Pharmacology I Exam 2 Study Guide

1 · Ophthalmic Drugs

Adam Wood, Pharm.D., DABAT

1.1 · Objective 4 — Getting a drug into the eye, and out again

Every formulation decision in this lecture comes back to one variable: how long the drug stays in contact with the eye. Most drugs are given as solutions; suspensions are used where solubility is limited; and gels, ointments and solid inserts exist to prolong contact in the cul-de-sac. More time in the cul-de-sac means more absorption, and inserts and implants extend that into sustained release.

Four things determine how much gets absorbed: time in the cul-de-sac and the precorneal tear film, nasolacrimal drainage, drug binding to tear and tissue proteins, and diffusion across the cornea and conjunctiva. Two of those can be manipulated — change the formulation, or block the tear ducts with silicone plugs or cautery so the drug cannot drain away.

Distribution into the eye happens normally after systemic absorption, and some drugs accumulate there — the named example is the bull’s eye lesion after chloroquine. Some drugs are also metabolized within the eye, which is exploited deliberately: dipivefrin becomes epinephrine and latanoprost becomes prostaglandin F2-alpha once inside. Elimination is otherwise ordinary hepatic and renal clearance.

The route table is worth holding by its trade-offs rather than its rows. Topical is convenient, economical and relatively safe, at the price of compliance, surface toxicity and systemic absorption. Periocular injection — subconjunctival, sub-Tenon’s, retrobulbar — reaches posterior uveitis and cystoid macular edema, at the price of globe perforation, optic nerve trauma and retinal artery or vein occlusion. Intracameral injection is prompt and used in anterior segment surgery and infection, but short-lived.

1.2 · Objectives 1–3 — Ocular antibiotics

Most conjunctivitis is not bacterial. The common causes given are viruses, allergies, environmental irritants and contact lenses, with immune-mediated reactions, systemic disease and tumors less common. The bacterial pathogens worth naming are Neisseria, Haemophilus, Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis. The spectrum shifts over time — the example is the fall in Haemophilus influenzae after the vaccine.

Small, mild, peripheral infections are treated topically and empirically, with broad-spectrum agents and no cultures unless an unusual organism is expected — the immunocompromised patient being the example. Topical therapy buys very high local concentrations at the cost of poor systemic bioavailability and frequent dosing. Whether a patient needs oral or parenteral treatment instead turns on clinical setting, age, immune status and how much is involved.

Drug choice is the testable part. Erythromycin ointment is the commonest ophthalmic antibiotic and is soothing on an inflamed eye, so it may reasonably be used before a bacterial cause is confirmed; it is also the agent for ophthalmia neonatorum prophylaxis. Azithromycin is dosed twice daily rather than four or more times, but is considerably more expensive and used less often. Fluoroquinolones are preferred for corneal ulcers and for suspected Pseudomonas aeruginosa, which is why they are also the choice for conjunctivitis in a contact lens wearer once keratitis has been excluded — set against cost and emerging resistance.

1.3 · Objectives 1–3 — Antivirals and antifungals

Ocular antivirals exist for viral keratitis, herpes zoster ophthalmicus and retinitis. They do not exist for adenoviral conjunctivitis, which is self-limited and treated with symptomatic relief — a common exam trap because the patient in front of you looks like they need something.

Topically, trifluridine inhibits thymidylate synthetase and is incorporated into viral DNA in place of thymidine, for herpes simplex keratoconjunctivitis. Ganciclovir competitively inhibits deoxyguanosine triphosphate binding to DNA polymerase, for herpetic keratitis and — by intravitreal injection — cytomegalovirus retinitis. Systemically, acyclovir, valacyclovir and famciclovir are the oral agents for zoster ophthalmicus and simplex keratitis, and foscarnet is intravenous for cytomegalovirus retinitis.

Natamycin is the only commercially available ophthalmic antifungal — that is the fact to hold, because everything else on the table is given by another route or compounded. It is a polyene: it binds sterol and increases fungal membrane permeability, covering Aspergillus, Candida, Cephalosporium, Fusarium and Penicillium. Amphotericin B is the agent with every route — topical, subconjunctival, intravitreal and intravenous — which is what makes it usable for endophthalmitis.

1.4 · Objectives 1–3 — Allergy and the red eye

Mast cells and basophils are the principal target cells. Immunoglobulin E binds Fc receptors, tyrosine kinases activate within 5 to 15 seconds, and histamine, platelet-activating factor and leukotrienes are released — producing vasodilation, swelling, redness and itch. Every drug below is aimed at one point in that sequence.

H1 agents are not really antagonists. They are inverse agonists — they drive the receptor into an inactive state rather than merely occupying it — while remaining competitive with histamine. They decrease capillary dilation, itch and swelling. Onset is within minutes, but allow two weeks to judge full efficacy. They are typically preferred over mast cell stabilizers, and can worsen ocular dryness.

Mast cell stabilizers — cromolyn, lodoxamide, nedocromil — inhibit degranulation, limiting release of histamine, tryptase and prostaglandin D2, and dampen basophils, eosinophils and neutrophils. They take 5 to 14 days for full effect and are not useful for acute symptoms, which is the whole distinction from the antihistamines. Often four times daily. Their place is predictable seasonal allergy in someone who does not tolerate the alternatives.

1.5 · Objectives 5–7 — Anti-inflammatories and dry eye

The two anti-inflammatory classes sit one step apart in the same cascade. Glucocorticoids inhibit phospholipase A2, so arachidonic acid is never liberated and the whole downstream family of mediators fails. Nonsteroidals block cyclooxygenase, so arachidonic acid that has already been liberated cannot become prostaglandin or thromboxane. The steroids therefore cut off more, and cost more to use.

Nonsteroidals — bromfenac, diclofenac, flurbiprofen, ketorolac, nepafenac — are indicated for postoperative inflammation and pain and allergic conjunctivitis, and are not routinely recommended for conjunctivitis generally. Adverse effects: lacrimation, keratitis, raised intraocular pressure and irritation.

Glucocorticoids also inhibit fibrin and collagen deposition, so they reduce scarring — useful where a scar costs vision. They are used for severe ocular allergy, anterior uveitis, external eye inflammatory disease and post-surgical inflammation, generally for refractory symptoms.

Dry eye is often a manifestation of something else — Sjogren syndrome, rheumatoid arthritis, vitamin A deficiency, Stevens-Johnson syndrome — so the first instruction is treat the disease. Then physical measures (punctal plugs, surgical occlusion) and tear substitutes: hypotonic or isotonic solutions with electrolytes, surfactants and thickeners to increase time in the cul-de-sac.

Cyclosporine inhibits interleukin-2 production and so T cell activation, reducing inflammatory markers in the lacrimal gland and increasing tear production. Indication: chronic dry eye associated with inflammation (keratoconjunctivitis sicca). Warn about ocular burning in about 17%, foreign body sensation and blurred vision — a drug that takes time to work needs its side effects flagged up front.

1.6 · Objectives 1–7 — Glaucoma

Raised pressure causes optic neuropathy → loss of retinal ganglion cell axons → visual field loss → irreversible blindness. Irreversible is the operative word: therapy prevents progression, it does not recover vision. Normal pressure is 10 to 21 mmHg.

Sort every agent by which side it works on. Increasing outflow: prostaglandins, alpha adrenergic agonists, cholinergic agonists. Decreasing production: alpha adrenergic agonists, beta blockers, carbonic anhydrase inhibitors. The alpha agonists appear on both lists, which is where most errors come from.

Prostaglandins (latanoprost, travoprost, bimatoprost, tafluprost) are analogs of prostaglandin F2-alpha and increase outflow. They are first line and the most commonly used, dosed once daily — and exceeding that inhibits the pressure-lowering effect. Warn about eyelash lengthening and iris color change, plus conjunctival hyperemia. Limited systemic effects.

