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227 Cards in this Set

  • Front
  • Back
Antianginal Drugs
(3 Classes)
-Nitrates & nitrites
-Ca2+ channel blockers
-Beta-adrenergic receptor blockers
Nitrates & Nitrites
(Summary)
Ex: Nitroglycerine & Amyl nitrite

Primary Affect: Peripheral vasodilation (relax arteries & veins)

Site of action: Soluble guanylyl cyclase of smooth muscles cells
Ca2+ channel blockers
(Summary)
Ex: Verapamil, Nifedipine, Diltiazem

Primary Affect: Peripheral vasodilation AND decreased HR, decreased heart contractility

Site of action: L-type Calcium channels of vascular smooth muscle & cardiac muscle
Beta-adrenergic receptor blockers
(Summary)
Ex: Propranolol, Nadolol, Metoprolol

Primary Affect: Decreased HR & decreased heart contractility

Site of action: Beta-1 adrenergic receptors of cardiac cells
Myocardial Oxygen Demand
1. Myocardial wall stress
-Afterload (heart must overcome the BP it pumps against; elevated arterial BP increases wall stress)
-Preload (Increased venous BP returns more blood to the hear, which increases ventricular volume & wall stress)
-Wall thickness (Oxygen demand DECREASES if myocardial wall thickens)
2. Heart rate (Faster rate requires more O2)
3. Heart contractility (Stronger beat requires more O2)
Nitrates & Nitrites
(Administration & Direct Result)
-Nitric & nitrous acid esters of organic alcohols
-Oral administration inactivated by first-pass effect (FPE)
-Sublingual administration avoids FPE (lasts about 15 minutes)
-Primary direction result: Relaxation of veins with Increased venous capacitance & Decreased ventricular preload
How Nitrates & Nitrites act as Vasodilators
Converted to NO --> activates guanylyl cylase --> increases cGMP levels --> activates Protein Kinase G (PKG) --> diminishes myosin light chain phopshorylation --> favors muscle relaxation
Nitrates & Nitrites
(Toxicities & Abuse)
-Toxicity: Hypotension, reflex tachycardia, fainting, headache

-Volatile nitrites --> populat recreational sex-enhancing drugs

-Light-headedness; relax the corpora cavernosa & corpus spongiosum of the penis --> penile erection (Sildenafil aka Viagra --> inhibits cGMP phosphodiesterase, which amplifies the effect of NO)
Effects of Increased Intracellular Calcium in Cardiac Muscle
-Incoming Ca2+ effect (through L-type Ca2_ channels) is amplified by Ca2+ induced Ca2+ release (CICR)

-Occurs via Ca2+ activated Ca2+ release channels (SR Ca2+ release channels remain open longer than L-type channels, so their contribution is greater)

-Increased intracellular calcium stimulates muscle contraction
L-type Calcium Channel Blockers
(Pharmacokinetics)
Effective orally
High first-pass effect
High plasma protein binding
Extensive metabolism
L-type Calcium Channel Blockers
(Mechanism)
-Decreased depolarization-induced channel opening (depolarization decreases frequency of channel opening)
-Decreased transmembrane Calcium flux

Inward If ("Pacemaker current"/"funny channels") & Ica are the primary determinants of the slope of Phase 4.
Thus blocking of Ica by the calcium channel blockers flattens Phase 4, which prolongs the time until the next upstroke & thereby decreases the heart rate.
Calcium Channel Blockers
(Toxicities)
-Cardiac arrest, bradycardia, atrioventricular block, & heart failure
Beta-Adrenoceptor-blocking Drugs
(Sympathetic Control of Cardiac Rate)
-These drugs exert their action via G-protein coupled receptors (GPCRs)
-Beta1 agonists (such as NE) bind to the Beta1-adrenergic receptor (a GPCR), which activates the PKA cascade in pacemaker cells via elevated cAMP levels
-Elevated cAMP increases If "funny channel" activity & actrivates PKA, which phosphorylates L-type Ca2+ channels & activates them. these events increase influx of Ca2_ & Na+.
-This steepens Phase 4 & makes the threshold more negative, which increases HR.
-Beta Blockers block tihs process & decrease HR
Beta-Adrenoceptor-blocking Drugs
(Sympathetic Control of Contractility)
1. Catecholamines bind to B1 adrenergic receptor, which activates PKA pathway in atrial & ventricular myocytes
2. L-type calcium channels are opened, Calcium enters, & CICR amplifies the signal
3. More Ca2+ is made available to contractile machinery, which strengthens contraction
4. Beta blockers decrease these effected by Decreasing Ca2+ entry (which decreases Ca2+ available to troponin C)
Beta-Blocker Uses
Angina
Hypertension
Cardiac arrhythmias
Ischemic heart disease
Beta-Receptor Antagonists
-Pure antagonists are the most clinically useful (some are partial agonists)
-Resemble isoproterenol in structure.
-Vary in affinities for Beta1 vs. Beta2 receptors (Metoprolol is selective for Beta1 adrenergic receptors)
Beta-Adrenoceptor-Blocking Drugs
(Pharmacokinetics)
-Orally effective
-Variable half-lives (Nadolol is noteworthy for its long duration of action)
Beta-Adrenoceptor-Blocking Drugs
(Toxicities)
Toxic effect in bronchial smooth muscle (Beta2 blockade constricts bronchioles & increases airway resistance)

Contraindicated in asthma (Beta1 receptor selective Beta-blockers, such as metoprolol, are preferred)
Regulation of Blood Pressure
(The Hydraulic Equation)
Blood Pressure α Cardiac Output x Peripheral Vascular Resistance (arterioles)

BP α CO x PVR
Sites of Blood Pressure Control
Heart (Pump Output)
Kidneys (Volume)
Arterioles (Resistance)
Venules (Capacitance)
Regulation of Blood Pressure
-Baroreceptor Reflexes --> Autonomic nerves
-Humoral Mechanisms --> Renin-angiotensin-aldosterone system
Local Hormones --> NO dilates blood vessels, endothelin-1 constricts them
-Controls set at a higher level in hypertensive patients
-Antihypertensive drugs act on these mechanisms
Regulation of Blood Pressure
(The Baroreceptor Reflex)
-Initiated at stretch receptors in the carotid sinus & aortic arch
-If BP rises, the stretch receptors are activated & send afferent sensory signals as to the extend of their stretch to the medulla
-These signals are converted at the appropriate synapses with interneurons to:
1. Excitatory postsynaptic signals --> feed via parasympathetic fibers to teh heart & slow it down
2. Inhibitory postsynaptic signals --> feed back to sympathetic fibers & inhibit their ability ot increase heart rate & constrict arterioles & venules
Regulation of Blood Pressure
(The Renal Response)
Long-term BP Regulation by controlling blood volume
-Decreased BP leads to increased reabsorption of salt & water, Increased blood volume & Increased BP
-Decreased BP increases Renin production, which increases Angiotensin II production
-Angiotensin II causes resistance vessel constriction & stimulates aldosterone synthesis in the adrenal cortex, which increases renal salt absorption & blood volume
-Vasopressin (released by the posterior pituitary) is also involved via its ability to regulate kidney water reabsorption
Antihypertensive Drugs
1. Diuretics --> increase salt excretion & reduce blood volume (act on the Kidneys)
2. Sympathoplegics --> reduce peripheral vascular resistance, inhibit cardiac function & increase venous pooling (act on the Heart, Arterioles, Venules, & Sympathetic Innervation)
3. Vasodilators --> relax vascular smooth muscle, dilate resistance vessles & increase capacitance (act on Arterioles & Venules)
4. Anti-angiotensin drugs --> reduce peripheral vascular resistance & potentially blood volume
Diuretics
-Deplete Na+ stores
-Decrease blood volume & cardiac output; later, cardiac output returns to normal & peripheral vascular resistance declines
-Na+ increases vessel stiffness & response to nervous stimulation
-Diuretics lower BP by 10-15mmHg
-Used in combination with sympathoplegic & vasodilators drugs to contravene Na+ retention
Diuretics
(Examples)
Indapamide --> has direct vasodilating effects in addition to its effect on Na+ stores

Amiloride --> inhibits smooth muscle contraction by affecting Ca2+ ion movements & stimulates Na+ excretion
Sympathoplegics
Inhibit the function of the sympathetic division of the ANS

