therapeutic index

narrow = not much difference between beneficial and toxic blood levels

ligand gated ion channels

g protein coupled receptors

enzyme linked receptors

intracellular receptors

up regulation

down regulation

excessive activation or receptors

excessive suppression of receptors

drug interactions iwth other receptors

drug triggers immune (allergic) response

drug changes receptor concentration

Phase I: oxidation -- usually renders a drug inactive

 - involves CYP450 enzymes

Phase II: conjugation -- increases solubility for fecal and renal excretion by attaching drug to a water molecule

2: enzyme family

6: isoform

D: subfamily

CYP450's

vary greatly between different races

1. Fast/hyperactive drug metabolism

2. slow drug metabolism -- reduced or absent enzymes

3. multiple slow metabolic pathways

1. blood level of drug A plummets bc it's being decgraded too quickly

2. blood level of drug A increases because it's not being degraded

inducers

inhibitors

First neuron: 

1. parasympathetic: medulla & sacral spinal cord = "craniosacral system" = cranial nerves + sacral nerves (bladder, rectum, reproductive)

2. sympathetic: thoracolumbar spinal cord = "thoracolumbar system"

Second neuron:

1. parasympathetic: terminal ganglia (sa node, sweat glands)

2. Sympathetic: mostly larger vertebral ganglia

parasympathetic --> bc ACh is the main neurotransmitter of the parasympathetic system

sympathetic --> because epineprhine/NE are the main neurotransmitters

nicotinic -- preganglionic

muscarinic -- postganglionic

alpha and beta

tissues are receiving messages from both parasympathetic and sympathetic systems

pupils will shrink if parasympahetic (cholinergic) signals dominate but will dilate if sympathetic signals dominate

ocular: miosis, + near vision

cardiac: slows rate, reduces contractility, decreases CO

vascular: indirect effects

Pulmonary: bronchiolar constriction

GI: increased secretion, relaxed sphincters, increased motility

Bladder: detrusor contraction

sexual response: arousal

CNS: reduced alertness

Glands: + secretion

eyes: mydriasis, + far vision

cardiac: increased rate and contractility

vascular: direct vasoconstriction

Pulmonary: bronchodilator

GI: reduced secretions, contracted sphincters, decreased motility

CNS: increased alertness

Glands: reduced secretions

bladder: relaxation

Uterus: relaxation

Sexual: orgasm

irreversible AChE antagonists

side effects: permenant parasympathetic activation

Tx: block action of ACh

Indications: ophthalmic (miosis), GI/GU (ileus, bladder atony), myasthenia gravis, mushroom (atropine) poisoning, anesthesia reversal

Adverse effects: miosis, sweating, N/V/D, urinary urgency, bronchospasm, bradycardia, syncope

stigmines: reversible AChE inhibitors

organophosphates: irreversible AChE inhibitors

myasthenia gravis

tx: ACh agonist, AChE inhibitors

immunosuppression

tested: edrophonium

thymectomy

beta sympathetic agonist + glucocorticoids & antihistamines

side effects: tachycardia, arrhythmias, hyperglycemia

prolonged vasoconstriction due to chronic afrin use leads to hypoxia which leads to vasodilation

thus tolerance develops 

Epinephrine: anaphylaxis, local anesthetic, acute asthma

NE: hypotension/shock

Dopamine: hypotension/shock

phenyleprhine, methoxamine, clonidine, methylNE

vasoconstriction (Afrin and HTN)

isoproterenol,

dobutamine - CHF, cardiogenic shock

terbutaline - asthma, arrest premature labor

side effects: tachycardia, anxiety, tremors, hyperglycemia

alpha blockers - prazosin - HTN, BPH

beta blockers -

- non-selective: propanolol (NOT ASTHMA)

- Selective (B1 >>> B2): metoprolol, atenolol --> Asthma

- Combined (A1, B1, B2): Lebatolol --> HTN, hyperthyroid

beta contraindications: arrhythmias (withdrawal), uncontrolled CHF, bradycardia

weight loss

dietary salt reduction
exercise
stress reduction

biofeedback

Normal: <120/80

PreHTN: 120-140/80-90

Stage 1: >140/90

Stage 2: >160/90

Cardiac Output:

