pharmacology exam 4

true/false: most cases of hypertension are asymptomatic

true

baroreceptors

pressure sensitive neurons in aortic arch, carotid sinuses, and sympathetic nervous system. responsible for rapid moment-to-moment regulation of bp

renin-angiotensin-aldosterone system

kidney provides long-term regulation of bp. alters blood volume

hypertension treatment strategies

the goal of hypertensive therapy is to reduce cardiovascular and renal morbidity/mortality

lowering bp even a modest amount significantly reduces cardiovascular disease

mild hypertension can be treated w one drug along with lifestyle changes. however, most patients req more than one drug to help control their bp

diuretics (3)

can be used as first-line drug therapy for hypertension. lowers blood volume

low dose is safe, inexpensive, effective

can combine w other meds

beta-adrenoceptor blocking agents — description

used as a first-line drug therapy for hypertension when other diseases are present

beta-adrenoceptor blocking agents — therapeutic use and 5 examples

hypertensive patients with concomitant diseases — useful in treating conditions that may coexist with hypertension

supraventricular tachycardia, previous MI, angina pectoris, chronic heart failure, migraines

beta-adrenoceptor blocking agents — adverse effects (3 categories)

common effects: bradycardia, fatigue, lethargy, insomnia, hallucinations, hypotension, decr libido

alterations in lipid profile: may disturb lipid metab, decr HDL, incr triglycerides

drug withdrawal: abrupt withdrawal can induce angina, MI, or sudden death. must be tapered over 2-3 weeks

ACE inhibitors overview

recommended when diuretics or beta blockers are ineffective or can’t be used

ACE inhibitors — therapeutic uses (2)

management of patients w chronic heart failure

standard in care of patients who have had MI

ACE inhibitors — adverse effects (6)

dry cough, rash, fever, altered taste, hypotension, hyperkalemia

angiotensin II-receptor antagonists (ARBs) (4)

alternatives to ACE inhibitors

block the AT1 receptors

effects similar to those of ACE inhibitors

adverse effects are similar to ACE inhibitors — also toxic to fetuses

renin inhibitors (4)

directly inhibits renin

lowers bp as effectively as ARBs, ACE inhibitors, and diuretics

can be combined w any of the treatments listed above

can’t be used if woman is pregnant

calcium-channel blockers overview (2)

recommended when the first line agents are not effective or can’t be prescribed

effective in patients that are hypertensive with angina or diabetes

3 classes of calcium channel blockers

1. diphenylalkylamines (higher affinity for heart)

2. benzothiazepines (higher affinity for heart)

3. dihydropyridines (higher affinity for blood vessels)

calcium channel blockers actions (2)

antagonists block the inward movement of calcium by blocking L-type channels

causes smooth muscle to relax and dilates many arterioles

calcium channel blockers therapeutic uses (3)

natural natriuretic effects (discharge of sodium thru urine)

don’t req use of diuretics

useful in treating patients w asthma, diabetes, and/or peripheral vascular disease

calcium channel blockers adverse effects (3)

constipation occurs in 10% of patients

dizziness, fatigue

should be avoided in patients with congestive heart failure — HF due to systolic dysfunction (contractility problem) rather than diastolic dysfunction (relaxation + abnormal filling problem)

centrally acting adrenergic drugs — clonidine (catapres, kapvay, nexiclon) (3)

decr sympathetic output in brain stem

alpha2-agonists that are used to treat hypertensive patients who have not responded to 2+ drugs

does not decr renal flow

centrally acting adrenergic drugs — alpha-methyldopa (3)

inhibits DOPA decarboxylase which decr sympathetic output

alpha2-agonist

does not decr renal blood flow

vasodilators

act by producing relaxation of vascular smooth muscle

these actions cause reflex actions that incr contractility and heart rate. can lead to MI, angina pectoris, or cardiac failure in predisposed patients

incr renin → incr water retention. can use along w diuretic and beta blocker to decr side effects

hypertensive emergency

occurs when bp is 180/120 or higher. can cause strokes, MI, damage to organs

therapeutic goal is to rapidly reduce bp

drugs administered thru IV and cause prompt vasodilation. drop in bp has to be smooth. sodium nitroprusside (prodrug that becomes NO). nitroglycerine, calcium channel blockers