Include:
-Methyldopa & Clonidine
-Ganglion-blocking agents
-Adrenergic Neuron Blockers
-Adrenoreceptor antagonists
Methyldopa & Clonidine
Sympathoplegics that act on the CNS in the Vasomotor Area of the medulla

The structures of these drugs are similar to methylnorepinephrine

Interact with α-adrenergic receptors on neurons that modulate the baroreceptor reflexes, which inhibits sympathetic influences & allows the parasympathetic influences to predominate (=lowering of BP)
Ganglion-blocking Agents
Sympathoplegics that act on the autonomic ganglia

Among the first drugs to be used against hypertension

No longer used due to excessive side effects
Adreneric Neuron Blockers
(How they work)
Sympathoplegics
-At the presynaptic terminal, BP is lowered by preventing the normal physiological release of NE

-Guanethidine enters the presynaptic terminal via the NE transporter & becomes concentrated in teh storage vesicles, replacing NE. It also blocks electrical activity at the terminal, apparently by blocking Na+ channels

-Reserpine blocks the storage vesicle NE transporter, leading to depletion of NE stores in the vesicles.
Adreneric Neuron Blockers
(Sympathetic Nerve Terminal)
Arrival of an action potential at the presynaptic terminal opens Ca2+ channels, which stimulates NE storage vesicle fusion with the plasma membrane & release of NE into the synaptic cleft.
Adrenoreceptor Antagonists
-Bind to α & β receptors in the target cell at the sympathetic nerve terminal.

Includes:
-β-blockers Propranolol, Metoprolol, & Nadolol
-α1-blockers Prazosin, Terazosin, & Doxazocin (act by decreasing IP3 levels in arterioles & venules, promoting vasodilation)
Vasodilators
-Relax vascular smooth muscle, leading to resistance vessel dilation & increased capacitance

Oral vasodilators: Hydralazine, Minoxidil --> used for long-term outpatient treatment of hypertension

Parenteral vasodilators: Nitroprusside, Diazoxide, Fenoldopam --> used to treat hypertensive emergencies

-Ca2+ channel blockers: long-term or short-term
-All relax smooth muscle of arterioles
-Elicit compensatory reponses; used in combination to oppose these responses
Vasodilators
(Hydralazine)
Potent orally effective vasodilator, but resistance develops

Dilates arterioles, but not veins

Used in combination

Mechanism unclear
Vasodilators
(Minoxidil)
Aka Rogaine

Effective oral vasodilator

Dilates arterioles, but not veins

Acts as an opener of smooth muscle K+ channels (this hyperpolarizes the membrane, which inhibits opening of Ca2+ channels needed for smooth muscle contraction --> promotes relaxation & vasodilation)

Major side effect = Tachycardia
Another side effect = hirsutism (increased hair growth)
Vasodilators
(Sodium nitroprusside)
Powerful vasodilator for hypertensive emergencies

Dilates BOTH arterial & venous vessels

Works like the nitrates & nitrites by stimulating guanylyl cyclase, leading to increased cGMP & vascular smooth muscle relaxation
Anti-angiotensin drugs
(Primary Effect)
Primary effect = reduction in peripheral vascular resistance, which reduces blood pressure by interfering with the renin-angiotensin-aldosterone system
Renin-Angiotensin-Aldosterone System
Renin is a proteolytic enzyme that cleaves angiotensinogen to form angiotensin I.

Angiotensin I is inactive, but is converted into angiotensin II

Angiotensin II is a very strong pressor agent, about 40 times stronger than NE
Anti-angiotensin drugs
(How they work)
Angiotensin-Converting Enzyme (ACE) converts angiotensin I to angiotenin II

ACE inhibitors reduce the concentration of the active hormone angiotensin II and therby reduce blood pressure

-Kallikreins cleave the protein Kininogen, which releases bradykinin (a potent vasodilator)
-Bradykinin is normally inactivated by ACE. Thus, inhibition of ACE by the ACE inhibitors increases circulating levels of bradykinin, thus reducing blood pressure by a second mechanism.
ACE inhibitors
Captopril - one of many
Enalapril & Benazapril

ACE inhibitors decreases systemic vascular resistance without increasing HR, & they promote sodium excretion & water loss
ACE inhibitors
(Toxicities)
Severe hypotension in hypovolemic patients (low in fluids)
Renal failure
Dry cough
Angioedema
Chronic administration of ACE inhibitors
Does not completely suppress the angiotensin II response since other enzymes can convert angiotensin I to angiotensin II

This has led to the development of drugs that block angiotensin II actions at teh angiotensin II receptor level (located at the plasma membrane of target cells)
AT1 Receptor Mechanism
Most of the known actions of angiotensin II are mediated by the AT1 receptor, which is a GPCR

Angiotensin binding to the AT1 receptor generates IP3, which diffuses to the SR & binds to teh Ca2+ release channel & activates it, leading to increased intracellular levels of Ca2+, which results in smooth muscle contraction & vasoconstriction
Angiotensin II Blockers
AT1 receptors are present in the plasma membrane of the postsynaptic membrane of target cells where they participate in Ca2+ mobilization.

AT1 receptors are also present in the presynaptic plasma membrane.

Ca2+ mobilization promotes NE storage vesicle fusion & NE release & binding to postsynaptic adrenergic receptors that mobilize more Ca2+, and it also interferes with proper function of the NE reuptake transporter, which prolongs the effects of NE on the target cells.

ATI blockers interfere with these actions
AT1 Receptor Blocker Sites of Action
Angiotension II also promotes aldosterone secretion by the adrenal cortex

Binding of angiotensin II to the AT1 receptor produces IP3 & DAG

IP3 elevates intracellular Ca2+ levels, which activates PKC & calmodulin-dependent protein kinase
DAG also activates protein kinase C

Protein kinases stimulate aldosterone synthesis

Aldosterone promotes Na+ & water retention

AT1 Receptor Blockers diminish this process = lowering BP by diminishing aldosterone production
AT1 Receptor Antagonists
ARB Prototypes: Losartan & Valsartan
Others:Candesartan, Iprosartan, Irbesartan, & Telmisartan

No affect on Bradykinin metabolism; therefore, they are more selective than the ACE inhibitors

