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What are the 5 major cholinergic drugs?
- 1) Muscarinic receptor agonists
- 2) Cholinesterase inhibitors
- 3) Muscarinic receptor antagonists
- 4) Nicotinic receptor agonists
- 5) ganglionic (nicotinic) antagonists
What are the symptoms of atropine poisoning?
- -dry mouth and less sweating
- -blurred vision
- -urinary retention
- -ataxia, hallucination
What are the two types of glaucoma?
Narrow angle: pressure from post chamber blocks the ocular angle (an therefore the canal of Schlemm)
Open angle (more common): you are making too much aqueous humor
What does succinylcholine do?
It is a depolarizing NMJ blocker
What are the 2 main enzymes that metabolize norepi (catecholamines)
- Monoamine Oxidase (MAO)
- Catechol-O-methyl Transferase (COMT)
What are the 5 main lipoprotein classes and which one has the most cholesterol?
- -LDL (highest cholesterol conc)
What are some lipoprotein levels that are proarthrogenic risk factors
- -increased LDL
- -increased total cholesterol
- -increased total cholesterol/HDL
- -decreased HDL
For antihypertensives, which are group A and which are group B. When would you use each? both?
Group A: ACEi/ARB, beta blocker, DRI
Group B: CCB's, diuretic
Group A for middle age and essential HT, group B for elderly, one of each for severe HT.
Describe the general progression of treatment in CHF
- 1st line: Use ACEi and beta-blockers
- 2nd line: diuretics and digoxin (narrow therapeutic window)
- final: use an ionotrope like dobutamine or epi while looking for heart transplant
How would you treat SVT, A fib, A flutter (generation arrhythmia's)
Use class 2 (beta blockers) and class 4 (CCB's) as first line
if arrhythmia persists after ablation use class 3 (K+ channel)
How would you prescribe for ventricular arrhythmia or ventricular fibrillation? Classes
Use class III like amiodrone (K+ channel modifier), and one drug from the other classes. Usually use lidocaine (class I).
describe the affinity constant (ka) and the disassociation constant (kd)
- ka - the ratio of DR to D and R
- kd - the ratio of D and R to DR
Why would you want spare receptors in a system (2 reasons)?
internalizes extra ligand, preventing an exaggerated response if too much ligand is around
explain the difference between an agonist, partial agonist, and antagonist (competitive and non-competitive)
- agonist: affinity and intrinsic activity
- partial agaonist: affinity and some IA, acts as an antagonist in the presence of a full agonist
- antagonist: affinity and NO IA
- -competitive: reversible binding, need a higher conc of agonist to produce full effect
- -non-competitive: irreversible binding (essentially knocking out receptors) actually lowers Emax no matter how much agonist you use.
What are the 4 fundamental signal transduction mechanisms?
G-coupled: almost half of all drugs use this. 3 major secondary messengers (cAMP, IP3, DAG)
Enzymes as receptors: e.g. tyrosine kinase
Ion channel receptors: e.g. GABA receptor conducts Cl- ions
nuclear receptors: for steroid drugs, thyroid hormones
What are the effects of antagonists and agonists on receptor numbers?
agonists: decrease receptor numbers (try to decrease sens)
antagonists: increase receptor numbers (try to increase sens), can cause rebound effect when treatment it withdrawn
What is pKa again?
It is the pH where half of the drug is ionized
What type of drugs accumulate in more acidic fetal blood? What is this called?
basic drugs due to ion trapping
What is the first pass effect?
how much of the drug is metabolized by intestinal wall and liver enzymes
What are the following basic body volumes:
-total body water
-Intracellular fluid space
-extracellular fluid space
-what portion of this is intravascular
- Remember to break down in 1/3's
- -total body water (60% of body weight): 42L
- -Intracellular fluid space (2/3 of 42): 28L
- -extracellular fluid space (1/3 of 42): 12L
- -what portion of this is intravascular (1/3 of 12): about 5 L
verbally describe what the volume of distribution is.
It is the APPARENT volume of fluid the drug dissolved in.
Describe two phase biotransformation
phase I: mostly uses CYP enzymes to make the drug more polar, but not necessarily inactive
Phase II: Drug becomes conjugated and is excreted rapidly
What is the most important CYP enzyme?
CYP3A4 - responsible for the metabolism of almost half of all drugs
what does CYP2C9 polymorhpism interfere with?
What are the three main types of drug interactions?
- drug-food (e.g. grapefruit juice)
- drug-herb (e.g. St John's Wort)
describe how an NSAID increases warfarin toxicity
- 1) bound warfarin displaced by NSAID on carrier protein (increases free warfarin)
- 2) NSAIDS decrease clotting action, further increasing PTT
- 3) NSAIDS compete for the same CYP enzyme
- 4) NSAIDs cause gastric injury which warfarin makes bleed.