Beta blockers block beta receptors in the ciliary epithelium, reducing catecholamine activation and cyclic AMP, and so aqueous production. Betaxolol is beta-1 selective; carteolol, timolol and levobunolol are non-selective. Non-selective is more efficacious but riskier, because beta-2 receptors mediate bronchodilation. Systemic effects reach through nasolacrimal absorption: worsening heart failure, bradycardia, heart block, increased airway resistance.

Alpha-2 agonists (apraclonidine, brimonidine) reduce catecholamine release presynaptically and aqueous production postsynaptically, and increase outflow. Contraindicated under two years — central nervous system depression and apnea. Apraclonidine is highly ionized at physiological pH, which limits blood-brain barrier penetration; brimonidine is more lipophilic but causes less allergic conjunctivitis.

Carbonic anhydrase inhibitors (dorzolamide, brinzolamide) reduce bicarbonate production in the ciliary epithelium, so less fluid is transported. Their problem is tolerability: bitter taste in about 25% and burning or stinging in about 33%. Cholinergic agonists (pilocarpine, carbachol, acetylcholine) activate muscarinic receptors, contracting the ciliary muscle and opening outflow — but give fixed small pupils, induced myopia and visual disturbance, and younger patients are usually intolerant because they still accommodate.

1.7 · Objectives 1–3 — Diagnostic and procedural agents

Anesthetics (tetracaine, proparacaine) inhibit sodium influx into the neuron so the signal cannot propagate. Indications: tonometry, foreign body removal, superficial corneal surgery. Two warnings that matter more than the mechanism: the eye stays numb for 10 to 20 minutes with no blink reflex, so it is unprotected; and do not write prescriptions for these — repeated use is toxic to the epithelium and delays healing.

Cycloplegics come in two flavors with the same endpoint. Antimuscarinics (atropine, cyclopentolate, tropicamide) competitively block muscarinic receptors — the exact opposite of pilocarpine — giving mydriasis. Sympathomimetics (phenylephrine) stimulate the dilator instead, and leave the pupil more reactive to light. Used diagnostically for fundoscopy, and therapeutically in uveitis to prevent synechiae and relieve ciliary spasm. Both cause photosensitivity and blurred vision.

Fluorescein reveals epithelial defects of the cornea and conjunctiva, for anterior segment staining and disclosing corneal injury. Adverse effects are hypersensitivity and burning.

1.8 · Objectives 9–10 — Administration, monitoring and patient education

The instillation sequence, with the step he marks as most important first: wash hands thoroughly; do not let the dropper touch anything; tilt the head back and pull down the lower lid to form a pocket; hold the dropper close without contact; one drop into the pocket; close the eyes, tilt forward and hold a finger over the lacrimal duct; keep the eyes closed two to three minutes; wipe and wash again. The finger on the punctum is the same trick as the silicone plug — keep the drug on the eye and out of the circulation.

Ointments suit children and poor compliers, because they work even if the drug only reaches the lashes. Squeeze a ribbon into the pocket; there is no need to cover the duct. Warn that vision blurs for about 20 minutes — no driving until it clears.

Contact lenses come out. With conjunctivitis, discontinue wear; resume once the eye is uninflamed and free of discharge for 24 hours; and the lens itself is discarded or disinfected first. The eye makeup goes too.

2 · Ear, Nose and Throat Drugs

Adam Wood, Pharm.D., DABAT

2.1 · Objectives 1–3 — Antibiotics for ear, sinus and throat infections

Three infections share one set of bacteria and one first-line drug. Acute otitis media is caused by viruses more often than bacteria; when bacteria are involved they are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, in that order of frequency, and the mix is shifting with vaccination. Acute bacterial rhinosinusitis has the same three, plus Streptococcus pyogenes, Staphylococcus aureus and gram-negative bacilli. Acute pharyngitis is mainly viral; group A beta-hemolytic Streptococcus accounts for 15 to 30% of cases.

Each amoxicillin substitution has a reason worth being able to say out loud. Clavulanate is added when a beta-lactamase producer is likely (sinusitis, recent antibiotics, treatment failure). The macrolide is an allergy option in otitis media, not an equal — half the pneumococci may resist it. Ceftriaxone is the escalation because it is parenteral.

2.2 · Objectives 1–7 — Otic antibiotics

Ear drops usually mix an anti-infective with a glucocorticoid: the antibiotic inhibits bacterial growth and the steroid decreases production of inflammatory cytokines. The agents on the slide are ciprofloxacin, ciprofloxacin/dexamethasone (Ciprodex), neomycin, polymyxin B and hydrocortisone (Cortisporin), and ofloxacin. Indications: otitis media and otitis externa.

2.3 · Objectives 1–8 — Antifungals

The two antifungals are opposites in exposure. Nystatin oral suspension is a nonabsorbable antifungal: it binds sterols in the fungal cell membrane and increases its permeability, stays in the mouth and gut, and so causes nothing worse than diarrhea, nausea, stomach pain and vomiting. Its indication is oral candidiasis, and the slide names three settings that produce it: inhaled steroids, HIV/AIDS and chemotherapy.

Ketoconazole is systemic, for systemic fungal infections, and its mechanism is given as altering fungal cell wall permeability by inhibiting a cytochrome P450 enzyme. That same class of enzyme is why it is dangerous: it is a CYP3A4 (cytochrome P450 3A4) inhibitor, so it raises levels of other drugs. Its own adverse effects are QTc prolongation, hyperlipidemia, orthostatic hypotension, and the liver list — hepatitis, abnormal liver function tests, cirrhosis and hepatic failure.

2.4 · Objectives 2–7 — Aspirin and Reye syndrome

Aspirin (acetylsalicylic acid) is absorbed orally, conjugated in the liver and excreted by the kidneys. It is an irreversible, noncompetitive inhibitor of platelets and is non-selective for cyclooxygenase-1 and cyclooxygenase-2. Irreversible is the word to hold: the platelet it touches stays inhibited, which is where both its antiplatelet use and its bleeding risk come from.

Slide 16 is a dose-effect table. The doses themselves are not examined; the ladder of effects it describes is. As exposure rises, the same drug is first an antiplatelet (complication: bleeding), then an antipyretic and analgesic (bleeding, gastrointestinal upset, nausea, hypersensitivity), then an anti-inflammatory — where tinnitus appears — and finally toxic, as salicylism: hyperventilation and alkalosis, then fever, dehydration and metabolic acidosis, then shock, coma, respiratory and renal failure, and death.

2.5 · Objectives 1–8 — Ibuprofen, naproxen and acetaminophen

Ibuprofen (Motrin, Advil) is an NSAID (nonsteroidal anti-inflammatory drug): anti-inflammatory, analgesic and antipyretic. It reversibly inhibits cyclooxygenase-1 and -2, decreasing prostaglandin synthesis — the contrast with aspirin's irreversible block. Indication: relief of mild to moderate pain. Adverse effects fall in three places: the stomach (gastric or duodenal ulcers, perforation, bleeding), fluid (edema and fluid retention) and the kidney (acute renal failure, decreased creatinine clearance). Naproxen (Aleve) is the other over-the-counter NSAID: a longer half-life, so less frequent dosing.

Ibuprofen contraindications: allergy to the product; it may exacerbate asthma; avoid in children under 6 months; and a past history of stomach ulcer or perforation, or renal dysfunction.

Acetaminophen (Tylenol; acetyl-para-aminophenol) is an analgesic and antipyretic — not an anti-inflammatory — whose mechanism is not fully elucidated. Indications: pain, and fever above 100 °F. It is very well tolerated, with no notable side effects at therapeutic doses. The one interaction: chronic alcohol use with acetaminophen increases the risk of liver damage. Its only listed contraindication is allergy. Its antidote, N-acetylcysteine, reappears in 2.9 as a mucolytic.

2.6 · Objectives 1–6 — Histamine and the H1 antagonists

Histamine is released from immune cells and produces the triple response: redness (direct vasodilation), wheal (edema from post-capillary permeability) and flare (redness around the primary insult, from reflex axonal vasodilation).

