S3 Week 1 Pharmacology

Front 1

Diagram of lipid pathways and where drugs act at:

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Front 2

Which Apoprotein is the one that takes LDL back to the liver?

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ApoB

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If a patient is deficient in lipoprotein lipase what will be elevated?

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Triglycerides

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Treatment goals for lipid therapy:

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Common Lipid Disorders:

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What do the statins do?

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Inhibit HmgCoA, the enzyme and rate limiting step responsible for endogenous production of cholesterol

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Statins:

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How do resins work?

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By binding to bile acids and preventing recycling

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Resins:

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What does Ezetimibe do?

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Decreases dietary absorption of cholesterol; Inhibits intestinal sterol transporter

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Ezetimibe:

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How does niacin work?

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- Reduces hormone sensitive lipase activity
- Decreases free fatty acids & triglycerides
- Reduces catabolism of HDL

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Niacin:

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Can also increase blood glucose levels and worsen insulin resistance in type II diabetics!

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How do fibrates work?

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- Activator of peroxisome proliferator activating receptor- a
- Increases synthesis of adipose lipoprotein lipase
VLDL & triglyceride breakdown, fatty acid oxidation in liver
- Increase ApoA = increases HDL

Front 15

Fibrates:

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Front 16

Chart of lipid lowering drug effectiveness:

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Niacin =greatest increase HDL
Statins=greatest decrease in LDL
Most favorable increase HDL:LDL ratio = niacin
Bile binders & ezetimibe can increase triglycerides

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Back 17

Niacin and gemfibrozil

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Lipid treatment exercise:

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Answers:
P1: Familial Combined Hyperlipoproteinemia (metabolic syndrome) - ideal = statin, niacin, fenofibrate
P2: Familial Hypercholesterolemia –heterozygous (likely cause : LDL receptor or Apo B) = start on statin (HDL good)
P3: Familial Hypertriglyceridemia (likely cause: disorder ApoA-V)= gemfibrozil, niacin (helps bring up HDL)

Front 19

Name the drug class under the boxes:

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Front 20

Secondary causes of lipid disorders:

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Front 21

Highlites in the formation of a clot:

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Front 22

Review of platelet aggregation:

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Aspirin:

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Other antiplatelet agents:

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Heparin:

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Lepirudin:

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Dabigatran: newly approved oral direct thrombin inhibitor

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Warfarin:

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MAO: Competitively inhibits vitamin K epoxide reductase (VKOR) to decrease regeneration of vitamin K supply necessary for these clotting factors
Vitamin K necessary co-enzyme in activating clotting factors
Reduces activation of factors II, VII, IX

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What is the anticoagulant of choice in pregnancy?

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Heparin

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Clot Busters:

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- Streptokinase-less expensive but:
severe allergic rxn in some people.
recommended to have corticosteroids available to trt such rxn.
- Alteplase, tenecteplase, reteplase:
Severe bleeding possible, esp with longer-acting.
Reverse excessive bleeding with aminocaproic acid

Front 30

Clinical indications for anticoagulant drugs:

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Aggrenox is aspirin + dipyridamole

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Review of Autonomic (sympathetic and parasympathetic) Nervous System:

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Front 32

Basic review of autonomic receptors:

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Which receptors increase coronary blood flow? B2 adrenergic receptors
During a stress response, which transmitter exerts the greatest stimulatory effects on B2 adrenergic receptors? Epinephrine

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More autonomic review:

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Review of receptors and second messengers:

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*Arterial pressure is a function of cardiac output and peripheral vascular resistance

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Baroreceptor reflex to increased BP:

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Front 37

Baroreceptor reflex to low BP:

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Front 38

Overview of sympathomimetic agents:

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Front 39

Effects of NE vs Isoproterenol:

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Why would NE decrease the heart rate? Compensatory baroreceptor effect.

So…isoproterenol does the opposite – it decreases blood pressure so to compensate the heart beats faster.

What best explains why ISO produces a drop in blood pressure while producing an increase in HR? Vasodilation via B2 without vasoconstriction via A1 activation.

Front 40

Epinephrine:

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Front 41

Epinephrine Part 2:

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Epi increases renin release and activates the renin-angiotensin-aldosterone system through activation of which receptor? B1

Adenyl cyclase and cAMP 2nd messenger system is activated and renin levels are elevated

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Norepinephrine:

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Dopamine:

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α1 effect : Seen only at very high doses = vasoconstriction.

