentry (2)

1) Unidirectional conduction through a region [There must be one-way conduction through certain regions of the heart otherwise the excitation could not loop back] 2) Slow conduction through that region of damage (conduction of the right speed) - the conduction velocity must be slow so that by the time the excitation loops back the aberrant pacemaking cell is repolarized (therefore the time it takes for excitation to be conducted must be longer than the refractory time of that first cell

Catecholamines and Congestive Heart Failure

1. SHORT TERM = ENHANCE CONTRACTILITY: adaptive 2. LONG TERM = TOXIC TO MYOCARDIUM: acceleration of CHF

Angiotensin converting enzyme (ACE) inhibitors

Captopril Enalapril Lisinopril

Inotropic Drugs

DIGOXIN DOBUTAMINE INAMRINONE MILRINONE

Drugs Affecting Preload

NITROGLYCERIN ISOSORBIDE DINITRATE SPIRONOLACTONE EPLERENONE

Drugs Affecting Preload and Afterload

NITROPRUSSIDE PRAZOSIN CAPTORPIL ENALAPRIL LISINOPRIL VALSARTAN LOSARTAN

Montelukast

Same as: Zafirlukast *CLASS:* Leukotriene Receptor Antagonism *MECHANISM OF ACTION:* -Prevents actions of cysteinyl leukotrienes (LTC4, LTD4, LTE4) at CycLT1 receptors *INDICATION:* -Prophylactic treatment of mild asthma *ADVERSE:* -Minimal side effects -Rare inflammatory condition including: pulmonary infiltrates, neuropathy, skin rashes, vasculitis *PK:* *Route:* Oral

Long-term blockade of receptors is likely to cause... ?

Up-regulation and/ or sensitization *Simple Solution:* -When withdrawing patient from a drug, TAPER THE DOSE

Angiotensin II AT1 receptor blockers (ARBs)

Valsartan Losartan

Inamrinone

(Same as Milrinone) *CLASS:* Phosphodiesterase inhibitors *MECHANISM OF ACTION:* -*Inhibit phosphodiesterase type 3 --> Increase cAMP* -*Increase contractility, vasodilation in venous and arterial circulation* *INDICATION:* -Short term management of severe heart failure *ADVERSE:* -Thrombocytopenia -*very arrhythmogenic* = *'Killrinone'* *PK:* *Route:* IV

Type I Calcium channel blockers

*"Balanced" myocardial, electrophysiologic and vascular effects* (target cardiac and nodal cells) -Verapamil -Diltiazem

Beta blocker withdrawal syndrome

*-Long-term treatment with a beta receptor antagonist ("beta blocker") increases cardiac beta adrenergic receptor density* -Subjects who had recently stopped using beta-blockers had a *transient fourfold increase in the relative risk of coronary heart disease* *-A withdrawal syndrome immediately following the cessation of beta-blocker use may be an acute precipitant of angina and myocardial infarction in hypertensive patients who have no prior history of coronary heart disease.* Rebound: Ceasing use of propranolol can increase HR (even though propranolol itself decreases exercise induced HR) *Simple Solution:* -When withdrawing patient from a drug, TAPER THE DOSE

Class II Antiarrhythmics

*Block Beta-adrenergic receptors* -Propranolol -Metroprolol *Rationale for Use:* -Sympathetic activity may contribute to many forms of arrhythmia *MECHANISM OF ACTION:* Beta blockade (magnitude dependent on level of sympathetic tone): (think of actions of PKA being blocked) -Decrease rate of phase 4 depolarization in automatic cells (decreased heart rate and ectopic automaticity) -Slow conduction through AV node (blocks SNS enhancement of slow Ca++ channel activity) enhance AV block -Reduce myocardial contractility and oxygen demand (PKA phosphorylates Ca++ channels and activates them - beta-blockade prevents this) *INDICATIONS:* -Supraventricular tachyarrhythmias which use the AV node as one of the reentrant pathways -Atrial and ventricular arrhythmias -Ventricular arrhythmias associated with long-QT syndrome -Prevention of sudden cardiac death in post-MI patients

Two physiological strategies to treating Asthma

*Bronchodilation* -Beta2 Receptor Agonists -Methylxanthines -Muscarinic Antagonists -Leukotriene antagonism *Reduce Inflammation* -Glucocorticoids -Inhibit mast cell degranulation -Leukotriene antagonism -Anti-IgE antibody

Zileuton

*CLASS:* 5-Lipoxygenase Inhibitor *MECHANISM OF ACTION:* -*Inhibits formation of all 5-lipoxygenase products including leukotrienes [inhibits 5-lipoxygenase* -Although this drug has a wider profile of inhibition then cys-LT receptor blockers it is not significantly more efficacious *INDICATION:* -Prophylactic treatment of mild asthma *ADVERSE:* -Minimal side effects -Rare elevated liver enzymes *CONTRAINDICATIONS:* -Preexisting liver disease *PK:* *Route:* Oral

Eplerenone

*CLASS:* Aldosterone Receptor Antagonists *MECHANISM OF ACTION:* -Reduce plasma volume and alter electrolyte excretion -The beneficial effects of aldosterone receptor blockers in chronic heart failure most likely result from their anti-fibrotic and anti-arrhythmic properties *INDICATION:* - Currently used in combination with other therapies (ACE inhibitors) to treat moderate to severe CHF *ADVERSE:* -Hyperkalemia *ADVANTAGES:* -Less or no endocrine-related side effects, alternative if spironolactone intolerance *PK:*

Spironolactone

*CLASS:* Aldosterone Receptor Antagonists *MECHANISM OF ACTION:* -Reduce plasma volume and alter electrolyte excretion -The beneficial effects of aldosterone receptor blockers in chronic heart failure most likely result from their anti-fibrotic and anti-arrhythmic properties *INDICATION:* - Currently used in combination with other therapies (ACE inhibitors) to treat moderate to severe CHF *ADVERSE:* -Hyperkalemia -Gynecomastia -Impotence -Menstrual irregularities *PK:*

Tamsulosin

*CLASS:* Alpha1-Selective Antagonists *MECHANISM OF ACTION:* -*Relatively selective effect on urinary flow (block Alpha1A receptors)* -Alpha1 antagonist acting to relax smooth muscle of bladder neck, prostate capsule, prostatic urethra to decrease bladder outlet obstruction associated with benign prostatic hyperplasia *INDICATION:* -BPH (benign prostatic hyperplasia) *ADVERSE:* -Higher incidence of impaired ejaculation than with Prazosin or Terazosin *ADVANTAGE:* -Treats BPH with lower incidence of orthostatic hypotension than Prazosin or Terazosin

Terazosin

*CLASS:* Alpha1-Selective Antagonists *MECHANISM OF ACTION:* -Competitive antagonists selective for alpha1 receptors -Decreased TPR (total peripheral resistance) and reduction of sympathetically-mediated stimulation *INDICATION:* -Hypertension -BPH (benign prostatic hyperplasia) -Raynaud's Syndome *ADVERSE:* -"First dose phenomenon" - hypotension and/or syncope when first start using these drugs (sometimes patients are told to first using these drugs at night)

Prazosin

*CLASS:* Alpha1-Selective Antagonists *MECHANISM OF ACTION:* -Competitive antagonists selective for alpha1 receptors -Decreased TPR (total peripheral resistance) and reduction of sympathetically-mediated stimulation of smooth muscle -Decreases preload and afterload *INDICATION:* -Hypertension -Congestive heart failure *Note:* Decreases preload and afterload BUT does not effect RAAS, so it does not block LVH, cardiac remodeling, apoptosis; THEREFORE it is not first-line therapy for CHF -BPH (benign prostatic hyperplasia) -Raynaud's Syndome *ADVERSE:* -"First dose phenomenon" - hypotension and/or syncope when first start using these drugs (sometimes patients are told to first using these drugs at night)

Losartan

*CLASS:* Angiotensin II AT1 receptor blockers (ARBs) *MECHANISM OF ACTION:* -All adverse biological effects relevant to a failing heart (e.g. apoptosis, hypertrophic growth) involve activation of AT1 receptors *Note:* ACE inhibitors alone do not fully antagonize tissue based RAAS -*ARBs act by binding specific membrane bound receptors that displace angiotensin II from its type 1 receptor subtype (AT1)* -*The ARBs do not inhibit the breakdown of bradykinin* --> therefore are NOT vasodilators *INDICATION:* -*Just as effective as ACE inhibitors in reducing long term mortality and morbidity* *ADVERSE:* -Angioedema (less incidence than with Ace inhibitors) -Dizziness -Increased liver enzymes -*Cough is not a common side effect of ARBs (replacement therapy if ACE inhibitor intolerance)* *PK:* *Half-life:* 6 -9 hrs