Have potential for complete inhibition of angiotensin II action

Cough & angioedema are less common than with the ACE inhibitors
Heart Failure
-Cardiac output is inadequate & contractility decreases (particularly the ventricles)
-When congestion is present = Congestive heart failure
-Extremely lethal
-Usually caused by coronary artery disease
-May involved systole or diastole failure or right or left ventricle failure (or both)
-May be acute or chronic
-Decreased exercise tolerance, tachycardia, edema, cardiomegaly (hypertrophy)
Compensatory Mechanisms in Heart Failure
(Extrinsic/Neurohumoral Compensation)
-Involves the Sympathetic nervous system & the Renin-angiotensin-aldosterone system
-Baroreceptor reflex reset (reflecting a lower sensitivity to arterial pressure), sympathetic output increases, parasympathetic outflow decreases
-Sympathetic activity causes: tachycardia, increased cardiac contractility, & increased vascular tone result
-This first increases cardiac output, but the increased vascular tone increases afterload & decreases heart ejection fraction, cardiac output & renal perfusion
-Angiotensin II further increases afterload, as well as renal Na+ & water retention (causes edema)
The Renin-Angiotensin-Aldosterone System
-Sympathetic stimulation via β1-receptors
-Reduced renal arterial pressure
-Reduced sodium ion delivery
Compensatory Mechanisms in Heart Failure
(Intrinsic Compensation)
-Myocardial hypertrophy (cardiomegaly)
-Due to increased activity of the heart & elevated Angiotensin II levels
-The dilatation & structure changes lead to diminished performance, remodeling, apoptosis
Heart Failure
(Primary defect & Baroreceptor Reflex)
-Primary defect = excitation-contraction coupling machinery
-Clinical condition also involves: Baroreceptor reflex, sympathetic nervous system, kidneys, angiotensin II, apoptosis involved
Drugs Commonly Used in Heart Failure
Diuretics
ACE Inhibitors
Angiotensin receptor blockers
Cardiac glycosides
Beta blockers
Bipyridines
Beta agonists
Vasodilators
(Dietary salt restriction)
Heart Failure
(Drug Pearls)
-Positive inotropic drugs (increase cardiac contractility) are among the most traditional remedies (i.e. cardiac glycosides)
-Noncardiac targets more valuable
-ACE inhibitors, β-blockers, & the diuretic, spironolactone, prolong life in patients with chronic heart failure
Cardiac arhythmias
-25% patients treated with digitalis
-50% patients under anesthesia
-80% patients with MI
-can seriously reduce cardiac output
-can cause lethal arrhythmias
-mild arrhythmias are usually left alone
Normal Pattern of excitation in the heart (phases)
Phase 0 = upstroke
Phase 1=early-fast repolarization
Phase 2 =plateau
Phase 3= repolarization
Phase 4=diastole
Atrial Purkinje and Ventricular cells Phase 0
-upstroke
-Na Current
-voltage gated Na channels
-High conduction rates
-threshold around -75mV
Atrial Purkinje and Ventricular cells Phases 1 and 2
-Na channels inactivate, Ca2+ and K+ channels activate
Atrial and Purkinje and Ventricular cells Phase 3
-Ca 2- channels inactivate K+ channels continue to open
-Repolarization
SA and AV node (pacemaker cells) Phase 0
-upstroke is a Ca2+ current
-higher threshold, slower
SA and AV node (pacemaker cells) Phase 3
-No phases 1 or 2
-K+ current begins quickly
SA and AV node (pacemaker cells) Phase 4
-slow depolarization
-K+ currents decrease
-Ca2+ and If increase
Sympathetic Control of Pacemaker Cell Firing Rate
-stimulate beta receptors
-increase adenylyl cyclase
-increase PKA (Protein kinase A)
-increase Ca2+ channels and If funny channels
-increase phase 4 slope and decrease threshold
Parasympathetic Control of Pacemaker cell firing rate
-stimulate M2 receptors, decrease adenylyl cyclase, decrease PKA
-decrease Ca2+ and If funny channels
-decrease Phase 4 slope
- increase K+ channels, decrease phase 4 slope, decrease MDP (maximum diastolic potential) lenghthens the time it takes to get to the next threshold
Cardiac Arrhythmias
-disturbances in impulse formation
-disturbances of impulse conduction
Mehcanisms of Cardiac Arrhythmias DDA
-disturbances of impulse formation
-latent pacemakres become dominant
-myocytes become ectopic pacemakers
- increase MDP can induce automaticity = one form of depolarization-dependent automaticity (DDA)
Mehcanisms of Cardiac Arrhythmias EAD
-disturbances of impulse formation
-prolonged action potential duration can cause Depolariation dependent automaticity (DDA)
-ca2+ channes reopen, EAD can result (early after depolarization)
-exacerbated during slow heart rates
Mechanisms of Cardiac Arrhythmias DAD
-arise from baseline (resting potential)
-often caused by Ca2+ overload
-increase Ca2+ in, increase non-specific cation channel, increase 3Na/Ca exchanger
Mechanism of Cardiac Arrhythmias Circus Movement
-disturbance of impulse conduction
-AV block, bundle branch block
- reentry: circuls movement; one impulse excites the heart more than once
Reentry or Circus Movement requirements
1. closed conduction loop
2. unidirectional block
3. slowed conduction
common reentry arrhythmias
-paroxysmal supraventricular tachycardia (PSVT)
-Atrial Flutter and Fibrillation (AF/AF)
-Ventricular tachycardia and fibrillation (ventricle is the pacemaker)
Drug therapy of arrhythmias
-decrease ectopic pacemaker activity : reduce phase 4 slope, increase threshold
-decrease abnormal impulse conduction: decrease conduction through certain regions, increase refractory period of certain cells
Class I antiarrhythmic
-Na channel Blockade
-primary action in FAST tissue:
-decrease sodium channels and abnormal phase 4 depolarization
-increase threshold and refractory period
-disrupt reentry
-reduce ectopy
-but they slow phase 0 upstroke, which slows conduction velocity in fast tissue, which can PRODUCE arrhythmias
class 1A, 1B, 1C
-degree of sodium channel blockade
-effect on AP duration
Class 1A
-quinidine, procainamide, disopyramide
-Moderate Na channel block; prolong AP, refractory period, inhibit K+ channels
-used for AF/AF, ventricular tachycardia
Class 1B
-lidocaine, tocainide, mexilitine, and phenytoin
-Mild sodium channel block; greater effect in damaged tissue
-used for arrhythmias following MI
Class 1C
-flecainide, encainide, propafenone
-POTENT channel block; arrhythmogenic
-used when other options fail
Class II
-beta adrenergic receptor blockers
-propanolol, acebutolol, esmolol, metoprolol
-decreased beta 1- adrenergic receptor mediated stimulation of Ca2+ and funny channels
-normally stimulate Beta receptors will increase adenylyl cyclase and increase
PKA which increase Ca2+ channels and If channels which increases Phase 4 slope and decreases threshold
- these stop all of that
-causes decrease phase 4 and phase 0, increase threshold, increase refractoriness in SLOW TISSUE
-decrease ectopy, decreased reentry in SLOW TISSUE
-decreased pacemaking, increased refractoriness in ischemic fast tissue
-decreased ectopy, decreased reentry in fast tissue
-used for PSVT, post MI and AF/AF
Class III
-drugs that prolong the refractory period (K+channel blockade)
-amiodarone, bretylium, sotalol
-prolong AP duration, increase refractoriness of SLOW AND FAST tissue
-decrease reentry arrhythmias
-used for PSVT, ventricular tachycardia and AF/AF
Class IV
-Ca2+ channel blockers
-verapamil, dilitiazem
-affect slow tissue
-decrease phase 4 and phase 0, increase threshold, increase refractoriness, decrease conduction velocity
-decrease ectopy, decrease reentry
-used for PSVT, AF/AF
other antiarrhythmic drugs
Adenosine
-adenosine
-A1 receptor agonist, similar to M2 acetylcholine receptor
-decrease Ca2+ and funny channels
-increase K+ channels
-decrease MDP, decrease Ca 2+ dependent action ptoentials
-decrease ectopy, decrease reentry in slow tissue
-bolus dose stops heart
-used for PSVT, other slow tissue reentry arrhythmias
Other antiarrhythmic drugs
Digitalis
-increase contractility
-increase VAGAL TONE, increase M2 receptor activity
-decrease Ca2+ and If activity, increase K + channel activity, decrease Phase 4 and Phase 0, increase threshold, decrease MDP, decrease conduction and refractoriness
-decrease ectopy, decrease reentry in SLOW tissue
-used for PSVT and AF/AF
Hyperlipoproteinemias
-cause pancreatitis and atherosclerosis
-lipoproteins = proteins and lipids
-lipids = triglycerides and cholesteryl esters
-lipoproteins with Apo B ( B100) carry lipids TO arteries = LDS, IDL, VLDL, Lp(a) = "bad cholesterol"
-HDL (No apo B) carry lipids AWAY from the arteries = good cholesterol
Atherosclerotic Plaques
-foam cells accumulate damaged lipoproteins
-lipid-filled foam cells, proteins, lipids, Ca2+ ---> plaques
-arterial lumen narrows = angina
-small undetectable plaques also accumulate; some are unstable and rupture
-clotting --> thrombus---> MI, stroke
-lipid-lowering drugs stablize plaques
hyperlipidemias
-involve increase triglyceride, increased cholesterol or both
-caused by genetics and/or lifestyle
-atherosclerosis increases with increased LDL and decreases with increased HDL
-<200 mg/100 ml total cholesterol
-<130 mg/100 ml LDL
-treate with diet adjustment, then lipid-lowering drugs
Lipid Lowering Drugs:
The Statins
-Atorvastatin (lipitor)
-Pravastatin (Pravachol)
-Simvastatin (Zocor)
-Lovastatin (Mevacor)
-competittive inhibitors of HMG CoA reductase (enzyme for cholesterol synthesis)
-"reductase inhibitors"
-decrease cholesterol biosynthesis