- HR

- Contractility

- Filling pressure

Peripheral resistance:

- arterial diameter

- arterial length

- elasticity

BP = CO x PVR <-- Hydraulic Equation

diuretics

sympathoplegic/adrenergic blocking agents

vasodilators

reduce R-A-A system

-lol: beta blocker

-pril: ACE inhibitor

-sin: alpha blocker

-sartan: angiotensin receptor blocker

-pine: calcium chennel blocker (other than verapamil, diltiazem)

indications: HTN

contraindications: kindey failure

adverse effects: HYPOKALEMIA, Hyperglycemia, rash, ED, hyperuricemia, postural HTN

Furosemide, torsemide, bumetanide, ethacrynic acid

indications: HTN, pulmonary edema (emergency), kidney hyperuricemia, hyperkalemia

Adverse effects: ototoxicity, HYPOKALEMIA, HYPOMAGNESMIA, hypotension

luminal membrane agents: triamterene, amiloride

Mineralcorticoid (aldosterone) antagonists: spironolactone, eplerone

Adverse effects:

HYPERKALEMIA

indications:

luminal: combined with thiazides or loops for HTN

mineralcorticoids: cirrhosis, PCOS, HTN adjunct

contraindications:

Luminal: ACE inhibitors, NSAIDs

Thiazide + loop

Loop/thiazide + K sparing

pretty much every combo has HCTZ in it

Aldactazide

Dyazide

Maxzide

Moduretic

Hypothalamus/posterior pituitary axis: Antidiuretic hormone/vasopressin

Baroreceptors/atrial receptors: atrial natrietic peptide

Renin-Angiotensin-Aldosterone System

All this results in "diuretic braking" - with continued diuretic use, a new Na+ equilibrium set point is acheived and more diuretic may be needed

usually

beta blockers

alpha blockers

central sympathoplegic

HTN meds

block beta-1 cardiac receptors which reduce CO

a few also modulate nitric oxide production which vasodilates

dose-dependent bradycardia ---> syncope

AV node conduction slowing

Ventricular arrhythmias upon abrupt cessasion

propanolol & nadolol

INdiacations: HTN, angina, SVT

Contraindications: COPD, asthma

FATIGUE
BRONCHOSPASM

ARRHYTHMIAS

ED

Metbolic changes

metoprolol and atenolol

indications: HTN, angina (increase exercise tolerance)

contraindications: OK in copd/asthma but needs to be closely monitored

labetolol and carvedilol

indications: HTN + need for reduced pvr, heart failure

acebutolol and pindolol

possess partial sympathetic activity (ISA)

indications: HTN pts with DM or slow HR --> lessens metabolic effects

reduced HDL

hypoglycemia

Linked to increased risk of Type II DM in elderly

CHF

recent MI

alpha blockers

-azosin's: doxazosin, prazosin, terazosin

1st dose under supervision

cocomitant beta blocker

1st dose at bedtime

minoxidil

hydralazine

single drug: diuretic (HCTZ) or ACE inhibitor (-pril)

secondary choices are ARB (-sartan), beta blocker (-ol), Ca channel blocker (diltiazem), or alpha blocker

2-3 drugs wtih different sites of action = "stepped care"

1. ACE inhibitor (increases K+) + diuretic (decreases K+)

2. ACE inhibitor, diuretic, vasodilator

some have fixed dose combinations and can help the pt be compliant

1. DM: ACE inhibitor or Ca channel blocker

2. CAD: ACE inhibitor + Beta blocker

3. Renal disease: ACE inhibitor, Ca channel blocker, renin inhibitor (aliskiren), or clonidine + ARB

4. BPH: alpha blocker

BP > 210/150

hopsitalized

Sodium Nitroprusside (vasodilator)

+

Beta blocker (labetalol)

+

Dopamine agonist (fenoldopam)