Valsartan

*CLASS:* Angiotensin II AT1 receptor blockers (ARBs) *MECHANISM OF ACTION:* -All adverse biological effects relevant to a failing heart (e.g. apoptosis, hypertrophic growth) involve activation of AT1 receptors *Note:* ACE inhibitors alone do not fully antagonize tissue based RAAS -*ARBs act by binding specific membrane bound receptors that displace angiotensin II from its type 1 receptor subtype (AT1)* -*The ARBs do not inhibit the breakdown of bradykinin* --> therefore are NOT vasodilators *INDICATION:* -*Just as effective as ACE inhibitors in reducing long term mortality and morbidity* *ADVERSE:* -Angioedema (less incidence than with Ace inhibitors) -Dizziness -Increased liver enzymes -*Cough is not a common side effect of ARBs (replacement therapy if ACE inhibitor intolerance)* *PK:* *Half-life:* 6 hrs

Enalapril

*CLASS:* Angiotensin converting enzyme (ACE) inhibitors *MECHANISM OF ACTION:* -Inhibit the conversion of angiotensin I to angiotensin II -Increase bradykinin (a vasodilator) - decrease its degradation by ACE *Effects:* -Vasodilation (reduced pre- and afterload) -Decreased aldosterone levels -Decreased sympathetic activity -Reduced interstitial fibrosis -Reduced myocardial (hypertrophy, dilatation) and vascular remodeling (smooth muscle proliferation) -Anti-apoptotic (Reverse the bad things that occur with chronic stimulation of RAAS) *INDICATION:* -*ACE inhibition is considered mandatory treatment of chronic heart failure* -Studies show CHF patients on ACE inhibitors have significant less mortality than those on vasodilators alone *ADVERSE:* -Hypotension -*Hyperkalemia* -*Persistent cough → switch to angiotensin II AT1 receptor-blocking agent* (due to bradykinin accumulation)--->Can get angioedema - swelling of larynx and upper airway (can be life threatening) -Fetal pathologies if given in 2nd and 3rd trimesters *ADVANTAGES:* -Less GI effects than captopril -Longer half-life than captopril *PK:* *Route:* Oral *Absorption:* Enalapril, but not enalaprilat is rapidly absorbed when given orally *Metabolism:* Enalapril is a *pro-drug of lisinopril* that must be de-esterified to enalaprilat *Half-life:* 11 hrs - substantially longer than captopril *Excretion:* Renal

Lisinopril

*CLASS:* Angiotensin converting enzyme (ACE) inhibitors *MECHANISM OF ACTION:* -Inhibit the conversion of angiotensin I to angiotensin II -Increase bradykinin (a vasodilator) - decrease its degradation by ACE *Effects:* -Vasodilation (reduced pre- and afterload) -Decreased aldosterone levels -Decreased sympathetic activity -Reduced interstitial fibrosis -Reduced myocardial (hypertrophy, dilatation) and vascular remodeling (smooth muscle proliferation) -Anti-apoptotic (Reverse the bad things that occur with chronic stimulation of RAAS) *INDICATION:* -*ACE inhibition is considered mandatory treatment of chronic heart failure* -Studies show CHF patients on ACE inhibitors have significant less mortality than those on vasodilators alone *ADVERSE:* -Hypotension -*Hyperkalemia* -*Persistent cough → switch to angiotensin II AT1 receptor-blocking agent* (due to bradykinin accumulation)--->Can get angioedema - swelling of larynx and upper airway (can be life threatening) -Fetal pathologies if given in 2nd and 3rd trimesters *PK:* *Route:* Oral *Active as the parent compound*

Captorpil

*CLASS:* Angiotensin converting enzyme (ACE) inhibitors - 1st ACE inhibitor *MECHANISM OF ACTION:* -Inhibit the conversion of angiotensin I to angiotensin II -Increase bradykinin (a vasodilator) - decrease its degradation by ACE *Effects:* -Vasodilation (reduced pre- and afterload) -Decreased aldosterone levels -Decreased sympathetic activity -Reduced interstitial fibrosis -Reduced myocardial (hypertrophy, dilatation) and vascular remodeling (smooth muscle proliferation) -Anti-apoptotic (Reverse the bad things that occur with chronic stimulation of RAAS) *INDICATION:* -*ACE inhibition is considered mandatory treatment of chronic heart failure* -Studies show CHF patients on ACE inhibitors have significant less mortality than those on vasodilators alone *ADVERSE:* -Hypotension -*Hyperkalemia* -*Persistent cough → switch to angiotensin II AT1 receptor-blocking agent* (due to bradykinin accumulation)--->Can get angioedema - swelling of larynx and upper airway (can be life threatening) -Fetal pathologies if given in 2nd and 3rd trimesters *PK:* *Route:* Oral *Metabolism:* Hepatic, renal(50%) *Half-life:* 2 hrs

Omalizumab

*CLASS:* Anti-IgE Antibody *MECHANISM OF ACTION:* -*Binds to Fc domain of IgE (binding site for IgE binding receptor)--> prevents IgE from interacting with receptor* -Reduces airway responsiveness and decreases need for other asthma drugs *INDICATION:* -Management of asthma *ADVERSE:* -Concern for infection -Pain on injection *PK:* *Route:* IV or subcutaneous administration every 2 - 4 weeks

Ipratropium

*CLASS:* Antimuscarinic *MECHANISM OF ACTION:* -Antimuscarinic with receptor activity similar to atropine -Charged: this helps to decrease systemic absorption *INDICATION:* -Treatment of chronic obstructive pulmonary disease (COPD) and occasionally for asthma -->Useful in patients who cannot take B2 agonists (patients taking MAO inhibitors, patients with cardiac arrhythmias, or with unstable angina)* -used for long-term therapy -Combos of ipratropium and albuterol are produced to tx COPD *ADVERSE:* -Few because of poor absorption -Toxic doses may cause hypotension (ganglionic blockade) and muscle weakness (neuromuscular blockade) *PK:* -4x/day

Tiotropium

*CLASS:* Antimuscarinic *MECHANISM OF ACTION:* -Antimuscarinic with receptor activity similar to atropine -Charged: this helps to decrease systemic absorption -New longer acting analog of Ipratropium *INDICATION:* -Treatment of chronic obstructive pulmonary disease (COPD) and occasionally for asthma *ADVERSE:* -Few because of poor absorption -Toxic doses may cause hypotension (ganglionic blockade) and muscle weakness (neuromuscular blockade) *PK:* -Once daily

Guaifenesin

*CLASS:* Antitussive *MECHANISM OF ACTION:* -Irritate gastric mucosa and gastric nerve to stimulate the cough reflex -Stimulate respiratory tract secretions to increase respiratory fluid volumes and decrease mucous viscosity -Aids patient in coughing up mucus *INDICATION:* -Expectorant *ADVERSE:* -Few

Codeine

*CLASS:* Antitussives *MECHANISM OF ACTION:* -*A pro-drug: metabolized to morphine by CYP2D6* -*Agonist at mu opioid receptor* -Slight action at delta and kappa (similar to morphine) *INDICATION:* -Analgesia: mild-moderate pain especially when combined with aspirin or acetaminophen -*Antitussive -effective in chronic cough but questions regarding acute* (Antitussive mechanism is not well understood but appears to be mediated by different receptors than those mediating analgesic effects of opioids. May be due to codeine itself rather than morphine.) -Antidiarrheal *ADVERSE:* -Constipation -Respiratory depression (rare) -The FDA is currently investigating the safety of using codeine-containing medicines to treat coughs and colds in children younger than 18 years *ADVANTAGE:* -Codeine produces less analgesia than morphine *PK:*

Class I Antiarrhythmics

*CLASS:* Anttiarrhythmics - Class I *MECHANISM OF ACTION:* -Block fast Na+ channels that open during phase 0 depolarization -Make threshold potential less negative (more difficult to reach threshold), and decrease slope of phase 4 depolarization (takes longer to reach threshold) -*The Na+ channel blockers bind when the Na+ channel is in the OPEN or INACTIVATED state. The drugs dissociate ('unbind') when the channel reverts to the RESTED state* -Slow conduction and create conditions favorable for conduction block -*Suppress abnormal automaticity*-decrease automaticity in Purkinje fibers (and decreased abnormal automaticity in atrial and ventricular myocytes) *INDICATION:* -terminate reentrant arrhythmias -protect ventricles in supraventricular tachyarrhythmias

