3550 Midterm Notes PDF

Week 1 ====== Penicillin ---------- - Bactericidal - Considered a beta-lactam AB -- this disrupts the cell wall - Mammalians don't have a cell wall so penicillin doesn't affect it - Only effective during cell growth and division How the wall is weakened: 1. Inhibition of...

Week 1 ====== Penicillin ---------- - Bactericidal - Considered a beta-lactam AB -- this disrupts the cell wall - Mammalians don't have a cell wall so penicillin doesn't affect it - Only effective during cell growth and division How the wall is weakened: 1. Inhibition of transpeptidases: these enzymes are necessary for cell wall synthesis and by inhibiting them penicillin prevents them from being used to build the cell wall 2. Activation of autolysins: these enzymes break bonds in cell walls and so penicillin activates autolysins to disrupt the cell wall PGP -- molecular targets for penicillin that are only expressed in growth and division -- penicillin only works on PGP 1 and 3 Penicillin -- Bacterial Resistance 1. Gram-negative envelope: The envelope has 2 layers that are easy to penetrate, the GN adds another layer making it more difficult 2. Penicillinases: these enzymes break the beta-lactam ring making these drugs useless 3. Altered PGPs: MRSA alters them, and they have low affinity Differences in penicillin drugs determine their: 1. Affinity 2. Ability to penetrate 3. Resistance to stomach acid 4. Resistance to penicillinase 5. Pharmacokinetics Differences in penicillin drugs is classified by: 1. Narrow spectrum: penicillinase sensitive 2. Narrow spectrum: penicillinase resistance 3. Broad spectrum 4. Extended spectrum Penicillin G - Bactericidal - When the salts break apart: concerning if you have too much or are on a salt-restrictive diet - 4 types: Sodium, potassium, procaine, benzathine - Absorption - IV -- Sodium and potassium only - IM -- All: Benzathine takes weeks while sodium and potassium are quick - Metabolism and excretion - Renal excretion - Halflife increases with renal impairment - Adverse effects - Least toxic antibiotic - Pain at the IM site - Motor/sensory dysfunction if injected into nerve - Neurotoxicity if dose is too high - Gangrene or necrosis if injective into artery - Drug interactions - Aminoglycosides: give penicillin first but always separately because it will make the aminoglycosides inactive Other penicillin's - Pen V: stable in stomach and can be taken orally - Penicillinase-resistant penicillins: used only with penicillinase producing staphylococci - Broad spectrum penicillins: same as pen G - Extended-spectrum penicillins: increased spectrum, including pseudomonas aeruginosa Penicillin allergy - Most common - Not dose dependent - Must have previous exposure to penicillin in the environment or diet - 3 types of reactions - Immediate: 2-30 minutes - Accelerated: 1-72 hours - Delayed: days-weeks - Anaphylaxis: hypersensitivity, 10% mortality Cephalosporins -------------- - Beta lactam AB - Has 5 generations - MOA - Similar to penicillin - Resistance - Cephalosporinases - Pharmacokinetics - Absorption: poor in GI, give IM or IV - Duration: halflife 30min-9hr - Distribution: to bodily fluids and tissues - Elimination: renal except ceftriaxone which is hepatic - Drug interactions - Drugs that promote bleeding - Alcohol - Adverse effects - Allergy: stop if there are any signs - Bleeding: can decrease prothrombin levels and interfere with vit k metabolism, give vitamin k and monitor PTT Carbapenems ----------- - Betalactam AB - Resists betalactamases - Penetrates cell envelope - 3 drugs available - Prototype: Imipenem - Renal enzyme (dipeptidase) destroys it - Given with cilastin to prevent destruction - MOA: binds PGP 1 and 2 - Absorption: given IV - Excretion: renal - Drug interactions: valproate -- used for seizures but at low doses may cause seizures Vancomycin ---------- - Used in hospitals for c.diff and MRSA - No betalactam ring - MOA: disrupts precursor molecules that microbes used to build cell walls - Adverse effects: renal failure (hard on kidneys), trough levels must be monitored - Absorption: slow IV influsion over 1-2 hours otherwise allergic reaction symptoms may occur Tetracyclines ------------- - Inhibit bacterial protein synthesis - 4 types: vary based on how long they last in the body - MOA: bind to 30S ribosomal