The receptor mechanisms (Objective 2): H1 activates phospholipase C (inositol trisphosphate and diacylglycerol raise calcium, contracting venules, so post-capillary permeability rises); causes rapid, short vasodilation through endothelial nitric oxide; raises nasal, bronchial and gastrointestinal mucus; raises smooth muscle tone; stimulates sensory nerve endings; and bronchoconstricts. H2 activates adenylate cyclase (raising cyclic AMP), raises gastric acid, gives slow, long vasodilation, raises cardiac contractility, raises mucus and lowers smooth muscle tone.

H1 antagonists reverse the H1 list: they block gastrointestinal and bronchial smooth muscle contraction and rapid vasodilation, and decrease nasal and bronchial secretions, edema and vascular permeability, hives and itch. Indications: allergic reactions (allergic rhinitis, urticaria, insect bites, drug hypersensitivity); motion sickness, nausea and vestibular disturbances; over-the-counter sleep remedies; and an adjuvant role in anaphylaxis — adjuvant, not the treatment.

Class adverse effects: sedation; gastrointestinal disturbance; the antimuscarinic set — dry mouth, urinary retention, blurred vision; and, with topical use, hypersensitivity (dermatitis, photosensitivity). Azelastine (Astelin) is the H1 antagonist given as a nasal spray, for allergic and vasomotor rhinitis; its side effects are a bitter taste and epistaxis.

2.7 · Objectives 1–8 — Corticosteroids

Slide 41 shows what a glucocorticoid does, cell by cell. On inflammatory cells it reduces numbers of eosinophils (by apoptosis), mast cells and dendritic cells, and cuts cytokines from T lymphocytes and macrophages. On structural cells it reduces cytokine mediators from epithelium, reduces endothelial leak, reduces mucus secretion, and on smooth muscle increases beta-2 receptors while reducing cytokines. The molecular step beneath all of it: the steroid binds its receptor, the complex enters the nucleus and blocks the inflammatory transcription factor NF-kappa-B, so cytokine synthesis is inhibited.

Nasal corticosteroids — beclomethasone (Beconase AQ), budesonide (Rhinocort, over the counter), flunisolide (Nasalide), fluticasone (Flonase, over the counter — not Flovent), mometasone (Nasonex), triamcinolone (Nasacort). Many have inhaled versions for asthma, so do not mix up the names. Indications: allergic and vasomotor rhinitis. Side effects are local: epistaxis, septal perforation, unpleasant taste. No interactions are listed.

Dexamethasone interactions all run through potassium, glucose or clearance: with a diuretic, hypokalemia; with digoxin, a higher risk of arrhythmia because of that hypokalemia; macrolides decrease its clearance; and it decreases the effect of antidiabetic drugs.

2.8 · Objectives 1–8 — Decongestants

All three decongestants are alpha agonists that constrict blood vessels in the nasal mucosa. What separates them is the route and the price.

2.9 · Objectives 1–7 — Cough: antitussives, expectorants and mucolytics

Cough receptors in the respiratory tract respond to chemical and mechanical irritants; the impulse travels a brainstem reflex pathway to the cough center in the medulla oblongata; then deep inspiration, glottis closure and contraction of chest wall, diaphragm and abdominal wall. Complications are insomnia, exhaustion, musculoskeletal pain and hoarseness, and less often dysrhythmias, syncope, stroke and rib fractures. Treatment goals: reduce the number and severity of episodes, and prevent complications.

Three more agents thin sputum in lung disease. Dornase alfa (Pulmozyme), nebulized, is a DNA enzyme that selectively cleaves DNA from the nuclei of degenerating neutrophils, reducing the viscosity of cystic fibrosis sputum; it improves lung function and reduces exacerbations in mild to moderate disease, and helps severe disease less. Hypertonic saline, inhaled, is reported to improve the rheology and transport of mucus, airway surface hydration, mucociliary clearance and lung function. N-acetylcysteine (Mucomyst), traditionally the treatment for acetaminophen toxicity, is mucolytic when nebulized: it splits the disulfide bonds linking mucoproteins. Inhaled, it smells of rotten eggs (its sulfur), causes nausea and vomiting, and can cause bronchospasm.

2.10 · Objectives 9–10 — Protocols, monitoring and patient education

Protocols. Otitis media is judged to have failed treatment at 3 days without improvement. Sinusitis must meet the 10-day or worsening test before it is treated as bacterial. Pharyngitis is confirmed with a rapid strep test before prescribing. Treatment durations on the slides: otitis media 5 to 7 days, possibly up to 10 (5 may be too short for severe disease); sinusitis 10 to 14 days in children and 5 to 7 in adults; strep pharyngitis 10 days of amoxicillin, or one benzathine penicillin injection.

3 · Antihypertensive Drugs

Adam Wood, Pharm.D., DABAT

3.1 · Objectives 1–2 — The renin-angiotensin system the drugs act on

Renin release is controlled three ways: the renal baroreceptor (less renal perfusion, more renin), the macula densa, which senses sodium and chloride in the distal tubule, and the sympathetic nervous system, through beta-1 receptors on the juxtaglomerular cells. The slide prints the macula densa line without its arrow; in lecture he gave the direction as a decrease in sodium or chloride stimulating renin release.

Renin makes angiotensin I; ACE turns it into angiotensin II; and the same enzyme breaks down bradykinin. Angiotensin II acts at the AT1 receptor (heart, endothelium, vascular smooth muscle, kidney) to cause vasoconstriction and renal vasoconstriction, aldosterone secretion, sodium reabsorption, increased norepinephrine release and central sympathetic outflow, thirst and antidiuretic hormone, and cell hypertrophy with cardiac remodeling after a myocardial infarction. Overactivity of the system drives hypertension, heart failure, diabetic nephropathy and post-infarction remodeling — which is why those are the indications for the drugs that block it.

3.2 · Objectives 1–10 — ACE inhibitors

Agents (-pril): captopril, lisinopril, enalapril (whose active form, enalaprilat, is the intravenous one), benazepril, fosinopril, trandolapril, quinapril, ramipril, perindopril, moexipril. They share an identical mechanism and differ only in half-life and metabolism; most are dosed once daily, captopril more often because its half-life is short, and when the effect wears off before the next dose a twice-daily schedule is used.

Mechanism: blocking ACE lowers angiotensin II, so there is less vasoconstriction and renal vasoconstriction, less aldosterone and sodium reabsorption, and less angiotensin-driven norepinephrine release; bradykinin metabolism falls; and with the negative feedback gone, angiotensin I and renin rise.

Indications. Hypertension — lowering total peripheral resistance, systolic and diastolic pressure, and left ventricular hypertrophy — and preferred in diabetics (kidney protective effects). Left ventricular dysfunction and heart failure, where they reduce remodeling, afterload and preload, raise cardiac output and cut infarctions and hospital admissions: ACE inhibitors should be given to all with LV dysfunction unless contraindicated. After a myocardial infarction, to reduce remodeling and overall mortality. And diabetic nephropathy, by lowering glomerular pressure.

Interactions: NSAIDs (nonsteroidal anti-inflammatory drugs) decrease the ACE inhibitor effect — the slide’s reason is that they block the prostaglandin-mediated relaxation bradykinin produces; potassium-sparing diuretics, potassium supplements and salt substitutes cause hyperkalemia; several antihypertensives together raise the risk of first-dose hypotension. No drug-food or drug-herb interaction is given for any class in this lecture.

3.3 · Objectives 1–8 — Angiotensin receptor blockers

Agents (-sartan): candesartan, olmesartan, losartan, azilsartan, eprosartan, irbesartan, telmisartan, valsartan. Why they exist: ACE is not the only enzyme that makes angiotensin II — trypsin, cathepsin and chymase do too — so an ACE inhibitor never removes it completely. Mechanism: high-affinity, slowly dissociating, sustained blockade of the AT1 receptor, giving vasodilation, renal vasodilation, less aldosterone, less sodium reabsorption and less norepinephrine release.

Indications: hypertension; left ventricular dysfunction when an ACE inhibitor cannot be tolerated; diabetic nephropathy. AT1 receptors are saturated at starting doses, so raising the dose changes blood pressure little; adding a diuretic increases the effect, most come as combinations, and a diuretic helps in salt-sensitive hypertension, where they are less effective alone. In heart failure, start low and titrate up.