Quinidine

*CLASS:* Anttiarrhythmics - Class Ia *MECHANISM OF ACTION:* -Block fast Na+ channels that open during phase 0 depolarization -Make threshold potential less negative (more difficult to reach threshold), and decrease slope of phase 4 depolarization (takes longer to reach threshold) -*The Na+ channel blockers bind when the Na+ channel is in the OPEN or INACTIVATED state. The drugs dissociate ('unbind') when the channel reverts to the RESTED state* -Slow conduction and create conditions favorable for conduction block -*Suppress abnormal automaticity*-decrease automaticity in Purkinje fibers (and decreased abnormal automaticity in atrial and ventricular myocytes) *Class Ia* -Intermediate Dissociation Rate -Moderate Blockage -Prolonged Repolarization *Other Effects:* - Slows conduction by decreasing slope of depolarization - ↑ AP length and ERF (effective refractory period) by blocking K+ channels. - Has anticholinergic effects: increases A-V conduction speed [Ach turns off SNS by reducing cAMP and opening K+ channels] *ANS:* muscarinic and alpha adrenergic receptor blockade *INDICATION:* -Supraventricular and ventricular arrhythmias -When treating atrial fibrillation/flutter combine w/ beta blockers or CCBs to abrogarte the anticholinergic effects of class Ia agents on AV conduction *ADVERSE:* -Hypotension (due to alpha blockade) -Nausea, vomiting, diarrhea (1/3 pts discontinue due to GI effects) -Light depressant effect on cardiac contractility -*Excessive QT-interval prolongation and induction of torsades de pointes, "quinidine syncope"* -Ventricular tachycardia --> low CO --> syncope *PK:* *Route:* Oral only *Metabolism:* primarily hepatic

Lidocaine

*CLASS:* Anttiarrhythmics - Class Ib *MECHANISM OF ACTION:* -Block fast Na+ channels that open during phase 0 depolarization -Make threshold potential less negative (more difficult to reach threshold), and decrease slope of phase 4 depolarization (takes longer to reach threshold) -*The Na+ channel blockers bind when the Na+ channel is in the OPEN or INACTIVATED state. The drugs dissociate ('unbind') when the channel reverts to the RESTED state* -Slow conduction and create conditions favorable for conduction block -*Suppress abnormal automaticity*-decrease automaticity in Purkinje fibers (and decreased abnormal automaticity in atrial and ventricular myocytes) *Class Ib* -Fast Dissociation Rate -Weak Blockage -Shortened Repolarization *Other Effects:* - Slows conduction by decreasing slope of depolarization (more pronounced in fast heart rate*) *Note:* Class IB antiaqrrhythmics prefer to bind open Na+ channels - It is more likely Na+ channels are open in a person with a fast heart rate *HR-use dependent Na+ channel blocker* (more pronounced effect in fast HR; not give lidocaine if patient has bradycardia) - Decrease AP duration and ERF (effective refractory period) -[opposite of Class IA] *INDICATION:* -Short-term management of life-threatening ventricular arrhythmias -Lidocaine is NO LONGER routinely administered to all patient in the coronary care unit -Note: Lidocaine is also used as local anesthesia of skin and to treat burning and itching *ADVERSE:* -Few adverse effects -But toxicity typical of local anesthetics (drowsiness, tremors, convulsions) *ADVANTAGES:* -No ANS effects *PK:* *Route:* IV only for antiarrhythmic therapy *do not give epinephrine-containing solution!* -Injection solution for dentist and skin solution contain E; but you don't want to give someone with an arrhythmia E *Metabolism: Rapid hepatic *Half-life:* 1.5 hrs

Flecanide

*CLASS:* Anttiarrhythmics - Class Ic *MECHANISM OF ACTION:* -Block fast Na+ channels that open during phase 0 depolarization -Make threshold potential less negative (more difficult to reach threshold), and decrease slope of phase 4 depolarization (takes longer to reach threshold) -*The Na+ channel blockers bind when the Na+ channel is in the OPEN or INACTIVATED state. The drugs dissociate ('unbind') when the channel reverts to the RESTED state* -Slow conduction and create conditions favorable for conduction block -*Suppress abnormal automaticity*-decrease automaticity in Purkinje fibers (and decreased abnormal automaticity in atrial and ventricular myocytes) *Class Ic* -Slow Dissociation Rate -Strong Blockage *Other Effects:* - Slows conduction by decreasing slope of depolarization - marked effects at normal heart rates - little effect on action potential duration or refractoriness (some exceptions) *INDICATION:* -Treatment of life-threatening ventricular arrhythmias and atrial fibrillation (when not responding to other agents) -Supraventricular arrythmia with otherwise normal HR *ADVERSE:* -Proarrhythmic, due to fact that flecainide also blocks a K+ current involved in repolarization and prolongs action potential duration in the ventricles

Albuterol

*CLASS:* Beta2 Receptor Agonists *SABA: *short acting beta agonist* *MECHANISM OF ACTION:* -Therapeutic action due to bronchodilation secondary to B2 receptor -Activates GalphaS --> Activation of cAMP in bronchial smooth muscle--> inhibit MLCK --> cells no longer constrict *INDICATION:* -Asthma, COPD -*Rescue therapy in asthma* -*First line therapy for acute asthmatic bronchospasm* *ADVERSE:* -Tachycardia, Mild hypotension, Tremor -Duration of action only 3-4 hours -*Beta 2 agonists not recommended for monotherapy since they do not affect inflammation* *CONTRAINDICATIONS:* -Patients with underlying cardiac disease -Patients on an MAO inhibitor

Amiodarone

*CLASS:* Class III Antiarrhythmics-K+ Channel Blockers *MECHANISM OF ACTION:* -Diminish outward K+ current during repolarization -Prolong action potential (and QT interval) without altering Phase 0 or resting membrane potential. -Prolong effective refractory period -The effect is to slow things down! *Prolong repolarization --> increases refractory period* -Stops the circle of the re-entry arrhythmia *ANS:* some non-competitive alpha- and beta-receptor block (Class II properties) *INDICATION:* -Supraventricular and ventricular tachyarrhythmias -Effective at maintaining sinus rhythm in atrial fibrillation patients. -Second line of drug treatment (after vasopressin) for VF *ADVERSE:* *Short term therapy:* few adverse effects, Bradychardia and heart block in diseased heart *Long term therapy: *potentially fatal pulmonary fibrosis* seen occasionally in patients receiving long duration, high dose treatment (1/3 of patients discontinue within 1 year). -photosensitivity, corneal deposits, hypo/hyperthyroidism *PK:* *Route:* oral or IV *Distribution:*highly lipophilic (concentrates in tissues) *Metabolism: hepatic; t1/2= 20 - 100 days

Verapamil

*CLASS:* Class IV Antiarrhythmics- Calcium-Channel Blockers *MECHANISM OF ACTION:* *Decrease inward Ca current* -Decreased rate of phase 4 spontaneous depolarization -Decreased Heart rate *Major effect on slow acting APs* -Nodes, damaged cells *Slow conduction in tissues dependent on calcium current* -Slow AV conduction [if there are problems in the aria and need to protect the ventricles use this - blocks conduction at the AV node] *Prolong effective refractory period* *Ca2+channel blockers exhibit "use dependence" (more effective at faster heart rates)* THE EFFECT OF CLASS IV DRUGS ON AV CONDUCTION IS THE BASIS FOR THEIR USE IN TREATING SUPRAVENTRICULAR TACHYCARDIAS - disrupting the conduction from the atria to ventricle keeps the arrhythmia from entering the ventricles *INDICATION:* -Supraventricular tachyarrhythmias which use the AV node as one of the reentrant pathways ---slowing of AV conduction is the basis for their use in treating supraventricular tachycardias -Atrial fibrillation (to reduce the rate of ventricular response - slow AV conduction) *ADVERSE:* -Can cause heart block at high doses (Related to its inhibition of myocardial contractility) *Advantage:* -Verapamil and Diltiazem are less potent vasodilators than other Ca++ channel blockers and, thus, are the Ca++ channel blockers of choice for treating arrhythmias *PK:* *Route:* Oral, IV *CLASS:* Calcium channel blockers- Type I *MECHANISM OF ACTION:* -Improve oxygen delivery to ischemic myocardium by vasodilating coronary arteries -Reduce myocardial oxygen consumption by reducing afterload -Reduce myocardial oxygen consumption by reducing heart rate (increased time spent in diastole) and contractility -Decrease: PVR, HR, SA node firing, AV node firing, Contractility *INDICATION:* -Treatment of ischemic heart disease *ADVERSE:* -Problems in ~10% of patients: -*Major:* Cardiodepression (decreased contractility) -*Moderate:* Hypotension, AV Block, Peripheral edema -*Minor:* HA, Constipation