subunit, must get to cells interior - Uses: use has decreased because of resistance and creation of less toxic drugs - Duration: short acting = less lipid soluble, long acting = more lipid soluble - Absorption: orally but effect decreases with food, avoid Mg/Zn/Fe/Ca for at least 2 hours after this because it is a chelating agent - Distribution: most tissues and fluids - Elimination: hepatic and renal - Adverse effects: - GI symptoms -- nausea, vomiting, diarrhea - Bones/teeth -- altered colour and enamel - Fatty liver infiltration - Exacerbate renal failure - Photosensitivity - Superinfection Macroclides ----------- - Bacteriostatic, and can be bacteriocidal - Binds to 50S ribosomal subunit - Example: Erythromycin - 3 types: erythromycin base, sterate, succinate - Microbes have developed resistance: creation of export pump and alterations in target ribosomes - Absorption: only base absorbed - Distribution: most tissues except CNS - Elimination: hepatic - Adverse effects: sudden cardiac death, GI symptoms - Drug interactions: inhibits P450, prevents clindamycin and chloramphenicol from binding, avoid verapamil Other protein synthesis inhibitors: 1. Clindamycin: used with group A strep and gangrene, can help suppress toxin synthesis, concern is superinfection with c.diff 2. Linezolid: works on MRSA/VRE, blocks formation of 50S ribo subunit, can cause myelosuppression so monitor CBC Week 2 ====== Function of neurons ------------------- - Conduct AP down synapse to post synaptic cell which has receptors that receive the message - Drugs impact either axonal conduction or synaptic transmission, and influence drug receptor binding - Increase activation-mimic the neurotransmitter - Decrease activation-mimic release of the neurotransmitter Receptor selectivity - Allows for altering of one disease process but leaves the rest unaffected - Without different receptors, drugs would impact all of the processes - With different receptors we can select which processes are manipulated by drugs Regulation of physiologic processes - Most structures have SNS/PSNS -- except blood vessels/adrenal medulla, SNS often oppose each other - Regulation occurs with feedback loops - Baroreceptor reflex - Autonomic Tone - "baseline" - Managed by one branch of the ANS (often the PSNS) ANS Anatomy - **PSNS**: two neurons in the pathway from the SC to the organs - The junction between them is a ganglion (synapse) - **SNS**: similar to the PSNS *but* also has a pathway with the adrenal medulla (which functions as a postganglionic neuron) - **Somatic**: only one neuron - Drugs only have one site of action Transmitters of the PNS 1. Acetylcholine a. All preganglionic & postganglionic neurons of PSNS b. All preganglionic neurons of SNS c. Most postganglionic neurons of SNS that go to sweat glands 2. Norepinephrine d. Released by most postganglionic neurons of SNS (except sweat glands!) 3. Epinephrine e. Released by adrenal medulla Receptors of PNS - Cholinergic - Nicotinic~M~ - Contraction of skeletal muscle - Nicotinic~N~ - ~neuronal~ - Cell bodies of post-ganglionic neurons in SNS & PSNS - Cells of adrenal medulla - Promotes ganglionic transmission in all ganglia of SNS & PSNS - Promotes release of Epi from adrenal medulla - Muscarinic~1-5~ - All organs regulated by PSNS and sweat glands - Adrenergic - Alpha~1~ - Ocular a~1~ -- dilate pupil\ Blood vessels -- vasoconstriction\ male sex organs -- ejaculation\ smooth muscle of bladder - contraction - Alpha~2~ - Regulate transmitter release (& prevent release where there is too much transmitter in the synaptic gap) - Beta~1~ - Cardiac b~1~ - ↑HR & force of contraction & speed of cardiac impulse (for HR and rhythm)\ renal b~1~ -- release renin to blood (helps with vasoconstriction & ↑BP - Beta~2~ - Lung -- bronchial dilation - Uterus -- relaxation of uterine smooth muscle - Arterioles -- vasodilation - Skeletal muscle -- contraction - Liver & Skeletal muscle - glycogenolysis - Dopamine (CNS only) - Dilates renal blood vessels to increase perfusion - Drugs can help us to increase selectivity Muscarinic Agonists - Interact with muscarinic receptors - Muscarinic receptors are found on organs with PSNS innervation - *What would we expect muscarinic receptors to control?