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Alpha agonists:

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*Note: FYI: Selective uses of selective α1 agonists = tend to decrease HR via baroreceptor effect –use of phenylephrine could be a concern in situations where one needs to get BP up but also needs to get the heart pumping (eg…hypovolemic shock after massive blood loss).

Front 45

Beta agonists:

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Selective Beta agonist:

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Front 47

Summary of receptors involved in heart rate and vessel tone:

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α1 =vasoconstrictor increases TPR

α2 offsets = auto-inhibition

β1 receptor activation = inotropic & chronotropic

β2 receptor activation vasodilates coronory vessels (FEEDs the heart O2)/ offsetting vasodilation

LAST NOT LEAST = baroreceptor to keep it all in line….if compensatory systems get “reset” get…hypertension/disease

Front 48

Overview of MOA of Beta Blockers:

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Front 49

Treatment plans for stage I and II hypertension:

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Front 50

Blocking the a2 receptor decreases release of what neurotransmitter?

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Norepinephrine

Front 51

Hypertension Drugs and thier sites of action:

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Orthostatic hypotension

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Pharmacology of Alpha 2 agonists part 1:

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Practical issues – Per Dr. Asmar, these patients are always trying to drink something (some may overdo it on the volume injested . Dry mouth can a problematic side effect for many patients.

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Compensatory response to anti-hypertensive medication:

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alpha-2 receptor downregulation

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Trimethapan and Reserpine:

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B-adrenergic receptors

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Overview of alpha blockers:

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Adrenergic A1 stimulation without compensatory B2 vasodilation

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Overview of beta blockers:

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Propranolol:

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Propranolol Part 2:

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Front 63

Beta 1 selective antagonists:

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Front 64

Mixed Alpha antagonist Beta agonists:

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Why choose these over other beta blockers???
- Beta block/partial β agonist sympathomimetic activity (labetalol):
Beneficial to certain patients with
compromised cardiac function – less negative inotropic / chronotropic effects.
- Less effect on airway resistance
Less block of coronary vessels (if CAD)
Still relative contraindication in asthma
- Possess adverse effects of α1 antagonism

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What is the initial treatment recommendation for hypertension?

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Thiazide-type diuretics should be initial drug therapy for most, either alone or combined with other drug classes

If BP is >20/10 mmHg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic.

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MOA of thiazide diuretics:

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Decrease cardiac preload volume

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Thiazides:

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Adverse effects of thiazide diuretics:

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Notes:
Friendly mnemonic for thiazide adverse if you like it: Thia=“Hy UGLi” (hyperUricemia, Glycemia, Lipidemia)

Differential effects on potassium – if patients eat too much salt (common in this country), see thiazide induced hypokalemia.
If patient restricts salt intake, thiazides may not cause hypokalemia

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MOA of loop diuretics:

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Loop diuretics:

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Adverse effects of loop diuretics:

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Potassium sparing diuretics:

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COX inhibition reduces vasodilating prostacyclin

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MOA of ACE inhibitors:

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Low renin levels

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Adverse effects of ACE Inhibitors part 1:

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Adverse effects of ACE Inhibitors part 2:

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Lower aldosterone levels reduce K+ excretion

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Angiotensin receptor blockers:

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Renin Antagonist:

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Front 82

Therapeutic goals of treatment with vasodilators and calcium channel blockers:

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MOA of calcium channel blockers:

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Front 84

Bodywide effects of calcium channel blockers:

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Front 85

Comparison between effects of CCB and CCB-DHP type on vasculature:

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Comparison of CCB types:

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Afterload

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Common uses for CCB's:

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Adverse effects of regular CCB's:

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Adverse effects of DHP CCB's:

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Vasodilators used for severe hypertension:

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Hydrochlorthiazide

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Nitroprusside:

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Front 94

Hydralizine and Minoxidil:

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*Hydralazine=lmmunologic reaction more common in slow acetylators = Drug-induced lupus-like syndrome –serious. Detect with positive antinuclear antibody test. Symptoms include arthralgia, serum sickness with fever, vasculitis, hemolytic anemia. Dose-dependent, up to 10% of patients after years hydralazine.

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Other indications for vasodilators:

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Metoprolol