Diltiazem

*CLASS:* Class IV Antiarrhythmics- Calcium-Channel Blockers *MECHANISM OF ACTION:* *Decrease inward Ca current* -Decreased rate of phase 4 spontaneous depolarization -Decreased Heart rate *Major effect on slow acting APs* -Nodes, damaged cells *Slow conduction in tissues dependent on calcium current* -Slow AV conduction [if there are problems in the aria and need to protect the ventricles use this - blocks conduction at the AV node] *Prolong effective refractory period* *Ca2+channel blockers exhibit "use dependence" (more effective at faster heart rates)* THE EFFECT OF CLASS IV DRUGS ON AV CONDUCTION IS THE BASIS FOR THEIR USE IN TREATING SUPRAVENTRICULAR TACHYCARDIAS - disrupting the conduction from the atria to ventricle keeps the arrhythmia from entering the ventricles *INDICATION:* -Supraventricular tachyarrhythmias which use the AV node as one of the reentrant pathways ---slowing of AV conduction is the basis for their use in treating supraventricular tachycardias -Atrial fibrillation (to reduce the rate of ventricular response - slow AV conduction) *ADVERSE:* -Decreased cardiac contractility (contraindicated in most patients with CHF) -Relaxation of vascular smooth muscle causes decreased arterial pressure, and baroreflex response may increase heart rate (opposite to drug's direct effect on the sinus node) *Advantage:* -Verapamil and Diltiazem are less potent vasodilators than other Ca++ channel blockers and, thus, are the Ca++ channel blockers of choice for treating arrhythmias *PK:* *Route:* Oral, IV *Metabolism:* Hepatic *Half-life:* 4 hours *CLASS:* Calcium channel blockers- Type I *MECHANISM OF ACTION:* -Improve oxygen delivery to ischemic myocardium by vasodilating coronary arteries -Reduce myocardial oxygen consumption by reducing afterload -Reduce myocardial oxygen consumption by reducing heart rate (increased time spent in diastole) and contractility -Decrease: PVR, HR, SA node firing, AV node firing, Contractility *INDICATION:* -Treatment of ischemic heart disease *ADVERSE:* -Problems in ~5% of patients: -*Minor:* Hypotension, Peripheral edema, AV block, Cardiodepression

Digoxin

*CLASS:* Digitalis Glycosides *MECHANISM OF ACTION:* -*Directly inhibit Na+/K+ ATPase* - In response to the increase Na in the cell the Na+/Ca2+ pump will work to transport Na+ out of the cell, and consequently Ca2+ is brought in and its intracellular concentration is increased - More Ca2+ in the cell, means more Ca2+ is incorporated into the SR. -*During excitation more Ca2+ can be released and thus the contraction is stronger.* -*Increased myocardial contractility*: -->Increased cardiac output -->Decrease in sympathetic activity leading to decreased arterial and venous pressure (due to direct effects of drug and effect of higher BP) -->Increased diuresis - reduction of blood volume and edema *Other effects:* -vagomimetic effect through CNS action -Direct effects on the AV node to decrease conduction velocity and to prolong refractory period -Enhanced automaticity of the His-Purkinje system *INDICATION:* -Chronic congestive heart failure (digoxin is the only glycoside that has been evaluated in placebo-controlled trial) *ADVERSE:* -*Narrow therapeutic index* (therapeutic dose very near toxic dose) -Marked interpatient variability - monitor serum levels to guide therapy *Toxicity:* -*Cardiac arrhythmia*- can evoke almost any kind of arrhythmia (AV block, ectopic atrial or ventricular beats, ventricular tachyarrhythmias) --->"Reverse check" or "reverse tick" sign from digoxin effect [ST segment depression] -*Gastrointestional*-anorexia, vomiting, diarrhea, nausea -*Neurological*-headache, fatigue, disorientation, delirium, blurred vision - "halos" or white boarders *DRUG-DRUG INTERACTIONS:* -Quinidine (digoxin is not cleared as well) -Diuretics *PK:* *Route:* IV, Oral *Absorption:* -Variable; depends on dosage form *Distribution:* -Not distributed to fat: dose based on lean body mass *Excretion:* -Renal excretion (renal disease requires dose adjustment)

Dexamethosone

*CLASS:* Glucocorticoids *MECHANISM OF ACTION:* -Greater than 18 times more potent than cortisol with no mineralocorticoid activity *INDICATION:* -Asthma and COPD *ADVERSE:* *PK:*

Prednisone

*CLASS:* Glucocorticoids *MECHANISM OF ACTION:* -*Inactive until metabolized by 11beta-hydroxysteroid dehydrogenase I (11beta-HSD) to active form = prednisolone* -*Use during pregnancy*: fetus sees low levels of the active form; but converted to active form (prednisolone in mother) -->No 11beta-hydroxysteroid dehydrogenase I in fetal liver -->placenta has 11b-hydroxysteroid dehydrogenase II -->prednisone in mother's liver converted to prednisolone, but back to prednisone before seen by fetus *INDICATION:* -Asthma and COPD *ADVERSE:* *PK:*

Beclomethasone/Fluticasone

*CLASS:* Inhaled Glucocorticoids *MECHANISM OF ACTION:* -Suppression of inflammation -Glucocorticoid + beta agonist can be used to tx asthma *INDICATION:* -Useful in severe asthma attacks refractory to therapy with bronchodilators -NOT useful for chronic systemic use because of side effects *ADVERSE:* -Hoarse voice -Oral candidiasis -Concern of systemic absorption with daily use (swallowed) *ADVANTAGE:* Deliver high concentrations of glucocorticoids to lung (less systemic toxicity) *PK:* *Route:* Inhaled (daily inhaler) -Rinse mouth or use spacers in inhalers to minimize delivery of too much drug

Salmeterol

*CLASS:* LABA: *long-acting beta2 agonist* *MECHANISM OF ACTION:* -Selective beta2 agonist -Long-acting: more lipophilic, sit in cell membrane *INDICATION:* -Asthma prophylaxis *Long duration of action: NOT A RESCUE THERAPY* *ADVERSE:* -Tachycardia, Mild hypotension, Tremor -*Beta 2 agonists not recommended for monotherapy since they do not affect inflammation* *-Increased asthma-related deaths seen with monotherapy thus use with long-term control medication such as inhaled corticosteroid* *Monotherapy with LABA is CONTRAINDICATED* *CONTRAINDICATIONS:* -Patients with underlying cardiac disease -Patients on an MAO inhibitor *Monotherapy with LABA is CONTRAINDICATED*

Darifenacin

*CLASS:* M3 receptor-selective muscarinic antagonists *MECHANISM OF ACTION:* -M3 receptor-selective muscarinic antagonist *INDICATION:* -Overactive Bladder *ADVERSE:* Most common: dry mouth, constipation *ADVANTAGES:* -Proposed advantages over non-selective muscarinic antagonist used to treat OAB (especially in elderly): 1.lower incidence of constipation 2.less tendency to cause confusion

Cromolyn/Nedocromil

*CLASS:* Mast Cell Stabilizers *MECHANISM OF ACTION:* -Inhibition of Mast Cell Degranulation -Stabilize mast cells by unknown mechanism: prevents release of autacoids including histamine, LTs, etc -Prevent mild to moderate asthma attacks by reducing airway reactivity -Used with glucocorticoids to prevent moderately severe asthma *INDICATION:* -Prophylactic use before exposure to a known asthma trigger -AND chronic use as a controller therapy *ADVERSE:* -Minimal: bad taste, cough, wheezing, bronchospasm, headache -Do NOT relieve acute asthmatic symptoms (because histamine is already released) *PK:* *Route:* Oral

Theophylline

*CLASS:* Methylxanthines *MECHANISM OF ACTION:* -Relaxes smooth muscle/increases cAMP/blocks adenosine A2 receptors *INDICATION:* -Maintenance therapy for asthma/COPD -Not used as much since potent, long-acting B2 agonists available *ADVERSE:* -Side effects similar to caffeine: insomnia, agitation, tachycardia, tremor

Phentolamine

*CLASS:* Non-selective "Alpha Blockers" *MECHANISM OF ACTION:* -Competitive (reversible) antagonist at alpha 1 and alpha 2 receptors (reduces potency) *INDICATION:* -Management of patients with pheochromocytoma -NOT USEFUL in the tx of HTN *ADVERSE:* -Excessive cardiac stimulation (i.e., cardiac arrhythmia, myocardial infarction)- MORE THAN the baroreceptor reflex (blocking vasconstriction at alpha 1 and alpha 2 autoreceptors) [*Slide 33*]

Phenoxybenzamine

*CLASS:* Non-selective "Alpha Blockers"... *MECHANISM OF ACTION:* -Irreversible (orothosteric) antagonist at alpha 1 and alpha 2 receptors (reduces efficacy) *INDICATION:* -Management of patients with pheochromocytoma -NOT USEFUL in the tx of HTN *ADVERSE:* -Excessive cardiac stimulation (i.e., cardiac arrhythmia, myocardial infarction)- MORE THAN the baroreceptor reflex (blocking vasconstriction at alpha 1 and alpha 2 autoreceptors) [*Slide 33*]