* - *Decrease HR, increase digestion, increase contractility, secrete GA, bronchial and bladder contraction* - Bethanechol - Mechanism of Action - Binds reversibly to muscarinic cholinergic receptors and activates them - Pharmacologic Effect - Heart: slower - Sweat & secretions: increase - Smooth muscle of lungs & GI: contracts - Bladder: contraction of detrusor muscle (bladder wall) and relaxation of trigone and sphincter urination - Vascular: vasodilate and decrease bp - Ocular: miosis (constriction) & contraction of ciliary muscle (near-focusing) - Pharmacokinetics - Taken orally, 30-60min onset, duration approx. 1h - Minimal systemic absorption - Uses - Urinary retention: increased voiding pressure - Contraindicated in patients with bladder obstruction - Gastroesophageal reflux: - Counteract anticholinergic side effects (common: antidepressants) - Adverse Effects - CV: bradycardia, hypotension - GI: cramping, diarrhea, increased salivation - Asthma: can cause bronchoconstriction - Hyperthyroid: can increase HR and cause arrythmia Muscarinic Antagonists - Prevent activation of muscarinic receptors (block Ach) - Parasympathetic drugs - "muscarinic blockers" or "anticholinergics" - We can predict the action of this drug by knowing what a normal response is for muscarinic activation, and remembering that muscarinic antagonists will do the OPPOSITE - Atropine - Effects mainly on: - Heart: increase heart rate - exocrine glands: decrease secretions and saliva - smooth muscles: relax - eyes: relaxes ciliary muscle and focuses lens for far vision - CNS: small dose -- mild excitation; increasing doses cause hallucinations death - Pharmacokinetics - Topical (eye), IM, IV, SC - Uses - Pre-anesthesia -- preventative measures - Eyes -- dilation for eye exams - Heart -- treatment of bradycardia - GI hypermotility -- decrease secretions - Biliary colic -- relaxes the smooth muscle when passing a gallstone - Antidote for musc. agonist poisoning - Adverse Effects - Dry mouth - Blurred vision/photophobia: blocking receptors of ciliary muscle prevents near-vision focusing. Paralyzing the sphincter prevents constriction (cannot adapt to bright light) - Increase intraocular pressure -- avoid in patients with glaucoma - Urinary retention: decreased urge to pee - Constipation: decreased motility - Anhidrosis (no sweating): patients at risk of hyperthermia - Asthma: bronchodilates (good!), but thickens secretions (bad) - Drug Interactions: - Other drugs that are not muscarinic antagonists can have a similar effect (antihistamines, antipsychotics, tricyclic antidepressants) - Can increase the antimuscarinic effect of atropine - Avoid any combination of these meds Other muscarinic antagonists - Scopolamine - Similar to atropine except - Increased CNS sedation - Suppresses nausea - Used for motion sickness, and commonly in palliative care - Ipratropium Bromide (Atrovent, "orange puffer") - Given via inhalation for asthma & COPD; nasal inh for rhinitis - Minimal systemic absorption so few side effects Overactive bladder - Muscarinic receptors on bladder detrusor - Inhibit bladder contraction and urge to void - M~3~ specifically on bladder - *Knowing this, what would we want to do when consider a med?* - M~3~ also involves salivary glands, iris sphincter, lacrimal gland and ciliary muscle - Will still have these side effects! (but not M~1~ or M~2~ side effects such as tachycardia or CNS dysfunction) - Oxybutinin is a common M~3~ muscarinic receptor blocker - Side effects: dry mouth, tachycardia, blurry vision (these ↑ with other anticholinergics) - To minimize side effects -- long-acting oral or transdermal route Week 3 ====== Adrenergic Agonists - Activate adrenergic receptors - What effects would we expect to see? - Increased heart rate and blood pressure - Called "sympathomimetics" - Have four mechanisms to activate adrenergic receptors - Direct receptor binding (direct mechanism) - \*most common - Promotion of NE release (indirect mechanism) - Inhibition of NE Reuptake (indirect mechanism) - Inhibition of NE inactivation (indirect mechanism) - Two chemical classes: - Catecholamine - Made of a catechol group & an amine group - Inactivated by MAO and COMT - Given as continuous IV infusion only - Oral admin: no\ Duration of action: brief\ Cross the BBB: no - Short halflife (MAO & COMT) - Drug can oxidize and change colour - Do not use! - Examples: NE, epi, isoproterenol, dopamine, dobutamine - Non-catecholamine - Different structure (no catechol molecule) - Not substrates for COMT - COMT cannot inactivate these drugs - Slower metabolism by MAO - Longer halflife - Oral admin: yes\ Duration: longer\ Cross the BBB: yes - Examples: ephedrine, albuterol, phenylephrine - Differentiated by: - Ability for oral administration - Duration of action - CNS activity Alpha 1 Activation - Drugs: epi, NE, phenylephrine, ephedrine - Therapeutic responses: - Vasoconstriction (skin, viscera, mucous membranes) - Mydriasis \[pupils dilate\] \*\*use is rare - Uses: - Hemostasis - stop bleeding (skin, mucous membranes) \[ex: *Epi*\] - Nasal decongestion -- vasoconstricts nasal mucosa \[ex: *Pseudoephedrine*\] - Local anesthesia adjunct - Hypotension -- vasoconstriction will elevate BP\ (not 1^st^ line) \[*ex: all*\] - Pupil dilation -- for eye exams and eye surgery \[*ex: phenylephrine*\] - Adverse effects - Hypertension - Bradycardia - Necrosis from IV Alpha 2 Activation - Alpha~2~ receptors are pre-synaptic - Their activation inhibits NE release - Epinephrine and NE - *Peripheral* clinical significance is minimal - Both therapeutic and AE - Useful in CNS - Pain relief - Decreased sympathetic transmission to heart and blood vessels Beta 1 Activation - Important responses are from activation of receptors in the heart - Activated by epi, NE, isoproterenol, dopamine, dobutamine, ephedrine - Uses - Heart Failure:\ increases force of contraction & improve cardiac output - AV block (poor electrical conduction in heart):\ improves conduction within the heart - Shock:\ improve cardiac output to improve perfusion to vital organs - Cardiac Arrest:\ can help to initiate contraction in still heart - Adverse Effects - Altered Heart Rate/Heart Rhythm: tachycardia or abnormal rhythm from overstimulation of B~1~ receptors - Angina (Chest Pain): increases oxygen demand on the heart (worsens angina) - Be cautious administering B~1~ agonists in patients with a high risk for angina Beta 2 Activation - Effects from B~2~ receptors found in lungs and uterus - Also receptors in liver and skeletal muscles - Examples of B~2~ agonists: epinephrine, isoproterenol, albuterol - Uses: - Asthma: promote bronchodilation - Prefer B~2~-selective drugs - Given by inhalation (mostly) - Delay preterm labour: relaxes uterine smooth muscle - Adverse Effects - Hyperglycemia: B~2~ receptor activation in liver and skeletal muscles causes glycogenolysis - People with diabetes most at risk - Why not people without diabetes? - Tremor: B~2~ on skeletal muscle causes contraction - Minimize with starting at low dose - Concerning for people with diabetes because we don't know if this is due to hyperglycemia or the drug Dopamine Activation - Peripheral dopamine receptors cause dilation of renal vasculature - Works in kidneys - Dopamine is the only drug that works on dopamine receptors - Use - Shock: dilates renal blood vessels and improves perfusion (↓ risk of renal failure) Agonist Drug Prototype: Epinephrine - Activates a~1~, a~2~, b~1~, b~2~ receptors; catecholamine - Use - Vasoconstriction to increase bp - Increase heart rate - Bronchodilate - Relax uterine muscles - Drug Interactions: - **MAO Inibitors** (often antidepressants): enhance and intensify epi effect - **Tricyclic Antidepressants** (block uptake of catecholamines into adrenergic neurons -- how action of catecholamine is terminated): will intensify and prolong effect of epi/catecholamines - **Alpha and Beta-Adrenergic Blocking Drugs (Antagonists)**: oppose agonists; reduce the effect of epi - Nursing considerations - Monitor patients - Monitor for toxicity; give alpha or beta antagonist - If extravasation occurs, given phentolamine (a-antagonist) Adrenergic Antagonists - Direct blockage of adrenergic receptors - All except one are reversible -- competitive blockade - Uses - Essential hypertension: blocking a~1~ receptors on arterioles & veins causes vasodilation - A~1~ Agonist toxicity (hypertension & extravasation) - BPH: decreased contraction in prostatic capsule & bladder neck - Pheochromocytoma (catecholamine-secreting tumor): reduces bp pre-op and in patients who aren't surgical candidates - Reynaud Syndrome: prevents a~1~-mediated vasoconstriction - Alpha 1 Antagonist Adverse effects - Orthostatic