Pharmacology - 1st midterm

• 1) Muscarinic receptor agonists
• 2) Cholinesterase inhibitors
• 3) Muscarinic receptor antagonists
• 4) Nicotinic receptor agonists
• 5) ganglionic (nicotinic) antagonists

• -dry mouth and less sweating
• -tachycardia
• -blurred vision
• -urinary retention
• -ataxia, hallucination

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

It is a depolarizing NMJ blocker

• Monoamine Oxidase (MAO)
• Catechol-O-methyl Transferase (COMT)

• -chylomicrons
• -VLDL
• -IDL
• -LDL (highest cholesterol conc)
• -HDL

• -increased LDL
• -increased total cholesterol
• -increased total cholesterol/HDL
• -decreased HDL

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.

• 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

Use class 2 (beta blockers) and class 4 (CCB's) as first line

if arrhythmia persists after ablation use class 3 (K+ channel)

Use class III like amiodrone (K+ channel modifier), and one drug from the other classes. Usually use lidocaine (class I).

• ka  - the ratio of DR to D and R
• kd - the ratio of D and R to DR

increases sensitivity

internalizes extra ligand, preventing an exaggerated response if too much ligand is around

• 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.

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

agonists: decrease receptor numbers (try to decrease sens)

antagonists: increase receptor numbers (try to increase sens), can cause rebound effect when treatment it withdrawn

It is the pH where half of the drug is ionized

basic drugs due to ion trapping

how much of the drug is metabolized by intestinal wall and liver enzymes

• 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

It is the APPARENT volume of fluid the drug dissolved in.

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

CYP3A4 - responsible for the metabolism of almost half of all drugs

warfarin

• drug-drug
• drug-food (e.g. grapefruit juice)
• drug-herb (e.g. St John's Wort)

• 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.

they inhibit CYP3A4

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)

dose needed to maintain plasma conc when given repeatedly at a constant interval

• M = ClxCp/F
• Where:
• M = maintenance dose
• Cl = clearance rate (ml/min)
• Cp = plasma conc (mg/ml)
• F = bioavail fraction (for oral)

beta blocker

ACE inhibitor

ARB (angiotensin receptor blocker)

pituitary hormone

beta2-agonist

HMG-CoA inhibitor

alpha1 antagonist

Pro: thrombin, tissue factor, thromboxane, adenosine diphosphate

anti: heparin sulfate, prostacyclin, nitric oxide, antithrombin

irreversibly inhibits platelet cyclooxegenase and prevents the formation of thromboxane

• INR - warfarin
• aPTT - heparin

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

high LDL, high total, low HDL

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)

activates the PPRA-alpha nuclear receptor which causes metabolic changes. Increases FA oxidation, increased triglyceride clearance, increased HDL

prevent reabsorption of Na (natriuresis) and water (diuresis)

• 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

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.

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

They basically knock out the Na/K/2Cl cotransport channel. This reduces the reabsortion of these ions, as well as H+ and Ca++.

Inhibits the Na/Cl cotransport channel, which in turn causes more calcium and less water, K+, and H+ to be reabsorbed.

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.

LD=OD > Thiaz > CAI = K-sparing

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

• 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.

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

At the ganglia (Nn) and at the somatic NMJ (Nm)

They allow sodium influx and possible action potential

• PSNS: muscarinic
• SNS: alpha1,2; beta1,2; muscarinic, dopamine (D)

it mimics the effects of transmitters (e.g. sympathomimetic)

• 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)

G-protein coupled

AChE is located only at the synapses

BuChE is located systemically, found in plasma

• Eye: pupillary dilation, no accomodation reflex
• GI, urinary, bronchi: relax smooth muscle
• heart: increase HR

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.

increases both of them.

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

• 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.

tyrosine->DOPA->dopamine->norepi->epi

• stays as norepi in the SNS nerve endings
• norepi made into epi in the adrenal gland.

• 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

• 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.

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

increases heart activity (HR, contractility, CO)

dilates coronary arteries, dilates vessels to big skeletal muscles, dilates bronchioles

constrict all arteries, not found in vessels to big muscles

• 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)

the alphas and beta1 (more heart and vasoconstriction)

only the betas (increased heart rate with vasodilation)

they metabolize norepi

beta1

sodium nitroprusside (decreases TPR and BP)

beta-blockers