Adverse effects are the ACE inhibitor list minus bradykinin: hyperkalemia — renal disease or K+ sparing diuretics; first-dose hypotension; impaired renal function; and fetal morbidity and mortality — not given in the 2nd and 3rd trimesters.

3.4 · Objectives 1–8 — Calcium channel blockers

All calcium channel blockers block the L-type calcium channel, found in vascular smooth muscle, cardiac myocytes and the sinoatrial and atrioventricular nodes. Two facts shape the whole class. At therapeutic doses they do not reduce venous tone, so they lower afterload without changing preload. And because arteries depend on calcium from outside the cell while myocytes also draw on the sarcoplasmic reticulum, arteries are 3 to 10 times more sensitive to these drugs than the myocardium. Class uses: angina, hypertension, supraventricular arrhythmias, diastolic heart failure, cerebral ischemia and migraine prophylaxis.

Non-dihydropyridines: diltiazem (Cardizem) and verapamil (Calan)

Intravenous or oral. Indications: angina, hypertension, and supraventricular tachycardia — atrial fibrillation or flutter, paroxysmal supraventricular tachycardia. Adverse effects: peripheral vasodilation (flushing, headache, hypotension, peripheral edema, dizziness); the cardiac set — first-degree AV block, bradycardia, exacerbation of congestive heart failure; gastrointestinal effects, including constipation, which is worth asking the patient about; raised liver enzymes; central effects; gynecomastia or sexual dysfunction; gingival hyperplasia; skin reactions. Contraindications: advanced heart block and hypotension; relatively, heart failure, liver disease and gastroesophageal reflux disease.

Pharmacodynamic interactions: amiodarone (slower sinus rate, worse atrioventricular block), digoxin, and beta blockers — with a beta blocker the effects on blood pressure, heart rate and contractility are synergistic, so in combination use lower doses of each. CYP3A4 inhibitors lengthen the non-dihydropyridine’s own half-life.

Dihydropyridines (-dipine)

Oral only, except nicardipine, which has an intravenous form. Amlodipine, nifedipine and nicardipine treat angina and hypertension; felodipine, isradipine and nisoldipine, hypertension; nimodipine, subarachnoid hemorrhage. Adverse effects: peripheral vasodilation — peripheral edema, dyspnea, wheezing and rebound tachycardia, the heart’s reflex answer to an abrupt fall in resistance; gastrointestinal, central and skin effects; gynecomastia; gingival hyperplasia. Contraindications: severe aortic stenosis, and unstable angina or a recent myocardial infarction with the immediate-release form — avoid short-acting formulations. Interactions: amiodarone, digoxin and beta blockers pharmacodynamically; and CYP3A4 inhibitors lengthen their half-life.

3.5 · Objectives 1–8 — Beta blockers

Mechanism: competitive block of cardiac beta-1 (lower cardiac output, an acute reflex rise in peripheral resistance, reduced exercise tolerance); of the beta-1 receptors that release renin (less angiotensin II); of presynaptic beta-2 (less norepinephrine release); and of pulmonary beta-2 (less bronchial relaxation, so bronchospasm in asthma); plus central reduction of sympathetic activity and an altered baroreflex. Blood pressure falls only chronically, once the baroreflex resets.

Indications. Hypertension — but not recommended for first line management of HTN (hypertension). The slide adds that they work best in young patients with resting tachycardia, high catecholamines and high renin, that fatigue and limited exercise are the common complaints, and that they are still useful in the elderly. Beyond hypertension: glaucoma (timolol, betaxolol, carteolol — less aqueous humor), migraine prophylaxis (propranolol, timolol), hyperthyroidism (less tachycardia, tremor and anxiety, and less peripheral conversion of T4 to T3), angina (longer exercise time), acute myocardial infarction (avoid agents with intrinsic sympathomimetic activity), supraventricular arrhythmias (atrioventricular nodal block), acute panic attacks, benign essential tremor (skeletal muscle beta-2), and heart failure.

Interactions. Verapamil and diltiazem: synergistic falls in blood pressure, heart rate and contractility — use lower doses of each. Clonidine: the combination lowers blood pressure further, and abrupt clonidine withdrawal causes a severe rise in blood pressure (the slide’s label of clonidine as an alpha-2 “blocker” is a slip; it is an agonist, 3.7). Beta blockers also enhance prazosin’s postural hypotension.

3.6 · Objectives 1–8 — Alpha-1 blockers

Mechanism: reversible block of vascular alpha-1 receptors, dilating precapillary arterioles and lowering peripheral resistance, with a reflex rise in heart rate. Prazosin (Minipress) is the prototype, used for hypertension with beta blockers and diuretics; it slightly lowers LDL (low-density lipoprotein) cholesterol and triglycerides and raises HDL (high-density lipoprotein). Its adverse effects: orthostatic hypotension and postural dizziness, headache, drowsiness, lack of energy; a mild reflex tachycardia; raised renin with sodium and water retention; impotence. Use with caution in cardiac and renal failure. NSAIDs attenuate its response; beta blockers may enhance the postural hypotension.

Terazosin (Hytrin) and doxazosin (Cardura) have longer half-lives, so once daily, and treat hypertension and benign prostatic hyperplasia. Tamsulosin (Flomax) is alpha-1A selective: it treats benign prostatic hyperplasia with limited vascular effect, because vascular receptors are alpha-1B. Its adverse effects are hypotension, dizziness and diarrhea.

3.7 · Objectives 1–8 — Central sympatholytics

Mechanism: stimulation of postsynaptic alpha-2 (alpha-2A) receptors, and possibly imidazoline receptors, in the nucleus of the solitary tract and ventrolateral medulla, which lowers sympathetic outflow through the spinal cord and ganglia to the vessels and raises vagal output to the heart — so resistance, heart rate and cardiac output all fall. Advantages: efficacy independent of age, race and gender; suitable for monotherapy; work well in the elderly; no negative effects on lipids. Class side effects: drowsiness and sedation, dry mouth, sexual dysfunction, a narrow therapeutic range, and abrupt withdrawal hypertension.

Clonidine (Catapres) is an alpha-2 agonist and imidazoline agonist. It raises blood glucose by inhibiting insulin secretion and lowers antidiuretic hormone secretion. It causes sodium retention, so it is often given with a diuretic, plus dry mouth, sedation, orthostatic hypotension, impotence, bradycardia and withdrawal reactions (may be severe). Beyond blood pressure it has analgesic activity and blunts opiate withdrawal reactions. Guanfacine (Tenex) is less potent, the most selective for alpha-2 over alpha-1, less sedating, and only occasionally causes a withdrawal syndrome.

3.8 · Objectives 1–7 — Direct vasodilators

They dilate arterioles directly and lower resistance, and the body fights back: reflex sympathetic activation brings tachycardia, higher cardiac output, fluid retention and more renin, which in turn produces tachyphylaxis. For chronic hypertension they are given with a diuretic and a beta blocker: hydralazine, and minoxidil as triple therapy for severe or refractory hypertension. Nitroprusside, by intravenous infusion, is for hypertensive crisis.

Hydralazine (Apresoline) is N-acetylated in liver — fast and slow acetylators. Adverse effects: reflex rise in cardiac output and fluid volume; headache, dizziness, flushing; and a drug-induced “lupus syndrome” — high dose, long term, women, slow acetylators, Caucasians. Contraindicated in coronary artery disease, the elderly, and ischemia, because it adds sympathetic workload. Patient education: stools may turn black — warn ahead of time about any drug that changes stool or urine color.

Minoxidil (Loniten) has the harshest reflexes (cardiac output two to three times, renin stimulated), so myocardial ischemia; arrhythmias from its potassium channel action; and hypertrichosis of the face, back, arms and legs. Rogaine is the topical form for hair growth, and may have cardiovascular effects.