hypotension: reduces bloodflow to brain (dizzy, lightheaded, syncope) - Reflex tachycardia: baroreceptor reflex activtation - Nasal Congestion: vasodilation of nasal mucosa - Inhibition of ejaculation: ejaculation is mediated by a~1~ receptors - Alpha 2 Antagonist Adverse effects - Reflex tachycardia - Peripheral a~2~ receptors are presynaptic, activating them *inhibits* NE release - if these receptors are blocked, there is ↑ NE released, which causes reflex tachycardia (b~1~ impact) - Combining both a~1~ & a~2~ blockade is synergistic for reflect tachycardia Alpha 1 Antagonist: Prazosin - Use - Hypertension and BPH - Adverse effects - Reflex tachycardia, nasal congestion, postural hypotension - Nursing considerations - Educate patients; sit/laydown if needed, avoid abrupt position change - Administer before bed (↓ postural hypotension effects) - Smaller doses preferred, can gradually increase Beta antagonists - Most effects from cardiac b~1~ blockade: - Decreased HR - Decreased force of contraction - Decreased velocity (slowing) of cardiac electrical impulse - Uses - Angina -- reduces oxygen demands of the heart (less need for O~2~) - Dysrhythmia -- slow the conduction of electrical impulse to slow conduction - MI -- reduces size of infarct, risk for re-infarct; decrease pain - Heart failure -- standard of treatment; decreased "work" from heart - Hyperthyroid - Stage fright -- decreased tachycardia - Pheochromocytoma -- oppose beta action of catecholamines - ↓Perioperative mortality, glaucoma, migraine prophylaxis - Beta 1 antagonist Adverse effects - Bradycardia - Reduced CO: decreased heart rate and force of contraction - Heart failure - Rebound cardiac excitation - Beta 2 antagonist adverse effects - Bronchoconstriction - Hypoglycemia - Neonate considerations - Residual effects for several days (if mom used B~2~ antagonist while pregnant) - Risk for bradycardia (b~1~), resp distress (b~2~), and hypoglycemia (b~2~) - Close monitoring after birth (approx. 3-5 days) Properties of beta adrenergic blockers - 1^st^ generation: - Not selective (both b~1~ and b~2~) - Propanolol - 2^nd^ generation: - Cardioselective (b~1~ at usual dose) - Metoprolol - 3^rd^ generation: - Vasodilating (vessels dilate & non-selective other effects) - carvedilol propranolol - both b1 and b2 blockage - b1 -- decrease blood pressure/force of contraction/hr - b2 -- bronchoconstriction - b renal -- suppress renin secretion - uses - hypertension - angina - dysrhythmia - MI - Adverse effects - Bradycardia - Heart failure - Rebound excitation - Bronchoconstriction - CNS impact - Precautions - If severe allergy, epi not as effective (works on beta receptors, which are blocked by propranolol) - Diabetes, depression - Drug interactions - Calcium channel blockers - Insulin Clonidine - Central-acting a~2~ agonist - Used for hypertension, pain, and ADHD - Off-use: smoking cessation, opioid/methadone withdrawal, oppositional defiance disorder, Tourette Syndrome - Antihypertensive Action - Activation of a~2~ receptors in CNS (brainstem and areas that involve autonomic regulation of CV system) causes decreased flow of sympathetic signals to the blood vessels and heart - Decreased firing of these nerves causes bradycardia and decreased cardiac output (heart), and vasodilation (bv's) - Decreases blood pressure - Adverse effects - Drowsy - Dry mouth - Rebound hypertension - Constipation, impotence, gynecomastia, CNS effects (vivid dreams, nightmares, anxiety, depression) - Abuse -- at high doses, can cause euphoria, sedation, hallucinations, and intensify effects of other commonly abused drugs Week 4 ====== Kidney - Three important processes: - Filtration - Reabsorption - Active tubular secretion - Areas of reabsorption - Proximal convoluted tubule (PCT) - Loop of Henle - Early distal convoluted tubule (DCT) - Late DCT Diuretics - (most) block Na and Cl reabsorption - Prevents reabsorption of water - The amount of water in the urine is proportional to the amount of sodium reabsorption that is blocked - Which part of the nephron would impact urine volume the most? - A medication acting here will cause the most diuretic effect (or more volume of urine) Impacts of diuretics - Kidneys create 125mL/h of filtrate = 180L per day - Most reabsorbed - Decreasing even a little bit of filtrate can have a significant