3 important dysfunctions of blood that drugs treat

thrombosis — formation of unwanted clot in blood vessel. most common abnormality

bleeding — failure of hemostasis

anemia — low RBC count. nutritional deficiencies or problems w bone marrow

thrombosis vs embolus

thrombus — a clot that adheres to a vessel wall

embolus — a clot that floats in the blood

both are dangerous. may block blood vessels, depriving tissues of oxygen

to form a stable clot, there are two pathways that must both work to completion:

1. platelet plug formation — platelets bind, are activated, and aggregate at injury site. not stable and can be swept away due to shear forces in smaller vessels

2. fibrin overlay/stable clot formation — activation of many different coagulation factors w the end result being the formation of fibrin

3 steps of platelet response to vascular injury

1. platelet adhesion

2. platelet activation/platelet release reaction

3. platelet aggregation

platelet response to vascular injury step 1 — platelet adhesion (2)

when endothelium is injured, the platelets adhere to and cover the exposed collagen and VWF (von Willebran factor; secreted by endothelial cells, platelet aggregation + attachment to endothelium).

forms a thin layer @ area of injury

platelet response to vascular injury step 2 — platelet activation / platelet release reaction (3)

platelets undergo morphological changes. will send out pseudopodia and release the contents of alpha and dense granules

the molecules sent out by the activated platelet activate other resting platelets in the circulation

compare to pufferfish blowing up

platelet response to vascular injury step 3 — platelet aggregation

platelets aggregate at site of injury and will attach together via various receptors/proteins (main one is GP Ilb/Illa)

stable clot formation (2)

complex series of events involving activation of various factors to their active forms, ultimately leading to formatino of thrombin. thrombin is formed by cleaved of prothrombin by Factor X

thrombin cleaves fibrinogen (soluble) to make fibrin (insoluble). fibrin is incorporated into the growing platelet aggregate — this stabilizes the clot

dissolving the clot — fibrinolysis (2)

while the clot is forming, the fibrinolytic pathway is activated locally. plasminogen is cleaved to form plasmin by tPA

plasmin cleaves the fibrin meshwork as the wound heals. releases fibrin degradation products (FDPs)

platelet aggregation inhibitors (3)

aspirin (acetylsalicylic acid)

ticlopidine (ticlid) and clopidogrel (plavix)

abciximab

aspirin (acetylsalicylic acid)

when platelets are stimulated (thrombin, collagen, ADP, etc) this results in activation of phospholipases that cut arachidonic acid from membrane phospholipids

arachidonic acid is converted to prostaglandin H2 by cyclooxygenase (COX) enzyme — prostaglandin H2 is converted to thromboxane A2. thromboxane A2 is released + is essential for rapid formation of a clot + acts as a vasoconstrictor

aspirin (non-selective COX inhibitor)

blocks the actions of COX-1 (and COX-2 to a lesser extent) and impedes platelet aggregation

lasts as long as the life of the platelet — 7-10 days

used to prevent transient cerebral ischemia (TIA), prevent stroke, prevent MI, decr mortality in patients who have suffered MI

aspirin cont.

bleeding time is prolonged for those on aspirin treatment. depends on dose given. can be incr incidence of hemorrhagic stroke and GI bleeding

often used w other drugs that have anti-clotting properties

other NSAIDs (like ibuprofen — also non-selective!) inhibit COX-1 and COX-2 by competing with aspirin for the active site

ibuprofen doesn’t have the same bleeding risk as aspirin

ticlopidine (ticlid) and clopidrogel (plavix)

irreversibly inhibit the binding of ADP to its receptors on the platelet. this inhibits the action of GP Ilb/Illa receptors — platelets can’t bind to fibrinogen or each other

ticlopidine is used to prevent ischemic attacks and strokes in patients who have had a prior thrombotic event. has some severe adverse rxns: aplastic anemia (RBC, WBC, platelets), thrombotic thrombocytopenic purpura (TTP — blood clots in small vessels). only used in patients who don’t respond to other therapies

ticlopidine and clopidogrel cont

clopidogrel is used for prevention of atherosclerotic events following MI, stroke, or established PAD. side effects are not as bad as those with ticlopidine but patients can still get TTP

ticlopidine and clopidogrel cont cont

food interferes with absorption of ticlopidine

both bind to plasma proteins

undergo metab by CYP450 system. active metabolites of these drugs have yet to be identified

max effect is in 3-5 days

elim by both renal and fecal routes

abciximab

an antibody to the GP Ilb/Illa receptor

given in IV along with heparin (IV only) or aspirin

usually given to patients during and after coronary artery procedures to prevent platelets sticking together

major side effect is possibility of bleeding

also expensive which limits its use

anticoagulants: inhibition of coagulation (3)

coagulation needs to be restricted to the site of injury

several inhibitors of this system: protein C, protein S, antithrombin III

the mech of action for several of these agents (like heparin) activate the endogenous inhibitors

anticoagulants — thrombin inhibitors: mechanism of action

heparin binds to antithrombin III to form heparin-AT complex (inactivates thrombin and other coagulation factors). speeding up the actions of antithrombin — it normally acts slowly w thrombin and Factor Xa, but with heparin bound, it speeds up the enzymatic rxns by 1000x