Isosorbide Dinitrate

*CLASS:* Organic Nitrates *MECHANISM OF ACTION:* -Biotransformed into NO with the tissue (endothelial and smooth muscle cells, cardiomyocytes) -*Nitrates act as exogenous NO donors* -The venous system dilates maximally with very low doses. -Arterial dilation begins at low doses and increases with increasing dosage. -Resistance vessels (arterioles) require relatively higher doses before they dilate to any appreciable degree. -Nitrates work by decreasing the oxygen demand of the heart and increasing the oxygen supply. *INDICATION:* -Treatment of CHF -Treatment of ischemic heart disease *ADVERSE:* -Orthostatic hypotension -Tachycardia (HR is increased due to the baroreceptor reflex) -Headache -Dizziness, flushing, syncope -*Tolerance* (if given for prolonged periods of time) *PK:* *Route:* -Sublingual: Onset 2-4 mins; 2-4 hr duration -Oral: Onset 10-20 mins; 4-8hr duration *Metabolism*: Metabolized to Isosorbide-2-mononitrate (possible active metabolite) and Isosorbide-5-mononitrate (known active metabolite) *Half-life:* 1 hr *NOTE:* Isosorbide-5-mononitrate = has a longer t1/2 than parent compound Isosorbide dinitrate (5hrs) and a better bioavailability (orally and sublingually) - Isosorbide-5-mononitrate can also be given on its own

Nitroglycerin

*CLASS:* Organic Nitrates *MECHANISM OF ACTION:* -Biotransformed into NO with the tissue (endothelial and smooth muscle cells, cardiomyocytes) -*Nitrates act as exogenous NO donors* -The venous system dilates maximally with very low doses. -Arterial dilation begins at low doses and increases with increasing dosage. -Resistance vessels (arterioles) require relatively higher doses before they dilate to any appreciable degree. -Nitrates work by decreasing the oxygen demand of the heart and increasing the oxygen supply. *INDICATION:* -Treatment of CHF -Treatment of ischemic heart disease *ADVERSE:* -Orthostatic hypotension -Tachycardia (HR is increased due to the baroreceptor reflex) -Headache -Dizziness, flushing, syncope -*Tolerance* (if given for prolonged periods of time) *PK:* *Route:* -Sublingual: onset 2-4 mins; duration 30-60 mins; no first-pass effect -Oral: Onset 10-20 mins; duration 2-3 hrs; first-pass effect -IV: Immediate onset -Transdermal: Disc,patches, ointment, slow onset, variable duration (10-24 hrs); nocturnal angina -Aerosol: rapid onset; difficult to control *Metabolism:* metabolized to: 1,2-glyceryl dinatrate and 1,3-glyceryl dinitrate (inactive metabolites) *Half-life:* 1-4 mins

Adenosine

*CLASS:* Other antiarrhythmic agents *MECHANISM OF ACTION:* -Adenosine binding to purinergic receptor results in activation of K+ channels -IK.Ado in AV nodal cells ↑ -Diastolic hyperpolarization of AV nodal cells -Decreased AV nodal excitability -AV conduction ↓ -Interruption of AV reentry tachycardia -*Depresses AV conduction via activation of IK.Ade* *INDICATION:* -Drug of first choice for termination of supraventricular tachycardias involving the AV node as part of the reentrant pathway -Reduction of ventricular response during atrial flutter/fibrillation *ADVERSE:* -Flushing -Dyspnea -Transient bradycardia -AV block *PK:* *Route:* IV only *Half-life:* Extremely short (1-6 seconds)

Terbutaline

*CLASS:* SABA: *short acting beta agonist* *MECHANISM OF ACTION:* -*Stimulates beta2 receptors selectively* -*Relaxes bronchial and uterine smooth muscle* *INDICATION:* -*Rescue therapy in asthma* -Tocolytic (unlabeled use) to prevent/manage preterm labor *ADVERSE:* -Potential for cardiovascular effects -Tremors *CONTRAINDICATIONS:* -In pregnancy: should not be used for prolonged tocolysis (beyond 48-72 hr) or in outpatient or home setting --> Monitor mother and fetal heart function

Limitations of Beta Blocker Therapy in Chronic Heart Failure

*CONTRAINDICATIONS:* -Obstructive airway disease -Decompensated heart failure: consider treatment of phosphodiesterase inhibitor first for recompensation (temporarily increase HR and force of contraction), then initiate beta1-blockade -Sinus node or conduction system disease (could stop the heart) *MINOR SIDE EFFECTS:* -Fatigue -Sleep problems -Dizziness

Class IV Antiarrhythmics

*Calcium-Channel Blockers* *MECHANISM OF ACTION:* *Decrease inward Ca current* -Decreased rate of phase 4 spontaneous depolarization -Decreased Heart rate *Major effect on slow acting APs* -Nodes, damaged cells *Slow conduction in tissues dependent on calcium current* -Slow AV conduction [if there are problems in the aria and need to protect the ventricles use this - blocks conduction at the AV node] *Prolong effective refractory period* *Ca2+channel blockers exhibit "use dependence" (more effective at faster heart rates)* THE EFFECT OF CLASS IV DRUGS ON AV CONDUCTION IS THE BASIS FOR THEIR USE IN TREATING SUPRAVENTRICULAR TACHYCARDIAS - disrupting the conduction from the atria to ventricle keeps the arrhythmia from entering the ventricles *INDICATION:* -Supraventricular tachyarrhythmias which use the AV node as one of the reentrant pathways ---slowing of AV conduction is the basis for their use in treating supraventricular tachycardias -Atrial fibrillation (to reduce the rate of ventricular response - slow AV conduction)

Propranolol

*Class:* *Beta Blockers* *Mechanism of Action:* -nonselective competitive antagonist at beta adrenergic receptors -potential to block Na+ channels at high concentrations ("quinidine"-like action) *Indications:* -Hypertension (no effect on BP in normotensive individuals) -Angina -Cardiac arrhythmias [Class II Antiarrhythmics] -->Supraventricular tachyarrhythmias and treatment of various atrial and ventricular arrhythmias -Ischemic heart disease -prophylaxis for migraines -many other indications -Prevention of sudden cardiac death in post-MI patients *Adverse:* Potential for many: -Hypotension -Bradycardia -Cardiac depression (heart failure) -Bronchoconstriction (asthmatics) -Hypoglycemia in susceptible patients -CNS Effects: sedation, nightmares, insomnia -Beta blocker withdrawal syndrome

Beta Adrenergic Receptor Antagonists

*Class:* *Beta Blockers* - *OLOL* *INDICATIONS:* Primary CV indications for therapy with B-blockers: *1. ANGINA: first line therapy* -reduction in myocardial oxygen demand *2. CARDIAC ARRHYTHMIA* -slow AV nodal conduction *3. POST-MYOCARDIAL INFARCTION: standard of care* -reduction in myocardial oxygen demand -slow AV nodal conduction *4.HYPERTENSION: recommendations vary for first-line* -decrease cardiac output -inhibition of renin secretion -possible central inhibition of sympathetic outflow *5. CONGESTIVE HEART FAILURE* *Additional indications for tx w/ Beta Blockers:* management of pheochromocytoma, migraine, tremors, performance anxiety, alcohol or opiate withdrawal, hyperthyroidism *Drugs:* -propranolol -metoprolol -atenolol -esmolol -timolol

Pindolol

*Class:* *INTRINSIC Sympathomimetic* *Mechanism of Action:* -Partial agonist at all beta adrenergic receptors *Indications:* -Hypertension *Adverse:* -Not used that much in clinic -ISA drugs are not more preferred than using straight cardioselective beta-blockers *Potential Advantages:* 1. less cardiac depression (less resting bradycardia because at rest there is partial activation of receptors) 2. but still block exercise-induced increases in heart rate (because receptors are bound to pindolol instead of binding NE) 2. less tendency to cause bronchoconstriction (partial agonist at B2) 3. significantly reduces peripheral resistance (sub-max vasodilation at B2)

Labetalol

*Class:* *Mixed alpha/beta blockers* *Mechanism of Action:* -Racemic mixture with one isomer an a1 antagonist and another a nonselective b antagonist (with some B2 partial agonist activity). -Block alpha and get some vasodilation through B2 (partial agonist) -Thus, less tachycardia than alpha blockers, and decreased renin release through beta1 blockade. *Indications:* -Hypertension especially hypertensive emergencies *Adverse:* -Postural hypotension -Bronchoconstriction