impact - To counteract these, we can: - Give short-acting diuretics - Time administration\ (both allow the kidney to have drug-free periods) Loop Diuretics (Lasix/Furosemide) - **Mechanism of Action** - Act in the loop of Henle (ascending limb) - Prevents reabsorption of Na - **Pharmacokinetics** - Route: Oral, IV, IM - Oral: diuresis in 60min, effect for 8h (rapid need) - IV: diuresis in 5min, effect for 2h (critical need) - Hepatic metabolism, renal excretion - **Uses** - When rapid/large fluid excretion is needed - Can be used when the kidney is injured, or glomerular filtration rate (GFR) is low - **Adverse Effects** - Hyponatremia, hypochloremia, dehydration - Hypotension - Hyponatremia, hypochloremia, dehydration - Lack of reabsorption; monitor for signs and symptoms of dehydration - Hypotension - Loss of volume and relaxation of venous smooth muscle - Monitor for signs and symptoms: dizziness, lightheadedness, syncope - Hypokalemia - Keep within normal range (3.5-5mmol/L) - Promote eating potassium-rich foods, taking a supplement - Ototoxicity - Transient with Lasix, but may be permanent in other loop diuretics **Drug Interactions** - Digoxin - Other ototoxic drugs - Potassium spring diuretics: can counteract the k wasting effect of Lasix Thiazide diuretics - Also increase renal excretion of Na, Cl, K, water - Effect is less than loop diuretics - Diuresis is dependent on kidney function (urine flow); not used with kidney disease Hydrochlorthiazide - Mechanism of Action - Blocks Na and Cl reabsorption in early segment of DCT - Only 10% of Na & Cl reabsorption here - Pharmacokinetics - Diuresis begins about 2h after oral admin - Peak effect at 4h; duration up to 12h - Excretion: urine; metabolism: none - Uses - hypertension - edema - Adverse Effects - Same as loop, but no ototoxicity! Potassium sparing diuretics - Useful for moderate diuresis (urine output), and retaining K in the kidney - Often used in conjunction with loop or thiazide diuretic - Two types: aldosterone antagonist & non-aldosterone antagonist Spironolactone (aldosterone antagonist) - Mechanism of Action - Blocks aldosterone in distal nephron (DCT and collecting duct) - Amount of urine output is small - Pharmacokinetics - Onset slow (up to 48h) - Uses - Hypertension; used with loop or thiazide -- role to oppose K-wasting effect - Heart failure -- benefit is from blocking aldosterone in heart and blood vessels - Adverse effects - Hyperkalemia - Alone or with loop/thiazide drugs - Monitor K level (if over 5mmol/L, hold drug) - Endocrine effects - Steroid derivative; can have effects of steroid hormones - Gynecomastia, menstrual irregularities, impotence, hirsutism, deepening of voice - Drug interactions - Other drugs or foods that increase potassium Triamterene (non-aldosterone agonist) - Mechanism of Action: - Directly disrupts ion transport (Na/K) in the distal nephron - Diuresis is minimal - Pharmacokinetics: - Quick onset of action (direct inhibition of transport pump) - Uses: - Same as spironolactone, except no heart failure improvement - Adverse effects: - Hyperkalemia - Nausea & vomiting, leg cramps, dizziness, blood disorders RAAS - Produced by juxtaglomerular cells - Important for regulation of angiotensin - Release of renin triggered by: Hypotension, decreased blood volume, plasma Na concentration, renal perfusion pressure - Renin release is suppressed by: Increasing bp, adequate blood volume, adequate plasma Na content - Important for: - Regulation of blood volume and blood pressure - acts on distal nephron to retain Na - Pathologic CV Effects - Cardiac remodeling and fibrosis - Promote vascular fibrosis and disrupt baroreceptor reflex - Suppress NE uptake in SNS (arrhythmias) - Regulation of bp by RAAs - Things that lower blood pressure (hemorrhage, dehydration, low sodium) activate the RAAS, things that raise the blood pressure stop the RAAS Angiotensin Converting Enzyme Inhibitors (ACEIs) - Treat hypertension, heart failure, diabetic nephropathy, MI, and *prevent* adverse cardiac events (stroke, MI) - MOA - Reduce levels of angio I (inhibit ACE) - Dilate blood vessels, reduce blood volume, prevent pathologic change in the heart and blood vessels - Increase bradykinin\ (inhibit kinase II) - Bradykinin causes vasodilation; promotes cough and angioedema - Pharmacokinetics - Almost all oral (1 is IV), can be taken with or without food - Most have long half-lives (except captopril) - Prodrugs: must convert to active form of the drug in the body - Excreted by kidneys - Exception: fosinopril - Uses - Hypertension - Nephropathy - MI - HF - Adverse effects - First dose hypertension - Hyperkalemia - Cough - Renal failure - Fetal injury - Angioedema - Neutropenia - Drug interactions - Diuretics - Antihypertensives - Meds that increase potassium - Lithium - NSAIDs Angiotensin II Receptor Blockers (ARBs) - Mechanism of Action - Block angiotensin II at its receptors in blood vessels, adrenals, and other tissues: - Blood vessels -- dilation of arteries and veins - Heart -- prevents pathologic change to heart - Adrenals -- ↓ release of aldosterone and ↑ excretion of Na and water - Effects similar to ACEIs, - Exception: no inhibition of kinase II, so no increase of bradykinin (less cough!) - Uses - Hypertension - Heart failure - Nephropathy - Retinopathy - MI - Adverse effects - Angioedema - Less than ACEI, but stop and do not take again if angioedema develops - Fetal harm - Stop drug immediately if pregnant - Renal Failure: - In patients with renal stenosis (increased renin) - Drug interactions - Other antihypertensives Week 5 ====== Calcium channels - Pores in the cytoplasmic membrane that regulate calcium entry into cells - Calcium is essential for function in: - Vascular smooth muscle - Influx of calcium causes contraction - Heart - Myocardium: increased force of contraction - SA & AV nodes: regulates heart rate and conduction throughout the heart - Calcium channels are paired with beta~1~ cells - when beta cells are activated, calcium influx is increased Calcium channel blockers - Block the movement of calcium inside and outside of cells - 2 classes - Dihydropyridines -- act on arterioles - Non-dihydropyridines -- act on arterioles and heart Non-dyhydropyridines (Verapamil) - Direct effects: blocks calcium channels in heart and bv's: - In peripheral arterioles: vasodilation (↓ blood pressure) - In arteries of heart: vasodilation (↑ perfusion of the heart) - In SA node: ↓ heart rate - In AV node: slower conduction - In myocardium: ↓ force of contraction - Indirect effects: baroreceptor activation (from ↓bp) - ↑ firing of of sympathetic nerves causes release of NE, which increases HR, AV conduction, and force of contraction - Net effect: - Vasodilation with ↓ arterial pressure and ↑ coronary perfusion Verapamil - Pharmacokinetics - Admin: Oral or IV - Oral has first pass effect: only 20% to circulation - Effects approx. 30 minutes after admin, peak within 5h - Elimination: hepatic - Dose-reduce if patient has liver impairment - Uses - Angina: vasodilation improves oxygen delivery to heart - Hypertension: ↓bp by dilating arterioles - Dysrhythmias: slows AV conduction - Adverse Effects: - General: constipation, eczema outbreak - Cardiac: compromised cardiac function - SA node: - AV node: - Myocardium: decreased contractility - Drug & Food Interactions: - Drugs: digoxin, beta-blockers - give beta blockers many hours apart - Food: Grapefruit juice - Toxicity: - Oral admin: Gastric lavage - IV admin: IV calcium gluconate - Hypotension: a~1&2~ & b~1~ agonist ( ), IV fluids - Bradycardia: atropine Dihydropyridines (Nifedipine) - Block calcium channels in blood vessels vasodilation only - Less AE, but, more likely to cause reflex tachycardia - Direct Effects: - in vasc. smooth muscle (↑coronary perfusion; ↓bp) - Indirect Effects: - baroreceptor activation - ↑HR and ↑ force of contraction - Occurs with immediate-release form (not extended release) - Net Effects: - ↓bp, ↑HR, ↑force of contraction - Pharmacokinetics: - Oral: well-absorbed orally, goes through first-pass mechanism (\~50% to systemic circulation) - IR: effects quick, peak in \~30min - SR (XR): effects in 20 minutes, peak in \~6h - Uses: - Preferred in HF, bradycardia - Angina; often given with a beta blocker - Hypertension (extended-release form) - Less reflex tachycardia - Adverse Effects: - Flushing, dizziness, headache, edema, eczema - Drug Interactions: - Beta-blockers (good with nifedipine, bad with verapamil) - Toxicity: - Loss of selectivity - Effects noted on blood vessels *and* heart - Treatment is the same as verapamil Vasodilators - Usually selective for arteries