LMWHs do the same thing, only just with Factor Xa

anticoagulants — thrombin inhibitors: therapeutic uses (4)

heparin and LMWH prevent fibrin formation

used to treat deep-vein thrombosis and pulmonary embolism

used in patients undergoing surgery to prevent venous thrombosis

treatment of acute MI

anticoagulants — thrombin inhibitors: drugs of choice

heparin and LMWH are the drug of choice for pregnant women because they don’t cross the placenta due to their large size and negative charge

heparin is largely being replaced with LMWHs — use of the LMWH doesn’t req the same intense monitoring → saves on cost

anticoagulants — thrombin inhibitors: pharmacokinetics

absorption — the anticoagulant effect of heparin begins in minutes after IV; 1-2 hrs after SC

the actions of LMWH occurs 4 hours after SC

anticoagulants — thrombin inhibitors: adverse effects (6)

bleeding complications: chief adverse effect of heparin is hemorrhage. bleeding time must be monitored

hypersensitivity rxns: heparin is prepared from pig → risk it may be antigenic

thrombosis: chronic or intermittent admin of heparin can lead to reduction of antithrombin III activity → causes decr in inactivation of coagulation factors and incr risk of thrombosis

thrombocytopenia (low platelets): caused by heparin. type I is common, not serious, occurs within first 5 days of treatment. type II is rare, more dangerous, and can be life-threatening. platelets are activated via an immune response and aggregate (lowers number in circulation). can lead to thrombosis. heparin therapy must be stopped

elevation of aminotransferase levels: indication of liver disease, but when heparin is stopped, levels return to normal

osteoporosis and alopecia can also occur w chronic use

anticoagulants — vitamin K antagonists: overview (2)

warfarin (coumadin) antagonizes the cofactor function of vitamin K

warfarin is widely used as an oral anticoagulant, but use is decr in favor of LMWHs and platelet aggregate inhibitors

anticoagulants — vitamin K antagonists: mechanism of action (4)

several of the coagulation factors req vitamin K as a cofactor (prothrombin, factor VII, factor IX, factor X)

blocks the action of vitamin K epoxide reductase (responsible for activating vit K)

anticoagulant effects are not seen until 8-12 hrs after admin

peak effects seen at 72-96 hrs after admin. this is how long it takes to deplete the pool of clotting factors

anticoagulants — vitamin K antagonists: therapeutic uses (3)

warfarin is used to prevent progression or recurrence of acute deep-vein thrombosis or pulmonary embolism

used for prevention of venous thromboembolism during orthopedic or gynecological surgery

used in patients with MI, chronic atrial fibrillation, prosthetic heart valves

anticoagulants — vitamin K antagonists: pharmacokinetics (2)

warfarin rapidly absorbed after oral admin

can readily cross the placenta

anticoagulants — vitamin K antagonists: fate (2)

catalyzed by CYP450 system

excreted in urine and feces

anticoagulants — vitamin K antagonists: adverse effects (3 bleeding disorders + 1 warning)

hemorrhage is principle adverse effect. if patient bleeds, can be given vit K.

skin lesions and necrosis are rare complications observed primarily in women.

purple toe syndrome — painful, blue-tinged discoloration caused by cholesterol emboli

should NEVER be used during pregnancy

anticoagulants — vitamin K antagonists: drug interactions

EXTENSIVE list of drug interactions that can potentiate its anticoagulant effects

anticoagulants — vitamin K antagonists: disease states (3)

vit K deficiency, hepatic disease, hypermetabolic states

thrombolytic drugs overview

acute thrombolytic disease can be treated with drugs that convert plasminogen to plasmin — plasmin breaks down fibrin to dissolve clots

thrombolytic drugs: therapeutic uses (3)

originally used for treatment of deep-vein thrombosis and pulmonary embolism — these drugs are not being used for these conditions as much anymore