-increase LDL scavenger receptors, Increase LDL clearance
Lipid Lowering Drugs
Niacin
-Vitamin B3, nicotinic acid)
-decreased VLDL secretion, decreased LDL production
-increased secretion of cholesteryl esters and triglycerides
Lipid Lowering Drugs:
The Fibric Acid Derivatives
-fibrates
-Gemfibrozil and fenofibrate
-increase synthesis of lipoprotein lipase, HDL apoproteins
-increased triglyceride hydrolysis, decrease VLDL
Lipid Lowering Drugs:
The Bile Acid-binding Resins
-resins
-colestipol, cholestyramine, colesevelam
-used when only LDL levels are elevated, can increase VLDL
-bile acids = cholesterol metabolites
-secreted into small intestine and then reabsorbed
-resins = large ion exchange resins; never absorbed
-bind bile acids and prevent their reabsorption = 10x excretion
-Bile acids decrease 7-alpha hydroxylase, decreases cholesterol breakdown
-decreased bile acid concentrations, increase cholesterol breakdown which increases cholesterol elimination!
Lipid Lowering Drugs:
Ezetimibe
-decreased cholesterol uptake
-Vytorin (another name)
-mechanism unknown
-inhibits absorption of dietary cholesterol and cholesterol that is being recycled
combinations of lipid lowering drugs are useful when...
1. VLDL levels are raised by bile acid-binding resins
2. LDL and VLDL Levles are both high
3. A single drug is insufficient to lwoer LDL or VLDL levels
4. patients with hyperlipidemias also have high Lp (a) levels or HDL deficiency
Combinations of Lipid Lowering drugs options.
1. Fibrates plus bile acid binders
2. statins plus bile acid binders
3. niacin plus bile acid binders
4. niacin plus statins
5. Statins plus ezetimibe (Vytorin)
6. Bile acid binders plus niacin plus statins
Hemostasis
-decreased bleeding : platelet action
-platelets = pieces of bone marrow megakaryocytes
-regularly shaped; contain secretion vesicles with many factors: ADP, serotonin, von Willebrand factor, thrombin, fibrinogen
-vascular endothelial cells do not form thrombi or bind platelets
-a break in the endothelium triggers platelet activation and thrombus formation
Platelet activation and thrombus formation
-collagen, thromboxane A2 (TXA2), ADP, serotonin, thrombin, vWF and other molecules trigger platelet activation
-upon activation, platelets exocytose secretion vessicles, produce thromboxane A2, change shape and aggregate
-increases in local concentration of ADP, 5-HT (serotonin), vWF, thromboxane A2, thrombin etc activate additoinal platelets which magnifies the response
-aggregation produces a weak plug
Hemostasis part 2
-tissue factor (TF) initiates proteolytic reactions that convert prothrombin to thrombin
-thrombin converts fibrinogen to fibrin
-fibrin is incorporated into the platelet plug and crosslinked to produce a stable clot
Anitclotting Drugs:
Anticoagulants
Indirect Thrombin Inhibitors
Direct Throbin Inhibitors
The Coumarin Anticoagulants
Indirect Thrombin Inhibitors
- Heparin
-interact with antithrombin, a protease inhibitor
- increase protease inhibition, decrease clotting
-heparin = sulfated polysaccharides; administered by injection or intravenous infusion
-causes bleeding; contraindicated in patients with bleeding disorders
Direct Thrombin Inhibitors
-Hirudin (Refludan)
-bind to thrombin and inhibit it
-derived from medicinal leeches (Hirudo medicinalis)
-hirudin = polypeptide; produced by recombinant DNA technology
-administered by injection
Coumarin Anticoagulants (warfarin)
-toxic substances in spoiled silage; produced bleeding disorders in cattle
-also used as rat poision
-only oral anticoagulant
-structureal analogue of Vitamin K
-prothrombin and other clotting factors must be gamma -carboxylated before they become active in clotting cascade
-vitamin K gamma carboxylates (using CO2 and ATP)
-coumarin inhibits vitamin K regeration reaction (carboxylation reaction uses vitamin K up and must be regenerated again)
Fibrinolytic Drugs
-streptokinase, urokinase, tissue plasminogen activator
-finbrinolysis helps localize clotting
-catalyzed by plasmin (protease) which is generated from plasminogen
-fibrinolytic drugs increase fibrinolysis
-increase plasmin levles
-elevated plasmin levles suppress clot formation, dissolve clots
Antiplatelet Drugs
-Aspirin
-thromboxane A2 binds to platelet Thromboxane A2 receptor (GPCR, Gq and G 12/13)
-Galphaq increases IP3, inward Ca 2+, increase storage vesicle exocytosis
-Galpha 12/13 involved in shape changes via actin reorganization
-thromboxane A2 synthesis begins with cyclization of arachidonic acid by prostaglandin endoperoxide synthase (cyclooxygenase, COX)
-aspirin inhibits COX IRREVERSIBLY
-
Antiplatelet drugs: (Plavix)
-Clopidogrel (Plavix), ticlopidine
-block ADP receptor, decrease platelet aggregation
-platelet ADP receptors = P2Y1 and P2Y12 purinoceptors
-P2Y1 increases inward Ca2+
-P2Y12 decreases cAMP (Gi)
-cAMP decreases platelet shape change, aggregation
-ADP binding decreases camp, increases shape change, aggregation
-clopidogrel and ticlopidine block the P2Y12 receptor increasing camp, decreasing platelet shape change, aggregation
Antiplatelet Drugs (abciximab)
-Glycoprotein IIB/IIIa REceptor blockers (abciximab)
-Abciximab = anti-GPIIb/IIIa monoclonal antibody
-decreases GP IIb/IIIa binding to fibrinogen other proteins, decreases clotting
-adminsitered parentally
-used for patients with high acute risk of coronary thrombosis
COX inhibitors
-Aspriin
-Ibuprofen
-Tylenol
-Celebrex
-Aleve
The Kidney
-fluid volume and osmolarity regulation, electrolyte and acid-base balance, drug metabolite elimination
-produces renin, which regulates angiotensin synthesis, aldoseterone secretion, antidiuretic hormone secretion
-functional unit: nephron 10^6 per kidney
-filter blood, reabsorb essential constituents, exrete the rest
-membrane transport systems and channels involved
-increased urine = diuresis
-drugs that cause it are diuretics
Diuretic drugs (mechanisms)
-many affect membrane transporters
-others prevent water reabsorption
-others inhibit enzymes, hormone receptors, channels
-most affect specific anatomic regions
Proximal Tubule
-glomerulus filter blood; filtrate passes to proximal tubule
-NaHCO3, NaCL, glucose, amino acids, other organic acids reabsorbed by specific membrane transporters
-water follows passively
-85% of the NAHCO3, 40% NACL, 60 % water and all of the organic solutes reabsorbed here
Loop of Henle
-more H2O reabsorbed
-35% of the Na reabsorbed as NaCl (thick ascending limb)
-thick ascending limb impermeable to H2O, so salt reabsorption dilutes tubular fluid
-thick ascending limb=diluting segment
Distal convoluted tubule
-10% of NaCl reabsorbed
-impremeable to water, further dilution occurs
Collecting tubule and Collecting Duct
-2-5% of the filtered NaCl reabsorbed
-final urine volume and Na concentration determined
-primary site of K+ excretion
-site of diuretic-induced changes in K+ balance
Diuretic Drugs full mecahnism of action
-increase urine volume, increase salt excretion
-decrease extracellular fluid by decreasing total NaCl
-used in heart failure, kidney disease, cirrhosis of the liver and idiopathic edema
-maintain urine flow for surgical procedures; excretion of poisons
-used for hypertension
-also used for diabetes isipidus (ADH problems), kidney stones and hypercalcemic emergencies
Carbonic Anhydrase Inhibitors
-act in proximal tubules
-sulfonamide derivatives
-decrease HCO3 reabsorption; produce metabolic acidosis
-increase Cl- uptake --> elevated plama Cl- levels (hyperchloremia)
-useful for glaucoma, certain metabolic alkaloses, acute mountain sickness, gout, uric acid stones
- ACETAZOLAMIDE
Loop Diuretics
-FUROSEMIDE, ETHACRYNIC ACID
-act at thick ascending limb of Henle's loop
-most effective diuretics
-inhibit Na+ plus K+ plus 2 Cl- transporter
-decrease NaCl reabsorption, decrease lumen-positive potential
-increase Mg 2+ and Ca2+ excretion
-primary uses: Acute pulmonary edema, other edemas, hypercalcemia
-other uses: hyperkalemia, acute renal failure, anion overdose
-toxicities: hypokalemic metabolic alkalosis (K+ and H+ secretion), hearing loss, gout, hypomagnesemia, severe dehydration
Thiazide Diuretics
-act in distal convoluted tubule
-decrease sodium plus Cl- transporter
-used for hypertension, heart failure, nephrolitiasis (kidney stones) due to hypercalciuria and nephrogenic diabetes insipidus
-toxicities: hypkalemic metabolic alkalosis, hyperuricemia, impaired carbohydrate tolerance, hyperlipidemia, hyponatremia, tiredness
Potassium-sparing Diuretics
-Spironolactone, amiloride
-prevent K+ loss
-diminish aldosterone action = aldosterone antagonists
-spironolactone probably affects aldosterone receptors
-amiloride probably works by decreased sodium channel activity
-useful in states of aldosterone excess (genetic, heart failure)
-toxicities: hyperkalemia, hypercholermic metabolic acidosis, acute renal failure
Osmotic Diuretics
- Mannitol
-proximal tubule and descending limb of henle's loop reabsorb H20
-impermeant solutes cause H2O retention in nephron
- leads to water diuresis
- administered parentally
-increase H2O excretion with minimal Na+ excretion
-uses: decrese intracranial pressure, decrease intraocular pressure, increase renal toxin excretion
-toxicities: extracellular volume expansion, dehydration and hypernatremia
Histidine decarboxylase
-makes histamine from the amino acid histadine
Histamine storage