Nitroprusside (Nitropress) toxicity comes from its cyanide groups. Cyanide toxicity (trembling, vomiting, convulsions) is limited by giving sodium thiosulfate. Thiocyanate toxicity (weakness, anoxia, tinnitus, muscle spasms, toxic psychosis) follows long infusions or renal failure.

3.9 · Objectives 9–10 — The treatment algorithm, monitoring and patient education

Slide 108 is a picture of the management algorithm, and it is the deck’s only protocol content. Every motivated patient gets lifestyle counseling first. Then:

Reasons to reach for another class earlier (inset 1): a beta blocker should generally be used first after a myocardial infarction, and beta blockers are among the first drugs in heart failure with reduced ejection fraction. (The diuretic, mineralocorticoid-antagonist and heart-failure indications on the same inset belong to Lecture 9.) Beta blockers, non-dihydropyridines and alpha blockers are otherwise for these compelling indications, not first line.

4 · Drugs that Lower Cholesterol and Triglyceride Levels

Adam Wood, Pharm.D., DABAT

4.1 · Objectives 1–2 — Lipid transport, and the memory aid

Two sources of fat. Dietary (exogenous) fat is packed in the intestine into chylomicrons, carried by the lymph to the blood, stripped of triglyceride by lipoprotein lipase (releasing free fatty acids and glycerol), and the chylomicron remnant is removed by the liver through the LDL receptor-like protein. The liver makes its own (endogenous) triglyceride-rich VLDL from carbohydrate and fatty acids; lipoprotein lipase turns it into IDL, about half of which becomes LDL while half returns to the liver. In the enterocyte, dietary cholesterol is taken up through a cholesterol transporter (NPC1L1) and esterified before packaging.

LDL has one apolipoprotein, ApoB-100, the ligand for its receptor. About 75% of LDL is cleared by the LDL receptor, most of it in the liver; the receptor carries LDL into the cell, the lysosome breaks it down and releases its cholesterol, and the receptor returns to the surface. Less receptor activity means LDL accumulates, and atherosclerosis follows. Oxidized LDL enters macrophages through scavenger receptors (CD36 and SR-A). HDL is made in the intestine and liver and is catabolized by handing cholesteryl ester to VLDL and LDL and by hepatic uptake.

4.2 · Objectives 1–8 — Statins

Class and agents: HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors — lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin. Mechanism: Reduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic circulation. LDL, VLDL remnants and IDL all fall. They also have pleiotropic effects beyond lipids: better endothelial function, plaque stabilization, inhibition of vascular smooth muscle growth, platelet inhibition, reduced leukocyte adhesiveness and inflammatory markers, among others.

Contraindications: hepatic disease; pregnancy. Relative: concomitant cyclosporine or other immunosuppressants, gemfibrozil, niacin and erythromycin. Pregnancy puts statins in the same group as ACE inhibitors and angiotensin receptor blockers from Lecture 6 — the three he called a “no-go”. The contrast that makes a good question: the bile acid sequestrants are approved in pregnancy (4.4).

4.3 · Objectives 1–8 — Ezetimibe

Ezetimibe (Zetia), the cholesterol absorption inhibitor, selectively inhibits intestinal cholesterol absorption at the brush border, so less cholesterol reaches the liver, hepatic LDL receptors increase, and atherogenic particles carry less cholesterol. With a statin it gives “dual inhibition” of the two sources — the statin on synthesis, ezetimibe on absorption — and adds further LDL lowering. Absorption and metabolism: ezetimibe and its active glucuronide metabolite circulate enterohepatically, which returns the drug to its site of action and limits systemic exposure; it may be taken with or without meals.

4.4 · Objectives 1–8 — Bile acid sequestrants

Agents: cholestyramine (Questran), colestipol (Colestid), colesevelam (Welchol). Mechanism: they bind bile acids in the gut and prevent their enterohepatic recirculation at the terminal ileum, so they are lost in the feces. The liver makes more bile acid from cholesterol (cholesterol 7-alpha-hydroxylase rises) and makes more LDL receptors, so LDL and VLDL are removed and LDL cholesterol falls.

Adverse effects: gastrointestinal — bloating, flatulence, fullness, constipation, nausea; malabsorption of vitamins A, D, E and K and of folic acid; the resin’s chloride raises calcium excretion; raising the dose may add side effects without more benefit; and one that turns into a contraindication: may increase VLDL production → ↑ TG (triglycerides).

4.5 · Objectives 1–8 — Fibrates

Agents: gemfibrozil (Lopid), fenofibrate (Tricor), bezafibrate (Bezalip SR). Mechanism: activates PPAR-alpha (peroxisome proliferator-activated receptor alpha, a nuclear transcription factor) → more fatty acid oxidation → less secretion of triglyceride-rich VLDL → decrease in triglycerides; and increases expression of ApoA-1 → increase in HDL. The figure adds more lipoprotein lipase and less ApoC-III.

His example stem: a patient whose only problem is very high triglycerides — which drug is best at lowering them? “It’s either the fibrates or” niacin.

4.6 · Objectives 1–8 — Niacin

Niacin (nicotinic acid) is a B-complex vitamin; its amide, niacinamide (nicotinamide), is not an antilipemic. Mechanism: it reduces the mobilization of free fatty acids from adipose tissue, so the liver makes less triglyceride and less VLDL and apolipoprotein B, so less LDL is formed; and HDL rises — the largest HDL rise of any class. Products come as immediate release (a supplement, and Niacor), long-acting (supplement) and extended release (Niaspan). Indication: atherogenic dyslipidemia, including in combination when LDL is also high.

Each relative contraindication is one of niacin’s own adverse effects meeting a patient who already has it: raised uric acid in gout, raised glucose in diabetes, the liver in liver disease. The lovastatin/niacin extended-release combination (Advicor) carries the adverse effects of both — hepatotoxicity, myopathy and flushing.

4.7 · Objectives 1–6 — PCSK9 inhibitors

Alirocumab (Praluent) and evolocumab (Repatha) — the -mab tells you they are monoclonal antibodies, so they are injectable only, and they are expensive. PCSK9 (proprotein convertase subtilisin/kexin type 9) is responsible for processing hepatic LDL receptors; blocking it keeps LDL receptors active longer, and LDL falls by roughly half. The most serious adverse reaction is hypersensitivity. The slide gives no indications, contraindications or interactions.

4.8 · Objective 3 — Which class for which lipid

4.9 · Objectives 9–10 — Guidelines, monitoring and patient education

The older Adult Treatment Panel III (ATP III) goals were numbers: LDL under 100 mg/dL optimal, HDL over 60 high and under 40 low, total cholesterol under 200, triglycerides under 150. HDL rises with exercise. The American Heart Association and American College of Cardiology (AHA/ACC) guideline aims to reduce atherosclerotic cardiovascular disease (ASCVD) risk, the leading cause of death and disability in America, and changed the approach:

Statin intensity is defined by the LDL reduction it produces: high, 50% or more; moderate, 30 to 49%; low, under 30%. Only atorvastatin and rosuvastatin reach high intensity. Safety: choose the appropriate dose; keep side effects and drug interactions in mind; and if high- or moderate-intensity therapy is not tolerated, use the maximum tolerated dose.

The algorithm on slide 66 (adults without cardiovascular disease) runs: measure LDL and counsel everyone on lifestyle; LDL 190 mg/dL or more → evaluate for familial hypercholesterolemia, and if absent start a high-intensity statin; otherwise calculate 10-year risk and branch — start a moderate-dose statin, discuss it with the patient, or repeat screening. After starting, repeat LDL in 6 weeks and expect a 30 to 50% fall; if it has not fallen, evaluate compliance. (The algorithm’s risk cut-offs are not the same as the 7.5% on the benefit-group slide; no question should turn on the difference.)