used in restoring catheter and shunt functions by lysing clots that occlude these devices

used to dissolve clots involved in ischemic strokes

thrombolytic drugs: adverse effects (2)

these drugs can’t tell the difference between fibrin in unwanted clot vs one that’s supposed to be there → hemorrhage is a side effect

ppl with healing wounds, pregnant, history of cerebrovascular accident should not be given these drugs

thrombolytic drugs — alteplase: overview, therapeutic uses (3)

formerly known as tPA — a serine protease that cleaves plasminogen to plasmin

approved for treatment of MI, massive pulmonary embolism, acute ischemic stroke

thrombolytic drugs — alteplase: pharmacokinetics and adverse effects

very short half-life (~5 mins)

bleeding complications (GI and cerebral)

drugs used to treat bleeding

bleeding disorders can be inherited (hemophilia, VWD), arise after surgery, or result after being given an anticoagulant

these drugs can block plasminogen activation, heparin, or plasmin

can inject missing clotting factors (factor VIII or IX)

vit K can also be given

define anemia

below-normal plasma hemoglobin conc from decr red blood cells or an abnormally low total hemoglobin content per unit of blood volume

anemia causes

chronic blood loss, bone marrow abnormalities, endocrine deficiencies, renal failure

nutritional anemias are caused by deficiencies of iron, folic acid, and vitamin B12

anemia treatment

can be temporarily reversed by transfusion

diuretics overview (3)

drugs that incr urine.

block renal ion transporters that block reabsorption of sodium so sodium and other ions enter the urine in greater than normal amounts → water diffuses in to maintain osmosis

can also change urine pH

normal regulation of fluid and electrolytes by the kidneys — list regions (4)

proximal convoluted tubule

descending loop of henle

ascending loop of henle

distal convoluted tubule

normal regulation of fluid and electrolytes by the kidneys —proximal convoluted tubule

almost all reabsorption occurs here (all glucose and amino acids, most bicarbonate, Na, Cl, K, water)

water follows passively from lumen to blood

if water and solutes didn’t get reabsorbed, we would become extremely dehydrated

acid and base secretory system: this system is saturable and diuretic drugs compete with endogenous organic acids. can see an incr in a build up of uric acid (gout)

normal regulation of fluid and electrolytes by the kidneys — desc loop of henle (2)

the remaining filtrate (isotonic) enters the desc loop of henle

osmolarity incr (conc of solutes). the water is being reabsorbed

normal regulation of fluid and electrolytes by the kidneys — asc loop of henle (3)

the cells here are relatively impermeable to water → keeps water in the tubule

active reabsorption of Na, K, Cl

diluting portion of the nephron

normal regulation of fluid and electrolytes by the kidneys — distal convoluted tubule

cells here are also impermeable to water

image on other side too

edema (2)

in many diseases, the amt of sodium and chloride reabsorbed by the kidney tubules is high

leads to retention of water, incr in blood volume, expansion of extravascular fluid compartment → results in edema of tissues

causes of edema (6)

HF: diseased heart can’t incr output and the incr vascular volume results in edema

hepatic ascites: incr portal bp. blood flow is often obstructed by cirrhosis (scarring). fluid escapes the vasculature and collects in abdomen

secondary hyperaldosteronism: fluid retention is also promoted by elevated levels of aldosterone → incr Na and water reabsorption. incr vascular volume

nephrotic syndrome: when glomerular membranes are damaged by disease, they allow proteins to enter the filtrate. loss of protein from plasma reduces colloidal osmotic pressure, so water leaks from capillaries back into tissues → edema. retention of sodium will also lead to edema

premenstrual edema: result in imbalance in hormones, i.e. estrogen excess. facilitates loss of fluid to extracellular space

abnormal lymphatic drainage

nonedematous states: list 3

hypertension, hypercalcemia, diabetes insipidus

nonedematous states: hypertension

thiazide reduces blood volume and dilate arterioles

nonedematous states: hypercalcemia (2)

a serious condition that req fast response

loop diuretics are usually employed since they promote calcium excretion

nonedematous states: diabetes inspidius (2)

patients w this condition suffer from high amounts of urine being excreted (poluria) and excessive thirst (polydipsia).