or veins (or sometimes both) - Drugs with effects on arteries: - Decreased afterload (pressure that the heart as to *overcome* to pump blood); ↓ cardiac "work"; ↑ cardiac output & ↑ tissue perfusion - Drugs with effects on veins: - Decreased ventricular filling/preload (the "stretch" in the heart before it contracts); ↓ force of contraction, ↓ cardiac "work", ↓ cardiac output, and ↓ tissue perfusion - Adverse effects: - Postural hypotension: Decrease in blood pressure when going from supine/seated to seated/standing. - Reflex tachycardia - Vasodilation in arteries ↓bp; vasodilation in veins ↓CO (which ↓ bp) - Baroreceptors sense the drop in BP and relay the message to adrenal medulla - Medulla sends the messages through sympathetic nerves to increase the HR to compensate - Undesirable because: - Increases the work of the heart - Can increase bp (opposite of what is intended) - Give a beta-blocker to prevent effect - Expansion of blood volume Hydralazine - Effects: - selective dilation of arterioles (no effect on veins) - ↓ peripheral resistance, ↓bp, ↑contractility, ↑HR - Pharmacokinetics: - Oral: effects after 45mins, duration \~6h - IV: effects almost immediate, duration 2-4h - Metabolism: inactivated by acetylation - Slow acetylators -- increased drug levels in the body (excessive vasodilation) - Uses: - Hypertension (not commonly used anymore) - Hypertensive crisis: IV admin, small, incremental doses - Heart failure: short term, afterload reduce - Adverse Effects: - Reflex tachycardia (from ↑ blood volume), dizziness, headache, fatigue, weakness\ \ Systemic Lupus Erythematous-like syndrome (muscle and joint pain, kidney injury, pericarditis) - More common with high-dose in slow acetylators - Drug\ Interactions - beta-blockers and diuretics (prevent increased blood volume and reflex tachycardia) - use with caution with other antihypertensives Minoxidil - More intensive vasodilation, but also more severe AEs - Effects - Selective dilation of arterioles - Same effect as hydralazine - MOA - Direct action on vascular smooth muscle, drug metabolite causes K+ channels in muscle to open, K flows out and hyperpolarizes muscle cells (decreases ability to contract or constrict) - Uses - Severe hypertension (used only when other drugs have not been effective) - Always given with a beta blocker and diuretic - Adverse effects - Reflex tachycardia, sodium & water retention - Common and significant - Always given with betablocker and diuretic, possible dialysis - Pericardial effusion - Fluid buildup in the pericardium (sac around heart) - Often asymptomatic, can cause cardiac compromise - Hypertrichosis\ (abnormal hair growth) - Often impacts compliance, but can be treated cosmetically Sodium Nitroprusside - Fastest vasodilator (drug of choice for hypertensive crisis!) - Effects: venous *and* arterial dilation - MOA: - breaks down into NO, which activates an enzyme in vascular smooth muscle that causes vasodilation - Pharmacokinetics: - Admin - IV only; adjusting the dose (rate of infusion) will regulate bp - When stopped, BP back to pre-treatment levels - Metabolism: comprised of cyanide groups which convert to thianocyanate in liver, which is eliminated in kidneys (takes multiple days) - Adverse effects - Excessive hypotension - Careful BP monitoring is essential! - Thiocyanate poisoning - If given for a long time (if more than 3 days, measure plasma thiocyanate) - Symptoms: psychosis, erratic behaviour, confusion - Cyanide poisoning - More common with liver disease - Minimize with slow infusion - If symptoms develop, stop sodium nitroprusside infusion Hypertension - Impacts over 1 billion people worldwide; prevalence is increasing! - Leads to heart disease, stroke, and kidney disease - Typically, asymptomatic for a long period of time - Injury to important structures is slow and progressive - ongoing "silently" - No cure, but treatment of symptoms effective; treatment is lifelong - Compliance becomes challenging - Types - Primary - Chronic and progressive rise in blood pressure - Can be treated but not cured - Some demographics are more at risk - Secondary - Hypertension from *another* cause - *May* be cured - Ex., pheochromocytoma - Treating it - Treatment goal: - Reduce mortality and morbidity associated with cardiovascular disease and renal disease - Keep SBP \