5 · Myocardial Ischemia Drug Therapy

Adam Wood, Pharm.D., DABAT

5.1 · Objectives 1–3 — Angina, and the oxygen supply-and-demand frame

Ischemic heart disease is an imbalance between the oxygen supply and the oxygen demand of the heart muscle [slide 4]. Less blood flow to the tissue means a lack of oxygen supply [slide 4]. Coronary heart disease is atherosclerotic narrowing of one or more coronary arteries [slide 4]. Angina pectoris is the clinical manifestation of myocardial ischemia: chest pain [slide 4]. Chronic stable angina is listed as the chronic counterpart of acute coronary syndrome [slide 4]. Acute coronary syndrome groups unstable angina, acute myocardial infarction and sudden cardiac death [slide 4].

Angina is a late, symptomatic manifestation of ischemia that may occur with any degree of stenosis [slide 7]. (Slide 7 calls it “latent”; angina is the symptomatic phase, not a hidden one.) A narrowing of 50 percent of the left main coronary artery, or 75 percent of another major coronary artery, is considered clinically significant [slide 7]. A stenosis above 90 percent severely limits flow (the slide says “virtually no flow”), so ischemia can occur even at low demand [slide 7].

The two sides of the balance [slides 5 and 6]

Wall tension is the tension in the heart wall [slide 6]. It is affected by ventricular volume and pressure and is a function of preload and afterload [slide 6]. Preload is the initial stretching of the cardiac muscle cells before contraction; it tracks ventricular and diastolic volume [slide 6]. Afterload is the pressure the heart must eject blood against; it tracks systemic vascular resistance [slide 6].

Risk factors, goals and strategy [slides 9 to 11]

The three treatment arms and the drug classes (Objective 1) [slides 12 to 14]

Prevention of anginal attacks: metoprolol and other beta blockers, calcium channel blockers and long-acting nitrates are taken to prevent attacks; they are not rescue drugs. Rescue for an attack: sublingual nitroglycerin [slides 12, 14, 27 and 29].

The antianginal drugs improve exercise capacity, reduce exercise-induced ST-segment changes and decrease the frequency of symptoms [slide 14]. Of the three antianginal classes, nitrates lower oxygen demand mainly by reducing left ventricular volume, which lowers wall tension [slides 6 and 25]. The calcium channel blockers come in two subclasses, dihydropyridine and non-dihydropyridine [slide 14]. The slide-13 overview groups the drugs by effect: calcium channel blockers, nitrates and beta blockers decrease heart rate, contractility and systolic wall tension; calcium channel blockers, nitrates, aspirin and clopidogrel are listed under increasing coronary blood flow [slide 13].

Grades of angina [slide 15]

The higher the class, the less activity it takes to bring on symptoms. Only class IV may cause symptoms at rest [slide 15]. (The usual grading describes class I as angina only with strenuous exertion; the slide’s “none” means none with ordinary activity.)

Chronic stable angina is the chronic form of angina, and it is graded I to IV by how much activity brings on the symptoms; in classes I to III the patient is comfortable at rest [slides 4 and 15]. Read together with slide 41, unstable angina belongs to acute coronary syndrome, and a biochemical marker is what separates unstable angina from myocardial infarction, so a long-standing, unchanged exertional pattern with normal biomarkers is chronic stable angina rather than acute coronary syndrome.

5.2 · Objectives 1–7 — Beta blockers

Beta blockers are first line therapy for angina in the absence of contraindications [slide 17]. They are useful in patients with limited exercise capacity due to angina, and in patients who also have hypertension, anxiety, supraventricular arrhythmias, heart failure (stable, compensated; see below), or a prior myocardial infarction [slide 17].

Either beta-1 selective or non-selective agents may be used [slide 17]. Metoprolol and atenolol are the beta-1 selective beta blockers [slide 17]. Propranolol and nadolol are non-selective beta blockers [slide 17], and non-selective (non-cardioselective) beta blockers are avoided in asthma; cardioselective beta blockers and non-dihydropyridine calcium channel blockers remain options there [slide 34].

Mechanism (Objective 2). Beta blockers act on the demand side only. They decrease heart rate and contractility and lower systolic blood pressure, and they have no effect on oxygen supply [slide 16]. Their effect on left ventricular volume is an increase [slide 16]. The receptor-level mechanism is taught with the antihypertensives (section 3.5); here only the hemodynamic result is on the slides.

This table is the deck’s hemodynamic summary of all three antianginal classes [slides 16, 20 and 25]. Read it across: beta blockers and non-dihydropyridines slow the heart, while the dihydropyridines as a class and nitrates raise the rate.

Beta blockers may worsen claudication (leg pain with walking); worsened claudication is a listed beta blocker adverse reaction, and peripheral vascular disease is a listed precaution [slides 18 and 19]; read together, they suggest that claudication is the reason for the precaution. Beta blockers as a class, including non-selective agents such as nadolol and propranolol, can cause fatigue, sexual dysfunction, nightmares and worsened claudication [slides 17 and 19].

Hypotension is listed for all three antianginal classes: beta blockers [slide 19], calcium channel blockers [slide 24] and nitrates, as postural hypotension [slide 31]. All three lower systolic blood pressure [slides 16, 20 and 25].

Two entries that look alike are the ones to keep apart: systolic heart failure is a precaution, acute decompensated heart failure is a contraindication [slide 18]. Slide 17 lists heart failure among the conditions a beta blocker helps. Read together, slides 17 and 18 imply that the line is between stable and acutely decompensated failure.

Monitoring is of heart rate, blood sugar and lipids [slide 19]. Education: avoid rapid discontinuation; expect dizziness and fatigue [slide 19]. The reason to avoid stopping suddenly is given with the antihypertensive beta blockers (section 3.5): abrupt withdrawal can cause angina, myocardial infarction and high blood pressure. That reason is not on this lecture’s slides.

5.3 · Objectives 1–7 — Calcium channel blockers

Mechanism (Objective 2). Calcium channel blockers lower oxygen demand and raise supply [slide 20]. On the supply side they give mild dilation in areas of fixed stenosis and relief of vasospasm [slide 20]. On the demand side the two subclasses differ, as the hemodynamic table in 5.2 shows: non-dihydropyridines slow the heart rate and weaken contraction; dihydropyridines lower systolic blood pressure strongly and raise the heart rate [slide 20].

This is the deck’s calcium channel blocker table [slide 21]. The simple split: the non-dihydropyridines (diltiazem, verapamil) act on the heart — rate, contractility and atrioventricular conduction — while the dihydropyridines (nifedipine, amlodipine, felodipine) act on the vessels, with the most vasodilation and no change in atrioventricular conduction. On slide 21 diltiazem and verapamil both decrease contractility strongly; verapamil has the larger effect on atrioventricular conduction. Among the dihydropyridines, nifedipine and felodipine raise the heart rate while amlodipine leaves it unchanged [slide 21].

Place in therapy and drug choice [slide 22]

The switch when a beta blocker is not tolerated: a patient who cannot tolerate a beta blocker (for example because of nightmares and fatigue) and has no contraindication is switched to a non-dihydropyridine calcium channel blocker such as diltiazem or verapamil, the initial substitute [slides 19 and 22].

The slide gives no reason for avoiding short-acting nifedipine, only the instruction to avoid short-acting agents.

Calcium channel blockers improve myocardial oxygen supply by relief of coronary vasospasm and by mild dilation in areas of fixed stenosis, and they also lower demand [slide 20]. Headache, flushing and peripheral edema (ankle swelling) are the typical effects of a dihydropyridine [slide 24]; nitrates share headache and flushing with the dihydropyridines [slide 31].

Verapamil and diltiazem lower heart rate and slow atrioventricular conduction [slide 21]; beta blockers also lower heart rate [slide 16]. Read together with slide 23, which lists concurrent beta blocker use as a precaution for non-dihydropyridines, combining verapamil or diltiazem with a beta blocker calls for caution because the effects are additive: additive bradycardia and conduction delay.