-in basophilic eosinophils, MAST CELLS, and ECL cells (enterochromaffin like cells)
Enterochromaffin like cells
-found in the stomach and look like the chromaffin cells that are in the adrenal medulla
-they have histamine
-when stimulated will release histamine and cause effects of histamine
Histamine Receptors
H1- found on endothelial cells and smooth muscle cells and works through Gq usual effects increase in calcium and phospholipase
H2- parietal cells in stomach, works through Gs an increase in cAMP, kinase phophorlyating different proteins
-H3- brain neuron terminals
-H4-brain, eosinophils and other foreign elements of the blood (neutrophils, CD4 T Cells)
Cardiovascular effects of histamine
1. H1 receptors on endothelial cells (release of NO(nitric oxide- causes smooth muscle relaxation --> systolic and diastolic BP decrease, increased heart rate, reflex tachycardia from decrease in BP)
2. Direct effect on the heart (increase heart rate and force of contraction -receptors for histamine on the heart)
3. Transudation (histamine increase calcium will cause contraction of endothelial cells on capillaries -allows for spaces between cells when they seperate, fluid and small proteins leak out)
TACHYCARDIA AND TRANSUDATION = major 2 effects
histamine on sensory neurons
-H1 receptors- histamine causes pain and itching via sensory nerve terminals (insect bite)
-H3 receptors- decreases in release of neurotransmitter from nerve
-when histidine occupies receptor it will decrease release of those neurotransmitters (ACh, norepi etc)
-similar to alpha 2 receptor effect with norepi binding to decrease norepi release
Triple Response
1. Red spot (dilation of vessel at site of injection)
2. Wheal- by transudation of fluid from capillaries in the area: bump from edema
3. Flare around it (reddening around the wheal) due to axon flare
H1 antagonists: 2 groups
1. First Generation
-cause drowsiness
2. Second Generation
-do not cause drowsiness because do not cross the blood brain barrier
First Generation H1 antagonists
-diphenhydramine (benadryl)
-promethazine
-work well to blcok histamine effects at H1
-cause drowsiness
-muscarinic antagonists = may cause dry mouth, urinary retention, blurred vision
-Uses: allergic rhinitis, itching, bite
-Local anesthetics if patient cannot take other anesthetics
Second Generation H1 antagonists
-fexofenadine, loratadine, cetirizine(ZYRTEC)
-loratidine works for 10-12 hours because it has a long half life; its first metabolic product form still has antihistaminic activity
-do not cause drowsiness = do not cross BBB (blood brain barrier) , pump in the cells in blood rain barrier that pump the drugs back out
How does HCL get secreted in the stomach?
-stimulus for secretion: food in the stomach, brain: seeing food, smelling
-stimulates G cells to secrete gastrin
-feedback mechanism from D cells: releases somatostatin which has negative inhibitory effect on gastrin secretion which is triggered by ph<3 (too low then it will slow down the release of HCl)
Enterochromaffin like cells
-have histamine in them
-Receptor = CCK2
Parietal Cells (receptors)
-CCK 2 receptor
-M3 receptor (innervated by vagus)
HCl secretion
-gastrin bind CCK2 on parietal cell (not much effect)
-vagal stimulation (secretion of Hcl - not much)
-Most important: gastrin binds CCK2 on ECL and chromaffin 1 cells which causes release of histamine - reacts with H2 receptors on parietal cells and leads to the secretion of HCl
-direct action of histamine on H2 receptors of parietal cells is most important for release of HCl
Parietal Cells (sructure)
-have ruffles = canaliculi= where HCl is secreted
-chanel: allows flux of potassium and chloride
-potassium pumped into cell in exchange for hydrogen
-Channels come preassembled as do the pump molecules when you stimulate through H2 receptor- the channel and pump migrate to the canaliculi
H2 selective blockers
-Ranitadine
-famotadine
-cimetadine (not used much anymore)
-reduce production of HCl by 50-80%
-not preferred drugs: problems
-TOLERANCE builds up to their effects sometimes as early as 3 days
-REBOUND ACIDITY if abruptly stop taking drugs - get even more acid production than you had before- taper off use
-Not a lot of toxicity : GI problems: constipation, diarrhea, cramps
Drugs that work on H2 receptors oversecretion
-ulcers, heart burn, GERD etc
Proton Pump inhibitors
-omeprazole, lansoprole (prevacid), esomeprazole (nexium=- more expensive )
-omeprazole consists of L&D isomers
-Astra Zeneca marketed
- drugs are weak bases with pkas around 4
-given orally as coated tablets so that they are not dissolved or absorbed by stomach so that the lipophilic drug can get to the sm. intestine to be absorbed
-no acid rebound and pump is permanently inacitivated
-toxicities= GI problems
-have to take them an hour before a meal so that pumps are activated when the drug is in your system
Protom pump inhibitors mechanism of action
-drugs come around to stomach and are secreted into canaliculi of parietal cells env is very acidic
-get pH trapping: 1000 times more concentration in the canaliculi wher ethe pmp i
-pharmacokinetically have achieved a big selectivity by trapping the drug where it is going to work
-drugs given in inactive form - in acidic env they change to active form.
-active form reacts with sulfhydryl gorups on the pump and forms disulfide bond = IRREVERSIBY inhibits the pump blocks 90% acid prodcution in the stomach
Problems with Proton Pump inhibitors
1. people in intensive care for stress related ulcers: at risk for developing hospital-aquired pneumonia = 2%
On proton pump inhibitors risk jumps to 5%
2. One study/report on this-these drugs MAY give rise to increased risk of focal arrhythmias in the heart
Steroids
-endogenous compounds used in 2 ways:
1. physiologic concentrations to solve problems where one or another steroid hormone is not being produced
2. pharmocologic concentrations to treat certain disease: extension of usual physiologic properties of the hormone
Adrenocorticoids
1. Glucocorticoids
2. Mineralo-corticoids
Gonadal hormones
-estogen
-prgestins
-estrogens and progestins are made in the ovaries and sometimes in the adrenal cortex
-post-menopausal women: main source of estrogen is from molecule made in adrenal cortex which is converted to estrogen
-androgens : made in the testes
Steroid drugs: how they bind
-steroids are very lipophillic and enter the target cell easily
-bind to intracellular receptor which forms a dimer and enters the nucleus
-in nucleus steroid binds to a particular region of the DNA (different for each receptor and each hormone) (usually a promoter region)
2 possibiliteis once steroid binds to DNA in cell
1. Binding will turn on the synthesis of the particular gene that it binds to at the beginning- lead to mRNA ---> lead to synthesis of protein
2. prevent the transcription of particular gene --> decrease amt of particular protein that is made
Steroid effects take....
-HOURS
-Ex. glucocorticoids good for treating anaphylaxis but not to stop immediately (shock) (need epi for this=quick)
-process involves making protein/making less of existing protein- takes HOURS
-even if steroid is cleared effect linger for hours or days depending on turn over of the protein
Slectivity for steroids
-one steroid vs another depends on the type of receptor and where it is
-each steroid has different anatomical areas where it functions
Glucocorticoids Effects
-Permissive effect: person not making glucocorticoids, catecholamines will have less of an effect on the vascular smooth muscle
-better effect of catecholamines (bronchiole smooth muscle and lipolysis (breakdwon of fat) when you have the glucocorticoids- do not know why
-effect on increasing glucose
Glucocorticoids Effect on glucose
-increase glucose by:
1. Promote protein breakdown to amino acids
2. promote lipid breakdown to glycerol (by catecholamine permissive effect)
3. by increasing enzymes involved in gluconeogensis = increase gluconeogenesis
4. inhibit glucose uptake in fat cells
-all increase blood glucose
Glucocorticoids pharmacologic applications
-addisons disease (adrenal insufficiency) -tx or augment glucocorticoid that is not being produced naturally)
-tx for inflammation, allergies, immunosuprresion, autoimmene disease
-premature infants: not enough surfactant necessary to promote oxygen exchange -glucocorticoids promote production of surfactant
-Cancer Chemotherapy: in high concentrations these are toxic to lymphomas and leukemias
Mechanism of action: glucocorticoids for inflammation (cytokines and direct effect)
-T cells are activated --> produce cytokines-->stimulate B cells ---> make antibodies (IgE)--> binds to Mast cells and basophils --> release of histamine, serotonin, prostaglandins and other mediators cause inflammation and edema
-glucocorticoids: decrease production of cytokines --> decrease stimulation of B cells---> decrease production of Ige. inhibit the activation of CD8 cells and block release of mediators from mast cells etc
-direct effect on inflammed area to cause capillaries to become less leaky
Mechanism of Action glucocorticoid for inflammation: (phosphatidyl choline)
-Phophatidyl choline: broken down to form arachadonic acid by phopholipase A2
-Arachadonic acid converted to thromboxanes and prostaglandins by COX II
-glucocorticoids
1. induce synthesis of protein called lipocortin. lipocortin binds to phopholipase A2 and inhibits its ability to make arachadonic acid