Why are erythromycin and clarithromycin associated with significant drug interactions
they inhibit CYP3A4
What is the loading dose (equation and verbal explanation)
a dose that produces a desired plasma conc of drug in one, or very few doses.
- L = CpxVd/F where:
- L = loading dose
- Cp = desired plasma conc
- Vd = Volume of dist for the drug
- F = bioavail fraction (for oral)
What is the maintenance dose (equation and verbal explanation)
dose needed to maintain plasma conc when given repeatedly at a constant interval
- M = ClxCp/F
- M = maintenance dose
- Cl = clearance rate (ml/min)
- Cp = plasma conc (mg/ml)
- F = bioavail fraction (for oral)
What does the drug ending -alol mean?
what does the drug ending -pril mean?
What does the drug ending -sartan mean
ARB (angiotensin receptor blocker)
What does the ending -tropin mean
what does the drug ending -terol mean?
What does the drug ending -statin mean?
what does the drug ending -zosin mean?
Coagulation is a balance between pro-coagulation and anticoagulants (4 of each)
Pro: thrombin, tissue factor, thromboxane, adenosine diphosphate
anti: heparin sulfate, prostacyclin, nitric oxide, antithrombin
Describe the MOA of aspirin (as an antiplatelet agent)
irreversibly inhibits platelet cyclooxegenase and prevents the formation of thromboxane
What do you use (PT/INR or aPTT) to measure the effects of warfarin? of heparin?
- INR - warfarin
- aPTT - heparin
describe the MOA of heparin and LMWH
heparin: antithrombin III goes anound and inactivates all the factors on the intrinsic pathway. Heparin catalyzes this reaction.
LMWH: Smaller, so it cannot bind to thrombin (Iia), but it CAN inactivate factor Xa
What levels (high or low) would put a patient at a proarthrogenic risk for LDL, total cholesterol, HDL
high LDL, high total, low HDL
What is the MOA of statins?
statins inhibit HMG-CoA, which is an enzyme that catalyzes cholesterol biosynthesis. BUT, the liver NEEDS cholesterol, so it increases the numbers of LDL receptors and gets it's supply from LDL (this lowers LDL plasma levels)
What is the MOA of fibrates
activates the PPRA-alpha nuclear receptor which causes metabolic changes. Increases FA oxidation, increased triglyceride clearance, increased HDL
What is the basic idea behind diuretics?
prevent reabsorption of Na (natriuresis) and water (diuresis)
Name the 6 functional areas of the nephron where diuretics work. Name the class of drug that works there.
- PCT - Carbonic anhydrase inhibitor
- thin descending loop - osmotic diuretics
- thick ascending loop - loop diuretics
- DCT - thiazides
- cotical collecting tubule - K+ sparing diuretic
- medullary collecting tubule - ADH antagonists
How do carbonic anhydrase inhibitors work in the PCT?
Inhibit carbonic anhydrase which is a catalyst in the intraluminal recombination of H+ and HCO3- into CO2 and H2O. You need this recombination for the reabsorption of Na+, K+, and HCO3-. leads to the production of alkaline urine.
How does mannitol work in the PCT and descending LOH?
Mannitol is a molecule that is freely filtered into the glomerulus, but then cannot be reabsorbed. It serves to decrease the osmotic gradient allowing for more Na and H2O to be excreted
How do loop diuretics (furosemide)
They basically knock out the Na/K/2Cl cotransport channel. This reduces the reabsortion of these ions, as well as H+ and Ca++.
How do thiazide diuretics work?
How does HCTZ work in the distal convoluted tubule
Inhibits the Na/Cl cotransport channel, which in turn causes more calcium and less water, K+, and H+ to be reabsorbed.
How do K+ sparing diuretics work?
They work on the cortical collecting tubule. Either via aldosterone antagonism or inhibition of sodium channels, they decrease Na and K+/H+ exchange. This means that there is more Na+ excreted and more K+ retained.
List the 5 major diuretics (CA inhibitors, Osmotic diuretics, loop diuretics, thiazides, and K-sparing in order of their potency
LD=OD > Thiaz > CAI = K-sparing
Describe the effects that CAI, loop diuretics, thizides, and K-sparing have on the blood electrolytes (Na+, K+, pH, Ca++)
Why would you use a thiazide in combination with a ACEi/beta-blocker
ACEi: decrease the production of aldosterone, spares K+ and prevents the body's natural adjustment to the drug
Beta blocker: reduced the (SNS-mediated) release of renin by the juxtaglomerular aparratus
Why should you hesitate to give theophylline in asthma (what does it do)?