they respond to thiazide diuretics — thiazide reduces blood volume, causing a drop in glomerular filtration rate (GFR) and promoting reabsorption of Na and water

thiazides and related agents overview (3)

most widely used diuretics

all thiazides affect the DCT

all have equal maximum diuretic effects. differ in potency

thiazides and related agents: actions (4)

decr reabsorption of Na (incr excretion) — causes excretion of very hyperosmolar urine → this is unique to this class: others are unlikely to produce hyperosmolar urine

loss of K — bc the Na is being kept in the tubule, the body tries to get more Na out into the cells by exchanging it for K, depleting K in the tissues. potassium levels must be measured often

decr urinary calcium excretion — promote reabsorption of Ca. this contrasts w loop diuretics that keep Ca in the urine

reduced peripheral vascular resistance — decr in blood volume results in decr bp and therefore decr cardiac output

thiazides — therapeutic uses (4)

hypertension — may have been the mainstay for a long time in treating hypertension bc inexpensive, convenient, well tolerated. many patients can take thiazides for years without need for other meds

HF — diuretic of choice for HF. if thiazides fail, loop diuretics may be useful

hypercalciuria — bc they inhibit urinary Ca2+ these drugs are useful for treating hypercalciuria

diabetes insipidus (nephrogenic form) — the amt of urine can be decr from 11 L/day to about 3L/day

thiazides: pharmacokinetics (3)

effective orally

take 1-3 weeks to produce stable reduction in bp

prolonged half life (40 hrs)

thiazides: adverse effects (8)

K depletion, hyponatremia, hyperuricemia, volume depletion (causing hypotension), hypercalcemia, hyperglycemia, hyperlipidemia, hypersensitivity (esp to those allergic to sulfa drugs)

loop or high-ceiling diuretics — bumetanide, furosemide, torsemide: mechanism of action (2)

inhibit cotransport of Na/K/Cl in the asc loop of henle → reabsorption of these ions is decr

most efficacious of the diuretics

bumetanide, furosemifde, torsemide: actions (2)

act quickly even in patients who have poor renal function or do not respond to thiazides

incr Ca2+ content of urine

bumetanide, furosemifde, torsemide: therapeutic uses (3)

drug of choice for reducing acute pulmonary edema of HF

used in emergency situations

treat hypercalcemia

bumetanide, furosemifde, torsemide: pharmacokinetics (3)

admin orally or parenterally

duration of action 2-4 hrs

secretion in urine

bumetanide, furosemifde, torsemide: adverse effects (5)

ototoxicity (damage to ear) (w furosemide being highest risk)

hyperuricemia (high uric acid)

acute hypovolemia

potassium depletion

hypomagnesemia (particularly in elderly)

potassium-sparing diuretics: overview (3)

act on the DCT and collecting duct to inhibit Na reabsorption and K excretion

major use of these is in the treatment of hypertension. used in conjunction w a thiazide

patients on these drugs need to be monitored closely for potassium levels (can get too high)

potassium-sparing diruetics — aldosterone antagonists (spironolactone and eplerenone): mechanism of action

these antagonize aldosterone @ receptor sites.

the complex can’t be internalized and bind to DNA.

normally, the aldosterone/receptor would turn on genes made in response to aldosterone → these proteins would stimulate the Na/K exchange sites of the collecting tubule

potassium-sparing diruetics — aldosterone antagonists (spironolactone and eplerenone): actions (1) and therapeutic uses (2)

in most edematous states, aldosterone levels are high — instrumental in retaining Na

secondary hyperaldosteronism (excessive RAAS); HF

potassium-sparing diruetics — aldosterone antagonists (spironolactone and eplerenone): pharmacokinetics

completely absorbed orally and strongly bound to proteins

potassium-sparing diruetics — aldosterone antagonists (spironolactone and eplerenone): adverse effects (2)

GI upset and peptic ulcers

can cause gynecomastia (large mammary gland in males) and menstrual irregularities → drug should not be given chronically

lipoproteins

make up plasma lipids

spherical macromolecular complexes of lipids and specific proteins (apolipoproteins). the clinically important ones are LDL, VLDL, and HDL

treatment goals aimed at decr LDL — decr risk of CAD; diet and exercise also play a role

drugs that lower the serum lipoprotien concentration

HMG CoA reductase inhibitors, niacin (nicotinic acid), bile acid-binding resins

HMG CoA reductase inhibitors: overview (2)

known as statins. lower LDL

HMG CoA reductase inhibitors: mech of action (3)

competitive inhibitors

these drugs are analogs of HMG-CoA (3-hydroxy-methyl-glutaryl — precursor of cholesterol

they have high affinity for HMG CoA reductase — RDS for cholesterol synthesis