2. inflammtion = induction of COX which is inhibited by glucocorticoids
-both cause decreases synthesis of prostaglandins and decreasing amt of prostaglandin avaialbe in basophils and mast cells
Glucocorticoids Problems
-taken for a week have a feedback mechanism suprressed form anterior pituitary- abruptly stop and will now have too little endogenous corticoid being produced- must taper off dosage
-effect electrolytes: aldosterone type effect: retain too much sodium
-diabetes: make it more difficult to control blood glucose
-immunosupressants - ppl taking these will be at greater risk for infection
-increase risk of cataracts in the eye
-promote bone loss leading to osteoporosis
-cause moodiness
-someone on long term glucocorticoids changes fat distribution: fat on face and top of back (hump)
Ovarian Steroid hormones
-used for hypogonadism (decreased natural productionof these hormones)
-have been used for hormone replacement therapy (post menopausal women-controversial benefits vs. toxicities)
-Used as oral contraceptives
oral contraceptive steroid hormones
-2 drugs usually combined = ethinylestrodiol (estrogen) & Norethindrone (progesterone)
-variants/modifications of the normal estrogen & progesterone that have an ethinyl group added to them which makes them more arally avaialbe
Effects of Oral Contraceptives on Anterior Pituitary
Ethinyestradiol
-anterior pituitary---> releases FSH--> follicle maturation & ovulation. ethinylestradiol inhibits release of FSH and thus inhibits follicle maturation & ovulation
Effects of Oral Contraceptives on Anterior Pituitary
Norethindrone
-Anterior pituitary ---> releases LH---> development of corpus luteum--> releases progesterone & is involved in the build-up of the endometrium of the uterus/implantation. Release of LH inhibited by norethindrone
oral contraceptives other changes
-progestin (norethindrone) affects the cervical mucous- changes consistency to make it more difficult for sperm to migrate up to reach the egg
-Ethinylestradiol + norethindrone will change the endometrium into a condition where it will not encourage implantation
Selective Estrogen Modulators (SERM)
-drugs will be agonist or antagonist depending on where receptors are
-Bone: agonist (favors bone production )
-Raloxifene (osteoporosis tx)
-Breast & uterine tissue - antagonist at estrogen receptors
-Tamoxifen (acts as antagonist -used to treat breast cancer)
Aromatase inhibitors
-adrenal cortical androgen = the main source of estradiol in post-menopausal women
-this androgen coverted to 17-beta-estradiol by enzyme= AROMATASE
-used to prevent recurrence of breast cancer (by not making 17-beta estradiol) that are estrogen dependent
-reduced recurrence by 43%
Prgesterone Antagonist
-Mifepristone (RU-486)
-PGE1 analog---> Misoprostol (cytotec)
-use is controversial because they have been used together for abortion
Testosterone Durgs
-testosterone can be used for hypognoadism
-coverted to dihydrotestosterone by an enzyme called 5-alpha REDUCTASE (found in the prostate
-in the prostate gland, DHT is inactive form of testosterone
Drugs that inhibit 5-alpha reductase
-dutasteride
-finasteride
Used in 2 ways:
1. men who have an elarged prostate by inhibiting formation of DHT leads to shrinking of prostate gland (and shrinking of sex drive)
2. used for prostate cancer
-prostaglandins were first found in the prostate
Drug interaction with oral contraceptives
1. IF on antibiotics-reduce bacteria in intestine. partly metabolized by glucuronidation. glucuronidated form is excreted and bacteria remove the glucuronic acid (via glucuronidase). Fewer bacteria= more glucuronic oral contraceptive will be eliminated
2. Rifampin induces p450 enzymes. Oral contraceptives are also metabolized by p450. If you increase amt of p450 enzymes, then you will metabolize more of the oral contraceptive & reduce effect of contraceptive
Thyroid Gland
-2 hormones
-2 tyrosine residues attached to one another
-iodo gropu at 3,5 position
-four iodo groups, 3,5,3,5 = tetraiodothyronine (T4)
-remove 5prime iodo group and have 3,5,3 = triiodothyronine (T3)
-T3 is 3-4x more potent than T4
thyroid gland structure
-follicles with cells lining lumen of follicle
-in the lumen there is a colloid with the protein thyroglobulin
Mechanism of synthesis for T3 & T4
-sodium & iodine get taken up by cotransporter into the cell
-transporter will bring in idoine at 10-20x the concentration in the extracellular fluid (effficient iodine concentrating)
-iodine now in, diffuses out the luminal side of cell (down concentration gradient)
-uses hydrogen peroxidase as an enzyme (part of luminal membrane)
-TPO (thyroid peroxidase) activates the iodine to active form IO- or I+ (charged)
-in cell mRNA made that makes protein- thyroglobulin which is secreted into lumen and iodinated using TPO again & tyrosine residues in the protein
-we get a tyrosine in protein with 1 iodine (monoiodotyrosine -MIT) or 2 (diiodotyrosine-DIT)
-thyroglobulin with iodinated tyrosine now taken into cell into lysosome
-protease now removes the iodo groups from protein, if it puts 2 DIT together = T4, if 1 DIT and one MIT = T3
Release of T3 & T4
-now T3 & T4 are released from basolateral side of the cell and enter the circulation
-4x as much T4 released as T3
-T3 3-4X more potent than T4
-T4 converted to T3 by a 5-prime deiodinase (mainly in the liver)
-hormone is bound to protein in circulation -little is free
-bound form acts as a reservoir for getting more hormones
Iodine deficiency
-not enough iodine in diet
- lead to oversecretion of TSH to stimulate thyroid gland--> goiter = swelling at front of the neck
Contents of 1 Peter 1
Praise for salvation (1:3–12)
The future inheritance as an incentive to holiness (1:13–21)
Living as the new people of God (1:22–2:10)
Hyperthyroid Signs & symptoms
-Graves disease
-postive inotropic & chronotropic effect (HR increases & force of contraction increases) & peripheral resistance decreases
-adrenergic effects NOT due to release of more catecholamines but may be due to synthesis of more beta receptors
-someone with hyperthryoidism a Beta Blocker is used as an adjunt to tx hypethyroid conditions
Graves Disease
-autoimmune disease
-person makes antibody that stimulates TSH receptor which stimulates thyroid to be overactive
-part of treatment would be to use a glucocorticoid (ex. dexamethasone)
2 types of hyperthryoid conditions
1. Thyrotoxicosis
2. Thyroid storm
Thyrotoxicosis
-exaggerated increase in energy production
- increase in thermogenesis (higher temp)
-people with this are heat intolerant & have perfuse sweating
-EXOPTHALMOS
-hypermetabolism, weight loss, increased O2 & skeletal muscle weakness
Thyroid storm
-more severe form of thyrotoxicosis
-all same signs & symptoms but ALSO pschosis, agitation & coma
-HR > 140 bpm
how do we take care of hyperthyroidsim?
-give person 131 I (radioactive iodine)
-thyroid accumulates iodine at 10-20x plasma concentration if you give 131 I, will be selectively taken into thyroid gland
-over days & weeks 131 I will emit Beta particals (beta emission) ends up destroying thyroid tissue and therfore decreasing output of thyroid hormone
-DO NOT DO THIS for a pregnant or nursing woman will effect fetus or nursing infants
Thioamides
-alternate way to tx hyperthyroidism
-methimazole, propylthiouracil (PTU)
-inhibit thyroid peroxidase (catalyzes formation of iodine & addition of iodine to tyrosines etc)
-Methimazole used more - less toxic & can be dosed once/day
-ONLY PTU blocks conversion of T4-T3 by inhibiting the 5-prime deiodinase
-giving iodine will block release of T4 & T3
-less than 1% cause agranulocytosis
-PTU can possibly cause liver failure
-evidence that Methimazole is TERATOGENIC- if pregnant =preferred tx = PTU
-hyperthryoidism in pregnant women will increase chances of miscarriage
Hypothyroid Signs & symptoms
-negative inotropic & chronotropic effect & peripheral resistance increases
-people who have had thyroid cancer have had thyroid removed will be hypothryoid if treated with 131 I will be hypothyroid
-replace hormone by giving T4. NOT T3 (active form) because half life T4 is ~7 days but T3 ~1 day
2 treatments of hypothyroidism
-levothroid & synthroid
-no diff in activity between the two
-synthroid costs 3X as much
Diabetes
-5-10% Us population
-Blood glucose >125 mg/dl after an 8 hour fast= diabetic
-BGL <55mg/dl you are hypoglycemic
Type I diabetes
-producing littler or no insulin
-tx= take insulin
type II diabetes
-insulin production may be down & tissue may be less responsive to effect of insulin
-treatment = various drugs may be able to help the condition
insulin
-produced from beta cells of islets of langerhans
-synsthesized as preproinsulin & turned into pro-insulin & then converted to insulin (connected by disulfide bonds
-stored in granules in beta cell and is a peptide
Beta Cell
-have Glut1 receptor (glucose transporter)
-beta cells pick up glucose & that glucose enters into metabolism for production of ATP (stimulation of insulin secretion)
Muscarinic receptor (insulin)
-innervated by vagus
-slow role in insulin release
-leads to IP3 & DAG cascade
glucocorticoids and length of action
1. Short
-cortisol (hydrocortisol)
-have activity for 8-12 hrs
2. intermediate
-prednisone
-activity for 12-26 hours
3. Long
-Dexamethasone
-have activity for 24-72 hrs