- Theophylline is a PDE inhibitor which lets cAMP levels build up causing bronchodilation and reduced mast cell degranulation
It sucks because it has a narrow therapeutic window and causes nausea, vomiting, seizures and arrhythmias.
How are the effects of ACh terminated? How is this different from NE?
ACh is metabolized quickly by AChE and butyrylcholinesterase and then take up by the pre-synaptic terminal (this is why you can't give ACh parenterally)
NE is taken up whole by the pre-synaptic terminal
Where are nicotinic receptors located? How do they work?
At the ganglia (Nn) and at the somatic NMJ (Nm)
They allow sodium influx and possible action potential
What are the receptors of the PSNS and the SNS?
- PSNS: muscarinic
- SNS: alpha1,2; beta1,2; muscarinic, dopamine (D)
what does the term -mimetic mean?
it mimics the effects of transmitters (e.g. sympathomimetic)
Where are the muscanaric receptors located? (M1, M2, M3)? What receptor type are they?
- M1 - (gastric) - gastric and salivary (increases secretion), also in the inner ear
- M2 - (Heart) - decrease HR and conduction, contractility of the atrium
- M3 - (bladder, glands, vascular endothelial cells) - contraction of detruser muscle; increases sweat, salivation; vasodilate and produce NO (further increasing vasodilation)
What is the difference between AChE and BuChE?
AChE is located only at the synapses
BuChE is located systemically, found in plasma
What are the effects of muscanaric (general) antagonists?
- Eye: pupillary dilation, no accomodation reflex
- GI, urinary, bronchi: relax smooth muscle
- heart: increase HR
What happens to heart rate and cardiac output if you give someone AChE inhibitor?
Can be confusing because ACh is used at the ganglia of both the PSNS and SNS. But think of the heart as a parasympathetic being, so heart rate and CO will both be decreased.
What are the effects of nicotine on blood pressure and heart rate?
increases both of them.
Give an example of a competitive and a depolarizing (non-competitive) NMJ blocker. Explain the MOA for both
competitive: d-tubocurarine, competitive antagonist with ACh, different structure than ACh
depolarizing: succynylcholine, non-competitive antagonist, binds and doesn't allow ACh to bind anymore. Almost identical to ACh
How to the following drugs work to treat glaucoma? prostaglandins, beta-receptor antagonists, alpha2 receptor agonist, muscanaric agonist
- prostaglandin: increases aq. humor outflow
- beta receptor: decreases aq. humor production
- alpha2: decreases production and increases drainage
- muscanaric agonist: contract ciliary muscle, increasing the outflow.
describe the synthesis of norepi and epi
- stays as norepi in the SNS nerve endings
- norepi made into epi in the adrenal gland.
describe what happens to norepi after it is released from the pre-synaptic terminal
- 1) activates the alpha1 and beta receptors on the effector organ
- 2) also stimulates the alpha2 receptors on the pre-synaptic terminal, which inhibits the release of further norepi
- 3) NE is taken up by the pre-synaptic terminal
- 4) NE is taken to the vesicles and repackaged into them
How do cocain, amphetamine, and Reserpine mess with SNS function?
- cocaine: prevents norepi from crossing back into the pre-synaptic terminal
- amphetamine: promotes release of norepi
- reserpine: prevents the norepi from being repackaged into vesicles.
What is (are) the major adrenergic receptors in the: heart, lungs, coronary arteries, skin/GI arteries, skeletal muscles (both big and small), what does stimulating them do?
heart: beta1 throughout heart (SA node, AV node, atria, ventricles): increase HR, increase conduction, increase contractility
Lungs: beta2 relaxes brochiole SM
coronary arteries: alpha1 and 2 constrict, beta2 dilates
skin/GI arteries: alpha1,2 constricts
skeletal muscles: alphas constric small, beta2 dilates big
what does the beta1 receptor do predominantly?
increases heart activity (HR, contractility, CO)
What does the beta2 receptor do predominantly?
dilates coronary arteries, dilates vessels to big skeletal muscles, dilates bronchioles
What to the alpha receptors do predominantly
constrict all arteries, not found in vessels to big muscles
what does epinephrine work on (both high and low conc)
- low conc = equal beta1 and beta2 activity (low alpha) (increased heart and more flow to skeletal muscles)
- high conc = equal alpha1 and 2 activity (low beta) (less heart and more vasoconstriction)
what receptors does norepi work on?
the alphas and beta1 (more heart and vasoconstriction)
what receptors does isoproterenol work on?
only the betas (increased heart rate with vasodilation)
What do the MAO and COMT enzymes do?
they metabolize norepi
What receptors (that we care about) does dopamine work on?
What would you give someone in an emergency HTN situation?
sodium nitroprusside (decreases TPR and BP)
what should you NOT use in vasospastic angina?