Carvedilol

*Class:* *Mixed alpha/beta blockers* *Mechanism of Action:* -Nonselective adrenergic antagonist: blocks beta1, beta2, and alpha1 receptors (1:10 alpha: beta antagonism) *Indications:* -Hypertension -Heart failure- shown to reduce mortality and morbidity in CHF -Left ventricular dysfunction post-MI *Adverse:* -Hypotension -Syncope -Bradycardia -Rebound hypertension is discontinued abruptly *PK:* -*ALWAYS start with low dose and increase gradually* because in short term activation of beta receptors is adaptive to CHF (enhance contractility) -Long term activation= TOXIC TO MYOCARDIUM: acceleration of CHF

Esmolol

*Class:* *Ultra short acting beta blocker (10 min)* *Indications:* -*Given by infusion to limit catecholamine-mediated cardiac stimulation, especially in surgery* *Adverse:* Similar to nonselective (can still have effects at beta 2): -Hypotension -Bradycardia -Cardiac depression (heart failure) -Hypoglycemia in susceptible patients -CNS Effects: sedation, nightmares, insomnia -Beta blocker withdrawal syndrome *Advantages:* -Lower bronchoconstriction risk *PK:* *Metabolism:* -Ultra short acting because it is *hydrolyzed in the blood --> therefore has a short half-life* (like acetylcholine)

Actions of PKA

*In ventricles:* -Phosphorylates Ca2+ channels activating them -Phosphorylates SR Ca pump, which increases the levels of calcium reuptake (more calcium released next stimulus) -Phosphorylates glycogen metabolizing enzymes, which increases formation of glucose-6-phosphate increasing energy supply *In Nodes PKA:* -Activates pacemaking channels (The F channel belongs to the Hyperpolarization-activated Cyclic Nucleotide-gated channels)

Compensatory Mechanisms in Heart Failure

*Increase sympathetic discharge* -Increased neuro-hormonal activation in heart failure -Positive chronotropic and inotropic response *Increase Renin Release* -Reduction in blood flow to kidneys --> release of renin --> renin converts angiotensinogen to angiotension I --> Angiotensin I is converted to Angiotensin II by ACE in lungs --> water retentention, circulation volume increases

Class III Antiarrhythmics

*K+ Channel Blockers* -Diminish outward K+ current during repolarization -Prolong action potential (and QT interval) without altering Phase 0 or resting membrane potential. -Prolong effective refractory period -The effect is to slow things down! *Prolong repolarization --> increases refractory period* -Stops the circle of the re-entry arrhythmia

Epinephrine

*MECHANISM OF ACTION:* -Stimulates all alpha and beta receptors *INDICATION:* -Treat bronchospasms, bronchial asthma, viral croup, anaphylactic reactions *ADVERSE:* -nonselective alpha and beta stimulation: tachycardia, arrhythmias, anxiety, tremors) *PK:* -Low bioavailability

Isoproterenol

*MECHANISM OF ACTION:* -Stimulates beta1 and beta2 receptors (but NOT alpha receptors) *INDICATION:* -Few, generally supplanted by other adrenergic agents -NOT used anymore *ADVERSE:* -Cardiac arrhythmias resulting in an increased mortality rate

Glucocorticoid Actions

*Metabolic Effects* -Antagonizes insulin action and promotes gluconeogenesis (increases blood glucose) -Increases muscle catabolism (increased amino acids) -Augments growth hormone action on lipolysis (increase triglycerides) *Anti-inflammatory Actions* -Decreases inflammatory response -Reduces cytokine release -Reduces production of eicosanoids (leukotrienes and prostaglandins) Note: Glucocorticoid receptor bound to lipid internally translocates to the nucleus to turn on transcription of anti-inflammatory genes

What cell types are voltage gated L type calcium channels present in?

*Smooth muscle* -Calcium entry induces CICR from ER and helps with contraction *Cardiac muscle* -Calcium entry is responsible for plateau of AP, helps with contraction, induces CICR from ER, and is important for refilling SR *Skeletal muscle* -Voltage activation of channel induces calcium release from SR

Ischemic Heart Disease- Therapeutic Goal and Pharmacological Objective

*Therapeutic Goal* -Relieve chest pain *Pharmacological Objective* -Dilate the coronary arteries -Redistribute blood flow in the heart -Reduce the oxygen demand of the heart

Nitrate Tolerance

-*Continuous or frequent exposure to organic nitrates may lead to the development of tolerance* -Transdermal nitroglycerin may provide therapeutic blood levels for 24 hours, but efficacy may persist for only 8-10 hours -*To avoid tolerance, nitrate-free periods of at least 8 hours (e.g. overnight) are suggested* *Possible mechanisms for nitrate tolerance:* -Decreased ability to convert nitrate to nitric oxide -Diminished release of NO, due to depletion of endogenous sulfhydryl compounds (sulfhydryl-regenerating agents can partially reverse tolerance) -Changes in guanylate cyclase activation due to accumulation of peroxynitrite (a metabolite)

Glucocorticoid Uses

-*Replacement Therapy:* Generally use lowest effective dose of oral hydrocortisone -*Anti-inflammatory:* Immune suppression (asthma, rheumatoid arthritis, Crohn's Disease, immune rejection) *Note: Symptomatic relief only: therapy does not improve underlying disease, and can worsen underlying disease* -*Depot injections* (intra-articular) for arthritis or gout, usually methylprednisone -*Immunosupressive Therapy* for transplant rejection -*Topical dosing* can use higher concentrations than systemic administration for psoriasis and dermatitis -*Inhaled glucocorticoids:* for asthma while minimizing systemic actions

Regulation of contraction in smooth muscle

-1 Calmodulin molecule can bind 4 Ca2+ ions (as the concentration of intracellular Ca2+ increases) -The Ca2+-calmodulin complex binds to the poorly active form of myosin light chain (LC) kinase, converting it to a more active form. -The active kinase (MLCK) catalyzes phosphorylation of a myosin light chain, which permits myosin to interact with actin, causing smooth muscle contraction -A decrease in the intracellular Ca2+ concentration leads to a dissociation of calcium and calmodulin from the kinase, thereby inactivating the kinase. -Under these conditions myosin light chain phospatase (which is not dependent on Ca2+ for activity but is regulated through phosphorylation) dephosphorylates myosin, causing smooth muscle relaxation. -The balance between phosphorylated (bound to actin) and unphosphorylated (dissociated from actin) myosin is key to the control of contractions in smooth muscle. -Whether the myosin light chain is phosphorylated or not, depends on the concentration of Ca2+.

Actions of Aldosterone

-Aldosterone acts on cytoplasmic mineralocorticoid receptors (MR) -Aldosterone-MR complex upregulates expression and activity of channels and pumps -*Sodium and water are retained increasing blood volume* --> increases preload -Renal secretion of K+ and Mg2+ -Promotion of myocardial fibrosis, fibroblast proliferation -Reduces baroreceptor sensitivity -Reduces myocardial uptake of NE -Alteration in Na channel expression

Leukotrienes in Asthma

-Arachidonic acid is generated from membrane lipids by PLA2 -5-lipoxygenase enzyme converts arachidonic acid to leukotriene --> leukotrienes are then released on the adjacent cell causing constriction -*Release of leukotrienes from mast cells within airways cause airway constriction*

Chronic responses of Angiotensin II

-Cardiac myocyte growth -Myocyte apoptosis -Cardiac myocyte toxicity -Fibroblast proliferation *fibrotic heart*) -Smooth muscle proliferation (vascular system) *contribute to the pathology of CHF*

Beta1 activation induces

-Cardiac stimulation (innervated) -Secretion of renin

Beta2 activation induces

-Cardiac stimulation (uninnervated, minor) -Bronchodilation -Uterine relaxation -Vasodilation (uninnervated) -Glycogenolysis (liver)

What is the indication for vasodilators?

-Chronic congestive heart failure -Hypertension and Pulmonary Arterial Hypertension -Ischemic Heart Disease -Erectile dysfunction

Angiotensin converting enzyme (2 actions)

-Converts Angiotensin I --> Angiotensin II -Converts Bradykinin to inactive fragments (Bradykinin = vasodilatory peptide; can also act a a pro-inflammatory molecule) *Chronically increased adrenergic drive delivers adverse biological signals to the cardiac muscle* -Myocyte toxicity -Myocyte apoptosis -Cardiac myocyte growth -Fetal gene induction -Proarrhythmic *Note:* Elimination of these adverse signals is the rationale for using anti-adrenergic agents in the treatment of chronic heart failure.