CYP3A4 (cytochrome P450 3A4). Verapamil and diltiazem, the non-dihydropyridines, inhibit CYP3A4 and are also substrates of it; the dihydropyridines such as amlodipine are only substrates (section 3.4). Slide 23 lists CYP3A4 interactions as a precaution. The worked example crosses to the lipid section: simvastatin is a CYP3A4 substrate (section 4.2), so a patient on verapamil who is then given simvastatin has higher simvastatin levels. In plain terms: adding simvastatin to a patient taking verapamil raises simvastatin levels because verapamil inhibits cytochrome P450 3A4, which clears simvastatin, so the main risk is statin muscle and liver toxicity (the statin adverse effects are in section 4.2).

Monitoring: relief of symptoms, and heart rate for the non-dihydropyridines [slide 24]. Education: dizziness and constipation [slide 24]. The pairing caution is the one to remember: concurrent beta blocker use is a precaution for the non-dihydropyridines [slide 23], and the dihydropyridine is the calcium channel blocker named for combining with a beta blocker [slide 22]. The interacting agents of the non-dihydropyridines (statins, digoxin and others) are in section 3.4.

5.4 · Objectives 1–7 — Nitrates

Mechanism (Objective 2) [slide 26]

1. Nitrates supply nitric oxide.
2. Nitric oxide stimulates the conversion of guanosine triphosphate to cyclic guanosine monophosphate.
3. Cyclic guanosine monophosphate activates protein kinase G, which lowers cytosolic calcium.
4. Lower calcium gives smooth muscle relaxation, vasodilation and lower blood pressure.
5. Phosphodiesterase type 5 breaks cyclic guanosine monophosphate down to inactive guanosine monophosphate.
6. Sildenafil, tadalafil and vardenafil inhibit phosphodiesterase type 5, so cyclic guanosine monophosphate builds up. Together with a nitrate this is the drug interaction the slide shows.

On the demand side nitrates lower systolic blood pressure and, most strongly, left ventricular volume, while the heart rate rises [slide 25]. On the supply side they dilate the coronary arteries, relieve vasospasm and have antithrombotic and antiplatelet effects [slide 25].

Short-acting nitrates [slides 27 and 28]

Long-acting nitrates [slides 29 to 31]

Tachyphylaxis and the nitrate-free interval [slide 32]

Tachyphylaxis is the loss of effect with continued dosing; the slide lists it as a consideration with nitrates. Its mechanism is not fully understood. Proposed contributors are depletion of cofactors, stimulation of counter-regulatory responses (the renin-angiotensin system and the sympathetic nervous system), plasma volume expansion, and decreased enzyme activity. The management is a nitrate-free interval, placed when the patient has the lowest symptom frequency. That is why the ointment and the patch are worn 12 hours on and 12 hours off.

Absorption, distribution, metabolism and excretion (Objective 4)

The slides give routes and durations only. Short-acting nitroglycerin is taken under the tongue as a tablet or a spray [slides 27 and 28]. Long-acting nitrates come as isosorbide mononitrate (12 hours) and isosorbide dinitrate (3 to 6 hours), and as nitroglycerin ointment and a transdermal patch worn 12 hours on and 12 hours off [slides 30 and 31]. In acute coronary syndrome the sublingual route is followed by an intravenous infusion in the hospital [slide 54]. No metabolism or excretion is given.

Long-acting nitrates are usually used as add-on (adjunctive) therapy, added when a beta blocker or calcium channel blocker is not enough [slide 29]. Nitrates lower left ventricular volume the most of the three antianginal classes, which lowers wall tension, while the heart rate rises [slides 6 and 25]. Reflex tachycardia is a nitrate adverse reaction, a reflex rise in heart rate that follows the fall in blood pressure; it is listed with headache, flushing and postural hypotension [slide 31]. In acute coronary syndrome, nitroglycerin and the other nitrates relieve chest pain but show no mortality benefit; they start sublingually and move to an intravenous infusion in hospital [slides 52 and 54].

Contraindications (Objective 7) [slide 33]

A nitrate, including nitroglycerin, is contraindicated in obstructive cardiomyopathy, in aortic valve stenosis, and with phosphodiesterase type 5 inhibitors.

• Aortic valve stenosis is a contraindication to nitrates.
• Obstructive cardiomyopathy is a contraindication to nitrates.
• Concurrent use of phosphodiesterase inhibitors: sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra). Concurrent use may lead to hypotension and myocardial infarction or stroke.

5.5 · Objectives 1–3 and 7 — Add-on therapy, comorbid conditions and variant angina

Combination therapy [slide 36]

Consider combination therapy if angina persists with monotherapy [slide 36]. A beta blocker and a calcium channel blocker may be combined if the patient can tolerate it, and there is some evidence that this increases exercise duration [slide 36]. If a third agent seems needed, the patient probably needs further workup, such as angiography [slide 36]. (In practice the calcium channel blocker paired with a beta blocker is a dihydropyridine, as slide 22 says.)

Which drug for which comorbid condition [slide 34]

Where the table and current practice agree: a beta blocker is first line after a myocardial infarction, with hypertension, and with reduced left ventricular function (amlodipine is the calcium channel blocker alternative there and the other calcium channel blockers are avoided); a dihydropyridine is first line with bradycardia or atrioventricular block, and non-dihydropyridines and beta blockers are avoided; and a non-cardioselective beta blocker is avoided in asthma [slide 34]. Slide 18 lists reactive airway disease as a beta blocker precaution, which agrees. In asthma the cardioselective beta blockers the table lists are used with caution [slides 18 and 34]. In a patient with angina and asthma, non-selective beta blockers such as propranolol are avoided, while cardioselective beta blockers and non-dihydropyridine calcium channel blockers remain options [slide 34].

Angiotensin-converting enzyme inhibitors [slide 35]

These are used in patients with coronary artery disease who also have diabetes and/or left ventricular systolic dysfunction [slide 35]. They do not significantly affect myocardial oxygen consumption and do not relieve the symptoms of angina [slide 35]. They may help prevent progression of coronary artery disease [slide 35]. They should be used indefinitely after a myocardial infarction, with left ventricular dysfunction, or with diabetes [slide 35]. They should be considered in all patients with coronary artery disease or other vascular disease [slide 35]. They are vasculoprotective, not antianginal [slide 12].

Antiplatelet therapy [slide 37]

Aspirin is given in the absence of contraindications [slide 37]. Aspirin is used in ischemic heart disease for preventing acute coronary syndromes: it is given to every patient with ischemic heart disease who has no contraindication, to prevent acute coronary syndrome rather than to relieve symptoms [slide 37]. Its place in therapy is to prevent acute coronary syndrome, in all patients with ischemic heart disease who have no contraindication [slide 37]. The slide gives about a 30 percent reduction in the risk of primary events with aspirin. Clopidogrel is as efficacious as aspirin in secondary prevention and is recommended for patients allergic to aspirin [slide 37].

The whole strategy on one slide [slide 38]

Variant angina [slides 8 and 39]

Calcium channel blockers and nitrates can reduce symptoms of variant angina, because both relieve vasospasm [slides 20, 25 and 39]. Avoid beta blockers: they may lead to worsened symptoms [slide 39]. In variant angina the usual first line drug, the beta blocker, is the one to avoid [slide 39].

5.6 · Objectives 1–3 — Acute coronary syndrome and thrombus formation

Classification [slide 41]

Acute coronary syndrome has two branches [slide 41]. ST-segment elevation myocardial infarction is one. Non-ST-segment elevation acute coronary syndrome is the other, and it contains unstable angina and non-ST-elevation myocardial infarction [slide 41]. The figure on the slide runs as follows: ischemic discomfort leads to a working diagnosis of acute coronary syndrome; the electrocardiogram then splits it, with no ST elevation giving unstable angina or non-ST-elevation myocardial infarction (also called non-Q-wave myocardial infarction), and ST elevation giving ST-elevation myocardial infarction (drawn on the slide as Q-wave myocardial infarction); a biochemical marker separates unstable angina from myocardial infarction. The heart cross-sections at 1 hour, 4 hours and 8 hours show the infarct growing into the area of ischemia [slide 41]. Slide 4 lists sudden cardiac death under acute coronary syndrome; the working classification on slide 41 is ST-elevation myocardial infarction versus non-ST-elevation acute coronary syndrome.