NSAIDS - block prostaglandin production = vasoconstriction

oral contraceptives - increase angiotensinogen production

1. ferrous sulfate 325 mg tabs 1-4/day for 3-6 mos

PLUS 500 mg vit C to reduce side effects and increase absorption

2. Last resort --> parentaral. Iron dextran, sodium ferric, or iron sucrose. Needs to be administered by hematologist

ORAL: GI upset - n/v/d, CONSTIPATION

Black stools

IM: anaphylaxis/hypersensitivity

chronic - hemachromatosis - organ failure

acute (peds) - necrotizing enteritis. >10 tablets can be fatal

caution pts with kids at home to keep iron locked up

pernicious anemia --

tx: folate. Can correct anemia but NOT neuro damage. B12 (cyanocobalamin) DOES correct neuro damage.

folic acid (folate)

beware of coexisting B12 deficiency

erythropoeitin

any drug name with "epo" is this --> rHuEpo, epoetin alfa

toxicity: increased blood viscosity due to increased # of rbc (HTN, thrombus), allergy

in pts with anemia of chronic disease, the risk of death from CVA and MI increases significantly when hgb >12, as with increased EPO

fibrinogen + thrombin --> fibrin

thrombin comes from prothrombin

platelets must adhere --> activate --> aggregate

plasmin degrades fibrin into D-dimer and fibrin split products

- plasmin comes from plasminogen

1. antithrombin III - action accelerated by heparin

2. proteins S and C - genetic defects attack here

abnormal factor V --> leiden mutation

- factor V cannot be inactivated by protein C

thrombosis

virchow's triad:

hypercoagulable state

circulatory stasis

endothelial injury

aspirin (81-325 mg/day)

toxicity: GI irritation/ulcer/bleeding

clopidogrel (plavix) and ticlopidine (ticlid)

toxicity: N/v/d, hemorrhage, leukopenia --> all pretty much with ticlopidine. plavix is safer

warfarin

INR - need it between 2-3.5

this checks prothrombin time

toxicities: hemorrhage, fetotoxic, multiple drug interactions

ALWAYS check for potential drug interactions

heparin

unfractionated heparin or low molecular weight heparin (lovenox)

never gien IM due to hematoma due to local anticoag

monitor: PTT and Anti-Xa levels

toxicity: hemorrhage, thrombocytopenia, bone loss (osteopenia)

heparin

NOT WARFARIN

less risk of thrombocytopenia/HIT

less risk of osteopenia

less monitoring

lovenox (enoxaparin)

dalteparin (fragmin)

tinzaparin (innohep)

all end in -aparin

lepirudin

1. thrombolysis - all -ase's: streptokinase, urokinase, alteplase, reteplase, tenecteplase. All parenteral.

- contraindications: surgery w/in 10 days, serious GI bleed within 3 mos, hx of HTN, bleeding disorder, previous hemorrhagic CVA, pregnancy

1. aminocaproic acid - increased risk of MI, renal failure

2. protamine sulfate

3. vit K, fresh frozen plasma

fatty streak

foam cells

Main: lower LDL, raise HDL

seocndary: lower trigs and total cholesterol

niacin

bile acid binding agents

HMG-CoA reductase inhibitors = "statins"

Fibric acid derivatives = "Fibrates"

inhibitors of sterol absorption

1st: statin

2nd: bile acid binding

3. niacin, fibrates

pregnancy: bile acid binding

transport to hospital

aspirin

oxygen

PCI or fibrinolytics

lifestyle changes

ACE inhibitors

Beta blockers

statins

Aspirin and/or plavix

stable

variant (prinzmetals)

unstable

50-70: sx wtih heavy exertion or vasospasm

70-90%: sx with moderate or light exercise - stable angina

>90: sx at rest: unstable angina

hyperthyroidism

severe anemia

arrythmias

nitrates

beta blockers

ca channel blockers

ace and arb

hyperlipidemia tx - statins

sublingual: faster onset, shorter duration

peripheral vasodilation

HA

--> more acute

transdermal: slower onset, longer duration

improved exercise tolerance, helps prevent nocturnal angina from emotional dreams

--> more preventative

beta blockers

contraindications: prinzmetals, severe LV failure

be careful because it can cause severe bradycardia & AV blockade

some will improve

most progress to MI or CHF in 3-5 years

aldosterone increases salt and water retention and thus causes cardiac remodeling

cardiac remodeling is the reason CHF gets worse and the heart loses contractility

hospitalize - O2, loop diuretics

stabilize: inotropic agents, LVADs

evaluate

reduce cardiac workload - limit activity, reduce weight, control htn

restrict sodium - 2 g/day

give diuretic: loop (spironolactone is dangerous)