Interventions causing smooth muscle relaxation (vasodilation)

-Direct inhibition of Ca2+ entry through voltage-dependent (L-type) Ca2+ channels in the smooth muscle outer membrane -Smooth muscle membrane hyperpolarization (e.g. activation of K+ outward currents) -Reduction of myosin phosphorylation

Treatment of Digitalis (Digoxin) Toxicity

-Discontinue digitalis therapy -Discontinue diuretic therapy, K+ infusion (only if patients are hypokalemic) -Administer digoxin specific antibodies (Digibind - binds digoxin/digitoxin)

Which Beta-Blocker Should be Used to Treat Chronic Heart Failure?

-Effects through beta1-, beta2-, and possibly alpha1-adrenergic receptors -*Predominance of beta1-adrenergic receptors in mediating the adverse effects of chronic increase in adrenergic drive -*Competitive agonists that bind with high affinity to human beta1-adrenergic receptors are best* Beta receptors mediate things such as: myocyte toxicity, myocyte apoptosis, and cardiac myocyte growth in CHF -Therefore Beta-blockers can be used to stop/reverse the cardiac remodeling that takes place in CHF

LV remodeling in CHF

-Excitation-Contraction failure -Cardiomyocyte hypertrophy -Fibrosis -Apoptosis

Class IB Antiarrhythmics LIDOCAINE

-Fast Dissociation Rate -Weak Blockage -Shortened Repolarization *Other Effects:* - Slows conduction by decreasing slope of depolarization (more pronounced in fast heart rate*) *Note:* Class IB antiaqrrhythmics prefer to bind open Na+ channels - It is more likely Na+ channels are open in a person with a fast heart rate *HR-use dependent Na+ channel blocker* (more pronounced effect in fast HR; not give lidocaine if patient has bradycardia) - Decrease AP duration and ERF (effective refractory period) -[opposite of Class IA]

Long QT syndrome

-Fibrillation can also come about because of mutation in K+ (less efflux) or Na+ channels (incomplete inactivation) of the cardiac muscle cells. -Effect of either type of mutation is prolonged depolarization -Known as long QT syndrome -Can also be acquired (drugs, antibiotics, hypokalemia) *Symptoms:* -Recurrent irregular heart beats -Prolonged ventricular depolarization. -Higher risk of sudden cardiac death Treated 8% at 5 years Untreated 50% at 10 years -Symptoms provoked high adrenergic states

Reentry model for fibrillation

-Fibrillations are a type of arrhythmia usually involving an ectopic focus of excitation in cells that then become spontaneous pacemakers -Damage disrupts normal bidirectional conduction --> unidirectional conduction (conduction occurs in one direction but not the other) = undirectional conduction block --> Forms a viscous circle of conduction =flutter

Glucocorticoid Side Effects

-Increased susceptibility to infection -Increased glucose levels and diabetes mellitus -Secondary hyperparathyroidism -Osteoporosis -Edema -Suppression of linear bone growth in children -Steroid psychosis (emotional response) -Cushing's Syndrome -*Withdrawal "rebound" phenomenon: adrenal insufficiency* -Myopathy (from muscle wasting)

Class IA Antiarrhythmics QUINIDINE PROCAINAMIDE

-Intermediate Dissociation Rate -Moderate Blockage -Prolonged Repolarization *Other Effects:* - Slows conduction by decreasing slope of depolarization - ↑ AP length and ERF (effective refractory period) by blocking K+ channels. - Has anticholinergic effects: increases A-V conduction speed [Ach turns off SNS by reducing cAMP and opening K+ channels]

Triggered activity: early afterdepolarization

-Interruptions of phase 3 repolarization that may appear when the action potential is markedly prolonged (A). -The EAD may then trigger one or more rather bizarre action potentials (B, C) whose exact origin is not clear. -This type of triggered activity is most commonly seen under conditions of very slow heart rate, low extracellular K+, and treatment with drugs (often antiarrhythmics) that prolong action potential duration. *EADs thought to be responsible for 'Torsades de pointes' seen with certain antiarrhythmics*

Managing CHF

-Key issue is the lower cardiac output -To change cardiac output you manipulate: 1)Contractility 2)Preload 3)Afterload -In CHF you must also deal with the cardiac remodeling *Contractility* -Inotropic drugs -Modulate elements of the contraction system *Preload* -Modulate volume: diuretics -Venodilators *Afterload* -Vasodilators *Remodeling* (prevention of adverse cardiac remodeling-hypertrophy, chamber dilatation, fibrosis, loss of functional myocytes) -RAAS modulators -Adrenergic modulators These 2 systems above are causing adverse remodeling

Chronic responses of NE

-Myocyte toxicity -Myocyte apoptosis -Cardiac myocyte growth (this leads to LVH --> LV stiffness) -Fetal gene induction -Proarrhythmic *contribute to the pathology of CHF*

Vasodilators used for treatment of CHF

-Nitroglycerin -Isosorbide dinitrate

Drugs used to treat ischemic heart disease

-Organic nitrates -Calcium channel blockers -Beta-adrenergic receptor blockers

Triggered activity: delayed afterdepolarization

-Oscillations in membrane potential that occur shortly after return to resting membrane potential. -In some cases, DADs may be sufficiently large to bring the cell to threshold and trigger an action potential or even a succession of action potentials. -DADs are sometimes seen when intracellular Ca++ is increased (in sick or damaged myocytes, in normal myocardium exposed to certain drugs such as digitalis, or under high sympathoadrenal tone), particularly when heart rate is very high. -Cytosolic Ca++ can increase due to premature or excessive release from the SR --> this stimulates the Na+/Ca2+ exchanger --> increasing intracellular Na+ --> depolarization

Biological Responses Mediated by Adrenergic Receptors in the Human Heart

-Positive inotropic effect -Positive chronotropic effect

The ill effects of chronically induced adrenergic and RAAS drive

-Short term these effects improve CHF (improve CO) -Long term activation --> necrosis, apoptosis, fibrosis, energy deficit --> all leading to myocardial cell death

Class IC Antiarrhythmics FLECANIDE

-Slow Dissociation Rate -Strong Blockage *Other Effects:* - Slows conduction by decreasing slope of depolarization - *marked effects at normal heart rates* - little effect on action potential duration or refractoriness (some exceptions)

Endothelium-dependent relaxation

-Substances act on the endothelial cell at their respective receptors to release nitric oxide (NO). NO diffuses into the vascular smooth muscle cell, increases guanylate cyclase activity and cGMP concentration, and promotes relaxation

Effect of NO in vascular smooth muscle

-The NO responsible for inhibiting the contractions (vasodilation) is released by epithelial cells that are activated by circulating ACh. -NO activates guanylate cyclase (GuCy), which catalyzes the conversion of GTP to cGMP initiating the following cascade: -cGMP activates PKG which phophorylates the K+ channel, the SR Ca2+ pump and the LC20 phosphatase making it active and consequently relaxing the contraction.

Classification of the Class I Antiarrhythmics

-The Na+ channel blockers bind when the Na+ channel is in the OPEN or INACTIVATED state. The drugs dissociate ('unbind') when the channel reverts to the RESTED state. -*Subclasses differ according to how rapidly drugs dissociate ('unbind') from the RESTED state of the Na+ channel:* -Ia drugs have an intermediate dissociation rate -Ib drugs dissociate rapidly and have a preference for open channels, -Ic drugs dissociate very slowly *Class Ia* -Quinidine -Procainamide *Class Ib* -Lidocaine *Class Ic* -Flecainide

Pediatric Use of Antitussives

-The United States Food and Drug Administration (FDA) Advisory Committee recommends against the use of OTC cough and cold medications in children younger than six years. -The AAP recommends against the use of OTC cough and cold medications in children younger than two years and highlights the lack of proven efficacy and potential for toxicity for children younger than six years. -What's left to do? -->Oral hydration -->Warm fluids -->Honey (> 1 year) -->Cough lozenge

Phosphodiesterases

-There are 11 known families of phosphodiesterases -Phosphodiesterase type 3 is present in cardiac myocytes and affects cardiac contractility -Phosphodiesterase type 5 is present in vascular smooth muscle and affects smooth muscle contraction

Antimuscarinic

-Tolterodine -Darifenacin -Ipratropium

Biological responses mediated by angiotensin II receptors

-Vasoconstriction -Positive inotropic response (a little bit) -Enhancement of peripheral noradrenergic neurotransmission -More NE release -Less NE reuptake -More vascular responsiveness -Increased sympathetic discharge from CNS -Release of catecholamines from adrenal medulla -Increase aldosterone release

Alpha1 activation induces

-Vasoconstriction (innervated) -Pupillary Dilation -Ejaculation -Inhibition of micturition -GI inhibition