ST-elevation myocardial infarction is the branch with ST elevation on the electrocardiogram in a patient with ischemic discomfort [slide 41]; it is the form for which fibrinolytics are indicated [slide 65]. If coronary blood flow is not restored, the infarct grows over hours into the area of ischemia [slide 41]; read together with slide 51, this is why reestablishing coronary blood flow is a goal of therapy.

How a thrombus forms, step by step [slides 42 to 50]

1. The plaque. The vessel wall has endothelium, smooth muscle cells, and an atherosclerotic plaque under a fibrous cap [slide 42].
2. Injury. A procedural injury such as balloon deployment, or a spontaneous injury, leaves injured endothelium [slide 43].
3. Platelets respond. Platelet adhesion, activation and aggregation occur at the plaque [slide 44].
4. Fibrin forms. Fibrin strands form [slide 45].
5. The occlusive thrombus. The clot blocks the artery [slide 46].

Thrombin is the link between tissue injury, coagulation and the platelet response [slide 47]. Exposed collagen leads to release of adenosine diphosphate and thromboxane A2, which activate and aggregate platelets [slide 47]. Tissue factor starts the plasma clotting cascade; prothrombin becomes thrombin, and thrombin turns fibrinogen into fibrin, which forms the thrombus [slide 47]. Thrombin is a critical mediator in coagulation and elicits multiple responses in platelets [slide 47].

Goals of therapy [slide 51]

The five goals are to reestablish coronary blood flow, relieve chest pain, prevent progression to myocardial infarction, prevent the development of heart failure, and prevent death [slide 51].

5.7 · Objectives 1–7 — Acute coronary syndrome: aspirin, nitrates, beta blockers, morphine

Aspirin, nitrates and beta blockers are the common pharmacologic therapy for both ST-elevation myocardial infarction and non-ST-elevation acute coronary syndrome [slide 52].

Because the beta blocker cautions in acute coronary syndrome are bradycardia and hypotension [slide 55], heart rate and blood pressure are the findings to check before and after a beta blocker is given (read together with slide 55).

The slides separate what each drug does for the patient’s survival from what it does for the patient’s pain: aspirin and beta blockers change outcomes; nitrates only relieve pain [slides 52 and 54]; morphine is held back for pain that nitrates do not relieve [slide 56]. Slide 52 says beta blockers cut the risk of myocardial infarction among unstable angina patients by 13 percent and cut deaths in myocardial infarction patients by 40 percent.

5.8 · Objectives 1–7 — Fibrinolytics and other antithrombotic drugs

The fibrinolytic system [slides 57 and 58]

The figure shows plasminogen being converted to plasmin, and plasmin breaking fibrin into fibrin products [slide 57]. Tissue plasminogen activator drives the first step [slide 57]. The brakes on the system are plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, alpha-2 antiplasmin and thrombin-activatable fibrinolysis inhibitor [slide 57]. All the fibrinolytic drugs act directly or indirectly to activate the conversion of plasminogen to plasmin [slide 58]. Plasminogen is inactive in the circulation and is converted to plasmin by tissue plasminogen activator [slide 58]. Plasmin lyses fibrin and fibrinogen [slide 58].

Mechanisms by agent [slides 59 to 61]

The three agents and what sets them apart [slide 64]

Alteplase, reteplase and tenecteplase are the three recombinant fibrinolytic agents on slide 64; streptokinase is a bacterial protein, not recombinant [slides 59, 61 and 64]. Tenecteplase is a recombinant fibrinolytic, like alteplase and reteplase [slide 64].

Reteplase and tenecteplase have a longer half-life than tissue plasminogen activator and are relatively resistant to plasminogen activator inhibitor-1 [slide 64].

Absorption, distribution, metabolism and excretion (Objective 4)

The slides give no absorption or excretion data. What they give is how each agent is made and how long it lasts: alteplase and tenecteplase come from recombinant Chinese hamster ovary cells and reteplase from recombinant Escherichia coli cells [slide 64]; reteplase and tenecteplase have a longer half-life than tissue plasminogen activator [slide 64]; and streptokinase forms a stable 1:1 complex with plasminogen [slide 59].

Adverse effects, all agents (Objectives 5 and 6) [slide 62]

• Bleeding.
• Allergic reactions; fever, chills and skin rash, which belong to streptokinase (see the box above).
• Anaphylactic reactions.
• Ventricular arrhythmias.

Allergic reactions including anaphylaxis (anaphylactic reactions) are listed for all fibrinolytic agents; fever, chills and skin rash occur mainly with streptokinase [slide 62].

The nine contraindications (Objective 7) [slide 63]

Each of these nine findings contraindicates fibrinolytics, and they apply to every fibrinolytic agent, including tenecteplase, alteplase and reteplase, with one exception: prior exposure to streptokinase or an allergic reaction to it bars streptokinase only [slides 62 and 63]. The nine findings are: active bleeding or a hemorrhagic disorder; pregnancy; aortic dissection; serious head or facial trauma (listed with recent surgery); and the other five below. Fibrinolytics cause bleeding as their main adverse effect [slides 62 and 65].

1. Recent surgery, including organ biopsy, puncture of non-compressible vessels, serious head or facial trauma and cardiopulmonary resuscitation (the slide says within 10 days).
2. Serious gastrointestinal bleeding (the slide says within 3 months).
3. History of hypertension with a diastolic pressure above 110 mmHg.
4. Active bleeding or a hemorrhagic disorder contraindicates fibrinolytics.
5. Previous cerebrovascular accident or an active intracranial process such as a tumor.
6. Aortic dissection.
7. Acute pericarditis.
8. Prior exposure to streptokinase or an allergic reaction to it.
9. Pregnancy.

Most of the list is one idea: anything that could bleed, or that a bleed would make catastrophic. The exception is prior streptokinase exposure, which is about antigenicity, not bleeding. The numbers on this slide come from an older source; the current wording for item 3 is severe uncontrolled hypertension. Item 5 is firm for a prior hemorrhagic stroke or a recent ischemic stroke, not for any old stroke. Current guidelines treat recent major surgery, recent gastrointestinal bleeding and pregnancy as relative contraindications, and acute pericarditis is an older-list item; any prior intracranial hemorrhage, aortic dissection, active bleeding, an intracranial tumor and significant head or facial trauma are the firm ones. Learn the categories, not the numbers.

Indications (Objective 3) [slide 65]

Fibrinolytics are indicated for ST-elevation myocardial infarction, the slide giving patients under 75 years within 12 hours of symptom onset. There is less benefit in patients over 75 years, more than 6 hours after onset, or with non-ST-elevation myocardial infarction [slide 65]; slide 68 goes further, saying fibrinolytics are not recommended in non-ST-elevation acute coronary syndrome, and that is the point to learn. Age is a reason for less benefit, not a bar. Relatively few patients receive these agents [slide 65]. The main risk is bleeding, including intracranial hemorrhage [slide 65].

Other antithrombotic agents [slide 66]

Slide 67 pictures a coronary stent: a balloon catheter carries it into the narrowed artery and it is left expanded in place (percutaneous coronary intervention with stent placement).

Non-ST-elevation acute coronary syndrome: how it differs [slide 68]

• Early treatment is similar to treatment of ST-elevation myocardial infarction.
• Fibrinolytics are not recommended, because the bleeding risk outweighs the benefit. This covers the fibrinolytic agents on slide 64: alteplase, reteplase and tenecteplase are not recommended in non-ST-elevation acute coronary syndrome.
• Enoxaparin is preferred over heparin, based on studies. Enoxaparin is a low-molecular-weight heparin and the slide’s “heparin” is unfractionated heparin; the preference comes from older studies, and current guidelines accept either.
• Glycoprotein IIb/IIIa inhibitors are used more commonly than in ST-elevation myocardial infarction.

5.9 · Objectives 8–10 — Interactions, monitoring and patient education

Interactions (Objective 8)

The slides name no drug-food and no drug-herb interactions for these drugs.

Protocols and monitoring (Objective 9)

Patient education (Objective 10)