all work by receptors increasing or decreasing protein synthesis, therfore the effect will not begin to happen until 4-8hrs
Mineralcorticoids
-aldosterone
-spiranolactone ---> an aldosterone antagonist (will antagonize the activities of aldosterone & lead to diuresis (treats hypertension)
-fludrocortisone--> (synthetic analog of aldosterone, so if you want to have the activities of aldosterone- in a person with chronic orthostatic hypotension (wil increase sodium retention & fluid volume)
GLP 1 and GIP
-a meal stimulates the release of glucagons Peptide 1 and gastric inhibitory protein (GIP
-increases cAMP and augments insulin release
Beta cells potassium channel
-when ATP goes up it will bind to the potassium channel & decrease the efflux of potassium (responsibel for membrane potential) causes depolarization of the membrane
-when the membrane becomes deplarized, it activates a Voltage-dependent Calcium channel (increases the influx of Calcium). The influx of calcium will lead to the fusion & release of insulin from the cell
Glucose Transport
-this is a tyrosine kinase
-this is a transmembrane receptor inside the intracellular portion that autophosphorylates & leads to a cascade phophorylation reaction
-glucose stimulates release of pumped molecules, such as Glut 1 & 2. This will stimulate the uptake of glucose into tissues
Metabolism
-in the liver, glucose stimulates glucose conversion to glycogen.
-In adipose tissue, it stimulates glucose to lipids.
-In muscle, it stimulates glucose to amino acids, which in turn stimulates synthesis of protein
-net effet is lowering of the intracellular glucose that is taken up through glucose uptake pumps
Untreated diabetics
Signs & symptoms
1. have BGL >200mg/deciliter
2. polyuria: large volume of urine production
3. polydipsia: excessive thirst
4. Ketogenesis: increase in the ketone bodies (acetone) and you can tell if someone is diabetic and have not been treated properly: can detect a fruity odor on their breath from acetone
5. weight loss
Untreated diabetics Long term problems
1. retinopathy: can lead to blindness
2. Ulceration: which can lead to gangrene
3. earlier onset of atherosclerosis (microcirculatory problems)
BGL monitoring
-blood glucose meter
-continuous glucose monitoring (needle inserted which continually monitors BGL and trasmits it to recorder and alters dosage)
-Hemoglobin A1C
Hemoglobin A1C
-form of hemoglobin which glucose is attached to one of the amino acids in the hemoglobin
- in non-diabetics the % of hemoglobin A1C=5% of total hemoglobin
-untreated diabetic Hemoglobin A1C=10% of total hemoglobin
-aim of tx is to get a number </=7.5% hemoglobin A1C
-measures the blood glucose levels over about 120 days because it reflects the amount of glucose over many days that is available to glycosylate (put glucose on the hemoglobin)
-elevated glucose proteins that shouldn't be glycosylated get glycosylated and lead to other problems in diabetics
Treatment Type I diabetics
-give insulin
1. Short acting: readily soluble and absorbed when given subcutaneously
2. Long Acting: tned to form aggregates (hexamers-six insulin molecules aggregated together). since they are aggregated they are slowly released from aggregate into the circulation and thus are longer acting
3. Really Long Acting: form a microprecipitant (is even less readily absorbed)
Ways to use different forms of insulin to tx type I diabetes
-people generally get a long acting insulin an dthen over the course of the day they take multiple injections of short acting insulin (especially when anticipating a meal)
-using an indwelling ifusion pump (short acting) insulin is constantly infused at a particular rate suitable for the individual
Main idea: try to maintain a gluocse concentration as constant as possible within a normal range
Type II diabetes
-tx with drugs other than insulin
-increase insulin secretion, or make tissues more responsive to available insulin
Preferred drug of choice for treating Type II diabetes
-Metformin
-Various activities: not certain exactly how it works
-reduces gluconeogenesis
-decreaes glucose absorption (from the intestine- eat a bunch of sugar prevents body from absorbing it)
-it decreases secretion of glucagon
-leaves a metallic taste in your mouth. One of the reasons that this drug unlike some of the others doesn't cause weight gain
-cuase: nausea, diarrhea etc (GI disturbances)
Secratogues
-promote insulin secretion
-sulfonylureas (including glipizide)
-Repaglinide (not a sulfonylurea is its own class)
Sulfonylurea
-noramlly in beta cell we have glucose update into the beta cell which resulted in increased ATP and that ATP then bound to Potassium channel to decrease pottasium efflux (leaving cell) to make the beta cell hypopolarized (less polarized) and that then allowed to entrance of calcium through voltage gated calcium channels. That then facilitated release of insulin= NORMAL work in the body
-this drug mechanism = work by binding to another part of the potassium channel and doing the same thing that ATP does. They decrease efflux of potassium leading to depolarization leading to calcium influx (increase in the cell) causes release of insulin from the cell
-glipizide (second generation)
Repaglinide
-mechanism is not clear
-take these 15-30 minutes before you eat a meal
-is a secratogue
Problems with secratogues
-after taking for years tachyphylaxis develops = drug begins to not be effective
-cause hypoglycemia (don't see much with metformin) = BAD
-weight gain (metformin does not)
-repaglinide + metformin = synergistic greater than additive effect when you take these together
Thiozoladinediones
-rosiglitazone "glitazones" still available in US but are begin PHASED OUT
-if you are not already on these then you should NOT Start
-They have SERIOUS CARDIAC TOXICITIES
-associated with bladder cancer as well
-will not be available in the next 2 years
Alpha-glucosidase inhibitors
-alpha-glucosidase is in the brush border cell of the small intestine
-takes starches and glycogen and plystarches and breaks it down to glucose which is then absorbed (into the body)
-Acarbose: inhibits the alpha glucosidase as a result there is decreased glucose available to be absorbed
-main problem: these substrates which are not broken down go to large intestine where they ferment and produce gas-leads to dicomfort, gas, flatulants
Usual approach for tx of Type II diabetics
-use Metformin and combine it with a sulfonylurea
Calcium
-normal range in blood 8.5-12.2 mg/dl
-important to muscle contraction, neurotransmitter release, hormone release with insulin as well
-of total calcium in body 99% is in bone(main repository)
Calcium concentration regulated by:
bone, intestine and kidney
Vitamin D synthesis
-can get it in the diet as well
-key regulator of calcium concentrations
-7-dehydro Cholesterol --> converted by UV light from Sun in the skin ---> into Cholecalciferol (vitamin D#)
-15 minutes of sun exposure or so would be sufficient to make enough the Vitamin D
-Cholecalciferol to the liver (has one hydroxyl) --> acted upon by an enzyme in liver (25, hydroxylase) ---> puts hydroxyl group on the 25 position ---> gives us 25 hydroxyl Vit D (reaction involves the liver- now have 2 hydroxyl)
-finally 25 hydroxyl vit D goes to the kidneys- acted upon by 1-alpha hdyroxy Vit D-calcitirol (MOST ACTIVE FORM OF VIT D)