Alpha2 activation induces

-Vasoconstriction (uninnervated) -Prejunctional inhibition of NE release

Quinidine syncope

-Ventricular tachycardia --> low CO --> syncope

Sildenafil

-Viagra *CLASS:* Vasodilators *MECHANISM OF ACTION:* -*PDE-5 inhibitor* -Leading to increased intracavernosal cGMP--> activates PKG --> smooth muscle relaxation --> vasodilation --> erection (enhances effects of NO; NO activates GC which makes cGMP) -Vasodilation of penile arteries and increase in penile blood flow *INDICATION:* -First line therapy for erectile dysfunction *ADVERSE:* -Flushing, dyspepsia most common -Prolonged erection (>2 hrs) can lead to penile ischemia -Dose-related, transient abnormal vision (photosensitivity, color tinge): Visual disturbances due to weak inhibition of PDE-6 (non-selective effect of drug) -PDE-6 involved in photoreceptor signal transduction *CONTRAINDICATIONS:* -Contraindicated with nitrates because combination can lead to severe hypotension and syncope (will increase cGMP too much) -May cause potentially fatal reductions of arterial pressure in patients taking nitrates for angina *(Nitrate use is contraindicated)* *DRUG-DRUG I/AS:* -Alpha adrenergic antagonists (can cause symptomatic hypotension) -CYP3A4 inhibitors (including grapefruit juice) can pro-long half-life -CYP3A4 inducers can reduce effectiveness *PK:* *Route:* Oral -Low oral bioavailability (40%). *Metabolism:* Hepatic metabolism (CYP3A4); active metabolite *Half-life:* 4 hrs; longer in men over 65 and in hepatic or renal insufficiency

Glucocorticoid Pharmacokinetics

-Well-absorbed from GI tract -Cortisol highly bound to cortisol-binding globulin and albumin; synthetics less bound -Lipophilic -Metabolized by liver and extrahepatic enzymes -*No 11b-hydroxysteroid dehydrogenase I in fetal liver, but placenta has 11b-hydroxysteroid dehydrogenase II, so prednisone in mother's liver converted to prednisolone, but back to prednisone before seen by fetus, thus USE prednisone during pregnancy* -*Note: To minimize systemic toxicity local delivery often used (inhalation, topical, intraarticular)*

Type of manipulations of cardiac muscle function

1) Inotropic: change in strength 2) Chronotropic: change in pace 3) Dromotropic: change in rate of conduction 4) Lusitropic: relaxation *Lusitropic = Loosey Goosey*

Mechanisms of Arrhythmias

1)*Abnormalities of impulse formation* A. alteration of physiological automaticity (enhanced or depressed) B. development of abnormal automaticity: ectopic pacemakers C. triggered activity: early or delayed afterdepolarizations (EAD or DAD) 2)*Abnormalities of impulse conduction* A. conduction delay or block B. reentry 3)*Abnormalities of impulse formation AND conduction*

Terminating reentry by manipulating conduction or refractoriness

1)*Slow down conduction:* Leads to conduction block and reentry termination due to low amplitude action potentials - inability to bring next cell to threshold -By the time it gets there you have lost the power of the wave therefore it is not strong enough to bring the next cell to threshold -cells that are damaged are must more sensitive to drugs 2) *Speed up conduction:* Leads to conduction block and reentry termination when rapidly conducted impulse encounters refractory tissue -Cells are still in refractory period and cannot be excited --> can't contineu conduction 3)*Prolong refractory period:* Leads to conduction block and reentry termination when impulse encounters refractory tissue -prolong refractory period of the cell --> can't excite --> can't continue conduction

Effect of Alpha Receptor Antagonism

1. Decreased BP (hypotension) 2. Increased HR (baroreceptor reflex) 3. Nasal congestion 4. Miosis 5. Improve urine flow 6. Decreased ability to ejaculate 7. Sedation/depression

Effect of Norepinephrine in vascular smooth muscle

1. NE activates a GPCR and PLC is activated 2. PLC breaks PIP2 into IP3 and DAG 3. IP3 activates SR receptor releasing Ca2+ 4. Ca2+ activates PKC and activates contraction via activation of MLKC

Alpha Receptor Agonists Clinical Uses

1. Nasal decongestants 2. Adjunct to local anesthetic action 3. Maintenance of blood pressure (e.g., in spinal anesthesia, shock) 4. Treatment of PAT (paroxysmal atrial tachycardia) 5. Eye drops (to "get the red out") 6. Mydriatic

Antiarrhythmic Drug Table

1: short time for life threatening ventricular arrhythmia 2: life threatening atrial and ventricular arrhythmia 3: when they use the AV node as one of the steps reentrant pathway

Long-term stimulation of receptors is likely to cause... ?

Down-regulation and/ or desensitization *Simple Solution:* -When withdrawing patient from a drug, TAPER THE DOSE

Cortisol

Hydrocortisone *CLASS:* Glucocorticoids *MECHANISM OF ACTION:* -Major endogenous steroid with glucocorticoid activity *INDICATION:* -Asthma and COPD *ADVERSE:* -Increased susceptibility to infection -Increased glucose levels and diabetes mellitus -Secondary hyperparathyroidism -Osteoporosis -Edema -Suppression of linear bone growth in children -Steroid psychosis (emotional response) -Cushing's Syndrome -*Withdrawal "rebound" phenomenon: adrenal insufficiency* -Myopathy (from muscle wasting) *PK:* *Distribution:* Highly bound to cortisol-binding globulin and albumin

Epi reversal

Initially an increase in BP is observed but this can be "reversed" by blocking alpha1 receptors and unmasking the beta2 vasodilation. *Note:* There is NO norepi reversal because of the low affinity of NE for beta2 receptor. Epi by itself: -Alpha 1 receptors- vasoconstriction -Beta 2 receptors- vasodilation -Effect on beta 2 is masked by action at alpha 1 -To see the effect at beta 2 receptors we have to block the alpha 1 receptors

Positive inotropes

Inotropes = increase contractility -Drugs that increase intracellular Ca++ -Drugs that facilitate Ca++ binding to troponin -Drugs that affect metabolism and endocrine function

What does it mean for a drug to have "intrinsic sympathomimetic activity"?

It can act both as an adrenergic receptor agonist and antagonist

Mirabegron

New Drug *CLASS:* Beta3 Receptor Agonist *MECHANISM OF ACTION:* -*B3 selective agonist: relaxes detrusor smooth muscle during urine storage phase thus increasing bladder capacity* *INDICATION:* -Overactive bladder *ADVERSE:* -Hypertension -Slow onset (up to 8 weeks)

Metoprolol

Same as Atenolol *Class:* *Beta Blockers* *Mechanism of Action:* -selective competitive antagonist at beta1 adrenergic receptors *Indications:* -Hypertension (no effect on BP in normotensive individuals) -Angina -Cardiac arrhythmias -Ischemic heart disease -Heart failure (CHF) *Adverse:* Similar to nonselective (can still have effects at beta 2): -Hypotension -Bradycardia -Cardiac depression (heart failure) -Hypoglycemia in susceptible patients -CNS Effects: sedation, nightmares, insomnia -Beta blocker withdrawal syndrome *Advantages:* -Lower bronchoconstriction risk

Atenolol

Same as Metoprolol *Class:* *Beta Blockers* *Mechanism of Action:* -selective competitive antagonist at beta1 adrenergic receptors *Indications:* -Hypertension (no effect on BP in normotensive individuals) -Angina -Cardiac arrhythmias -Ischemic heart disease -Heart failure *Adverse:* Similar to nonselective (can still have effects at beta 2): -Hypotension -Bradycardia -Cardiac depression (heart failure) -Hypoglycemia in susceptible patients -CNS Effects: sedation, nightmares, insomnia -Beta blocker withdrawal syndrome *Advantages:* -Lower bronchoconstriction risk

Zafirlukast

Same as: Montelukast *CLASS:* Leukotriene Receptor Antagonism *MECHANISM OF ACTION:* -Prevents actions of cysteinyl leukotrienes (LTC4, LTD4, LTE4) at CycLT1 receptors *INDICATION:* -Prophylactic treatment of mild asthma *ADVERSE:* -Minimal side effects -Rare inflammatory condition including: pulmonary infiltrates, neuropathy, skin rashes, vasculitis *PK:* *Route:* Oral

Vasodilators for Treatment of Chronic Heart Failure

Venous dilation --> Reduction of venous return --> Reduction of diastolic wall stress (preload effect) Arteriolar dilation --> Reduction of vascular resistance --> Increase in stroke volume -Chronic treatment of heart failure patients with non-neurohormonal vasodilators does not improve mortality; however, acute administration is an important strategy for treatment of acute, decompensated heart failure. *Vasodilator therapy is only effective if the patient has an elevated left ventricular end diastolic pressure.* *If the EDV is not elevated, vasodilator therapy will not help.*