ACE inhibitor or ARB

dig (esp if comorbid afib)

beta blockers -- stable Class II-IV CHF

vasodilators (bildil for AAs)

treat hyperlipidemia - statins

sodium nitroprusside

nesiritide

cardiac glycosides: dig

--> for outpatient CHF

beta adrenergic agonists:

Dobutamide, dopamine

phosphodiesterase inhibitors: amrinone, milrinone

stop dig

correct aggravating circumstances (hypokalemia, drug interactions)

neutralize circulating dig -- digoxin immune fab (digibind)

revascularization (CABG, PCI)

cardioplasty - reduce left vent volume

ISCHEMIA, HYPOXIA

alkalosis/acidosis

excessive catecholamines

drug toxicity

overstretching of cardiac fibers

scars

Class I: Na channel blockers (quinidine, procainamide, lidocaine)

- "use dependent" - target the most frequently depolarizing cells

class II: Beta blockers

- useful in treating tachyarrhythmias, and preventing ventricular arrhythmias

Class III: K channel blockers (amiodarone, sotalol, bretylium)

- useful in tachyarrhytmias

Class IV: ca channel blockers

- most effeective against atrial arrhythmias

v tach: lidocaine, amioderone

vfib: liodcaine, amioderone, epinephrine

svt: adenosine

atrial fib: propanolol, amioderone

afib

tx:

1. rate control: beta blockers, amiodarone, dig

2. restore sinus rhythm - cardioversion

3. anticoagulant to prevent stroke - warfarin, aspirin

adenosine

they're in PSVT

they can stop arrhythmias but they can also cause them

risky to use them chronically except amiodarone and beta blockers

peptide

steroid

TSH can bind to FSH receptors

thus ovarian cysts can result from untreated hypothyroidism

hypothalamus: releasing and inhibiting factors + vasopressin/oxytocin

anterior pituitary: acth, tsh, fsh/lh, prolactin, somatotropin (growth hormone)

Gh deficiency - dwarfism

short kids (normal GH but delayed growth) & turners -- works OK

adverse effects: usually none, hypo thyroidism, myalgia, arthralgia (growing pains), cytochrome P450 activation (may impact other meds), acromegaly (with high doses)

analogs: octreotide, lanreotide

indications: acromegaly & carcinoid sndrome

hypothyroidism

idiopathic hyperprolactinemia

pituitary tumor

tx: ergot dopamine agonists - bromocriptine, pergolide, cabergoline

FSH

LH

HCG

infertility

multiple births

ovarian hyperstimulation syndrome - ascites, pleural effusion, renal failure, CV collapse, PE

1. amenorrhea

2. endometriosis, fibroids

3. premature ovulation

1. oxytocin

- induce labor

- augment labor

- milk ejection reflex "letdown"

2. vasopressin (ADH)

- treatment of diabetes insipitus

thyroglobulin (Tg)

thyroxine binding globulin (TBG).

- increase - amount of free t3/t4 drops - estrogen

- decrease - amount of free t3/t4 rises - androgens

levothyroxine (T4)

adjust dose based on sx:

- lethargic, haven't lost weight --> give more

- jittery, nervous --> give less

elderly --> increases metabolism and cardiac O2 requirements in those who'vehad hypothyroid for a long time

HYPO: primary (gland failure) 99%

hashimoto's thyroiditis

absence/destruction

low iodine intake -- goiter

HYPER: grave's disease, Toxic Nodular Goiter

hyperthyroidism

 (thyrotoxicosis)

quickly control sx - beta blockers

utilize antithyroid agents to prevent thyroid storm

- thioamides, iodides, anion inhibitors

DEFINITIVE TX:

- thyroid excision/ablation

surgery causes more t3/t4 to be released --> thyroid storm

recurrent laryngeal in danger of being cut

thyroid storm

tx: hospitalization + beta blocker + ca channel blocker + potassium iodide + PTU + hydrocortisone

estrogen

progestin

glucocorticoid

androgen

mineralcorticoid

cortisol - natural

hydrocortisone - cream

prednisone - oral

methylprednisolone - IM

dexamethasone - iV/IM

triamcinolone - topical or aerosol

glucocorticoids

mineralcorticoids

androgens

glucose production

resistance to stress

hematopoeisis

anti-inflammatory

other

adverse:

1. sx of cushing's syndrome: Bone loss/osteoporosis, adrenal suppression, weight gain,

2. adrenal suppression: poor tolerance of trauma, sepsis, anesthesia

antiinflammatory

major surgical procedures - anti nausea

cancer chemo - anti nausea

accelerate fetal lung development

glucocorticoid inhibitors: cushing's

mineralcorticoid RBs (spironolactone): HTn, hyperaldosterone

low dose, short course

every other day dose

taper off

cushing's disease

cushing's syndrome

hyperkalemia (spironolactone)

excessive sodium loss

1. anticholinergic, antimuscarinic -- atropine

2. dependent on dosing - increased HR, oral dryness, inhibition of sweating, increased thirst, mydriasis

3. yes - anticholinergics' mydriasis effect can increase IOP

atropine

PAM

Epinephrine

0.3-0.5 mg IM/SQ

Tachy, arrhythmias, hyperglycemia

ARBs

ACE inhibitors

vasodilation

increased vascular permeability - fluid gets out to cause swelling

formation of fluid exudate - edema + fibrin

formation of cellular exudate - WBC, macrophages

Innate:

cellular - macrophages, granulocytes, NKs

humoral - complement

Adaptive:

cellular - T & B lymphocytes

humoral - immunoglobulins

glucocorticoids (steroids)

cytokine inhibitors

antimetabolites

monoclonal antibodies/antithymocyte antibodies

allergy

autoimmune disease

prevention of allograft rejection

1. suppress immune response via antihistamines and glucocorticoids

2. desensitization immunotherapy (allergy shots)-- induce immune system to make sufficient IgG against an allergen so that IgE won't bind

3. Anti IgE

azothioprine

toxicity: bone marrow suppression

mycophenolate mofetil:

more commonly used

- organ transplants, RA

cytokines

TNF-a

Interleukins

Interferon

cyclosporine - organ transplant and RA

- nephrotoxicity

tacrolimus - more effective than cyclosporine

- nephro and neurotoxicity

sirolimus - effective in graft vs. host reactions

- hyperlipidemia

antithymocyte globulins - horse or rabbit

- inhibit T cell function

- may stimulate immune response because they're from another animal

IVIG

mabs

- target specific cytokines or lymphocytes

tu - tumor

ci/cir - circulation

neu - neural

immune - li or lim

xi - chimeric

zu - humanized

cytokine release syndrome

severe form is cytokine storm

premeds: acetominophen

glucocorticoids

antihistamines

azathioprine

mycophenolate mofetil (MMF)

TNF-a blockers

autacoids

eicosanoids - prostaglandins

cyclooxygenase (cox)

lipoxygenase

cox 1- ubiquitous, physiologic - found in all tissues

cox 2 - induced only by inflammation

- when treating inflammation, you want to block cox 2, not cox 1

prostaglandin

E & F are main ones

cox inhibitors close the ductus arteriosus -- giving it to a pregnant woman could cause the ductus to close too early

prostaglandins assist in renal function so giving someone a cox inhibitor for a long period of time can cause renal problems

1. Non specific and irreversible - Aspirin

2. nonspecific and reversible - all other NSAIDS, including salicylates

3. selective Cox-2 inhibitors

GI: acid production increases, mucus production decreases, chronic blood loss (3-8 ml/day) due to small erosions

Resp: resp alkalosis due to hyperventilation, acidosis at high doses

renal: sodium & potassium retention

drug reactions

overdose potential: 10 g can be fatal to kids

Reye's syndrome

indomethacin

other indolacetic acids: slindac & etodiac

Celecoxib (celebrex)

Valdecoxib (bextra)

rofecoxib (vioxx) --> now off the market due to increased MI/CVA risk

lisinopril

propanolol

valsartan