-this will carry out processes discussed later on
Parthyroid Gland
-5 seperate little glands located on the thyroid gland
-Hypocalcemic: parathyroid increases
-Hypercalcemic: parathyroid decreses
Parathyroid cells
-there is a calcium sensing receptor
-when bound to clackum it cleaves through Gi protein --> decrease in cAMP ---> phophorylation to decrease release of parathyroid hormone
-when no calcium bound: activates Gq ---> IP3/DAG---> PTH increases
Calcitriol
-another way to mediate release of PTH
-binds to VDR (Vitamin D receptor)
-like steroids and thyroid hormone these receptors bound to calcitrione now bind to DNA and the effect: inhibit synthesis of PTH
-decreases PTH release by decreasing PTH synthesis
Kidney cell (structure with channels etc)
-in distal convuluted tubule
-PTH receptor (on cell)
-VDR receptor (inside cell)
-calcium channels (on luminal surfaces)
-calcium sodium exchanger (blood side of cell surface)
-ATPase (on blood surface which will pump calcium out into the blood
When PTH binds to PTH receptor in kidney cells
-increase in cAMP
-increase influx of clcium through calcium channels
-stimulate calcium sodium exchanger
-stimulate calcium ATPase
-causes reabsorption of calcium from the lumen of the kidney of distal convoluted tubule
Calcitriol binding in the kidney cell
Calcitriol comes in and binds to VDR---> will bind to DNA and produce 2 proteins
1. Cabindin 28K ---> binds to calcium which pulls clacium into the cellf rom the calcium channels and then that calbindin 28K facilitates movement of calcium down to the ATPase where the calcium will be pumped out of the cell
2. Calbindin 9K
-called calbindin because it binds calcium
-stimulates clacium ATPase pump
all increases reuptake of calcium into the blood (all of the above things) regulating blood calcium concentration
Small Intestine Calcium regulation
-normal or high calcium in the intestine main route of calcium is paracellular
-lower calcium in intestine-route will be transcellular: calcium comes down calcium channel and into the cell and is pumped out through the ATPase
Calcitriol into the Small intestine cell
-binds to VDR causes synthesis of :
-Calbindin 9K: stimulates the ATPase to pump calcium out of the cell and into the blood
-more calcium channes: allow more calcium to come into the cell to then be pumped out through the ATPase into the blood
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PTH (indirect effects)
-stimulates the 1-alpha-hydroxylase in the kidney cells which increases the formation of calcitriol
-PTH through increasing calcitriol synthesis indirectly effects uptake of calcium in the small intestine
Osteoporosis
-loss of bone in the body
Osteopetrosis
-abnormal increase in bone mass
Bone remodeling
-happens all the time
-oldbone is broken down and newbone is built up
-Bone is NOT static
Osteoblasts
-PTH will stimulate osteoblasts to form 2 proteins
-Rank ligand
-osteoprotegerin
Rank Ligand
-part of mature osteobalst
-binds to rank receptor and causes differentiation of precursor cells from macrophages into an osteoclast
-causes osteoclasts to make a protein pump of compound acid and production and secretion of Cathepsin K (proteases)
-acid released at binding site to bone causes breakdown of mineral of bone (hydroxyapetite into calcium and phosphate)
-liberates calcium into blood
-Cathepsin K finishes job by breaking down collage
-attracts osteoblasts that now come in an dlay down new bone
Osteoprotegerin
-soluble protein which acts as a decoy to bind to the rank lignad
-prevents rank ligand from binding to rank receptor and therfore prevents osteoclast differentiation
Drug applications with osteoporosis
-66% women over 80
-3% of 60-70 year old women
-bone density >/= 2.5 standard deviations from a normal mean bone density determined by young people bone densities
-if you are between bone loss and normal = osteopenia
-if bone density decreases = more sensitive to bone fractures (worst is the hip)
-need to have baseline bone mineral density test so that you know the levels have changed when you get older
Vitamin D and calcium intake
-important for osteoporosis
-Vitamin D is important for calcium absorption in the intestines
-calcium supplements come as calcium carbonate and calcium citrate (better absorbed and does not require you to take it with food)
Bisphosphonates
-look like pyrophosphonate (found in bone) work by mimicry
-alendronate (fosamax) taken weekly but costs a LOT
-Ibandronate; can be taken on a montly basis MORE EXPENSIVE
-bind selectively in bone and get into the osteoclasts and inhibit an enzyme, Famesyl synthase
-part of pathway that leads to synthesis of lipids that take part in a reaction called prenylation (add lipids to certain proteins)
-inhibiting reaction in pathway to making lipids then prenylation cannot take place and certain proteins which are only active when they are prenylated do not work
-leaves osteoclasts = apoptosis
Bisphosphonates
-look like pyrophosphonate (found in bone) work by mimicry
-alendronate (fosamax) taken weekly but costs a LOT
-Ibandronate; can be taken on a montly basis MORE EXPENSIVE
-bind selectively in bone and get into the osteoclasts and inhibit an enzyme, Famesyl synthase
-part of pathway that leads to synthesis of lipids that take part in a reaction called prenylation (add lipids to certain proteins)
-inhibiting reaction in pathway to making lipids then prenylation cannot take place and certain proteins which are only active when they are prenylated do not work
-leaves osteoclasts = apoptosis
Toxicities of bisphosphonates
-MAIN: irritation and ulceration of the esophagus important to take with full glass of water and remain upright for a half hour to make sure that all the bisphosphonates get into the stomach and out of esophagus
-osteonecrosis of the jaw: very very infrequent: usually happens when people with cancer (bone) are treated with these drugs in very very high doses
-tooth extraction while tkaing these may raise the risk
-"frozen bone": by inhibiting osetoclasts over a period of time you are preventing rejuvenation of new bone- may cause the bone there to become fragile
Toxicities of bisphosphonates
-MAIN: irritation and ulceration of the esophagus important to take with full glass of water and remain upright for a half hour to make sure that all the bisphosphonates get into the stomach and out of esophagus
-osteonecrosis of the jaw: very very infrequent: usually happens when people with cancer (bone) are treated with these drugs in very very high doses
-tooth extraction while tkaing these may raise the risk
-"frozen bone": by inhibiting osetoclasts over a period of time you are preventing rejuvenation of new bone- may cause the bone there to become fragile
other drugs to treat osteoporosis
-Raloxifene (estrogen receptor module)
-Teraparitide: first 34 amino acids of PTH. Given in low doses increases osteoblasts activity
-denusumab: latest drug, monochlorol antibody, binds rank ligand which prevents activation of osteoclasts
other drugs to treat osteoporosis
-Raloxifene (estrogen receptor module)
-Teraparitide: first 34 amino acids of PTH. Given in low doses increases osteoblasts activity
-denusumab: latest drug, monochlorol antibody, binds rank ligand which prevents activation of osteoclasts