Fast fibers

Quinidine poster child

 Procainamide: slow acetylators are prone to lupus like

 Disopyramide: stronger anticholinergic

SVT( need digoxin)** , VT

Blocks Na--> long phase 0, ^APD, ^ ERP in fast fibers

Unlike other class I this one prolongs Action potential

Pro: M antagonist (speeds AV**, prolongs QRS, prolong QT which may cause torsades) a1 antagonism (reflex tachy)

Side effect: Cinchonism (due to M, a1 antagonism) : ocular disfunction w/ diplopia, GI distress, tinnitus, vertigo

Class IB

least proarrythmic of all

Lidocaine IV

 Mexiletine oral

Hypoxia--> low ATP--> low Na/K ATPase activity--> ^ Na in cell--> ^ automaticity, long depolarization, low refractory, slow conduction

blocks Na inactivated channels: raised AP threshold

blocks late window Na channels: shortens APD, weak inhibitor of pahse 0

use: Post MI, digoxin toxicity, open heart surgery

Flecainide

Propafenone

life threatening VT, refractory SVT

Strongest inhibitor of phase 0, no change in length of action potential  

too good = sudden death

Propranolol (b1,b2 others are just B1)

Esmolol-IV

Acebutolol

lowers phase 4: lowers SA firing and AV conduction

Pro: AV block

Caution: asthmatics, Peripheral vascular disease, DM

Amiodarone

(does it all, long T1/2 due to iodione so shitty)

Sotalol

Dofetilide

Ibutillide

Dronedarone

Prolongs QT---> Torsade de pointe

Verapamil

Diltiazem

Constipation

Adenosine

DOC for paroxysmal supraventricular tachycardia

A1--> G1: lowers SA, A2a--> Gs vasodilate (even coronary), A2b--> Gq bronchoconstriction

Mg

polymorphic ventricular tachycardia (torsades)

Digoxin

Potassium Cl

digoxin toxicity (especially hypoK)

Indications of Antiarrhythmic

SVT ( Sinus tachy, PSVT, atrial flutter)

AV block

Ventricular arrythmia ( tachy, torsades)

SVT ( II & IV, adenosine & all, all )

atropine

( all but IV, Mg & II IV)

LH --> leydig cell

FSH --> serotoli cell -_> estrogen

T: spermatogenesis (sertoli), muscle, ^ RBC, ^ bone

DHT: acne, bald, prostate, puberty changes

Anabolic steroid Testosterone derivative

Adverse: lower HDL, ^ LDL, ^ HR (- MAO), ^ RBC --> HTN, lower II,V,VII,X --> ^ PT, hepatic blood filled cysts, adenoma,  DM, gynecomastia, testicular atrophy, ^BPH, Teratogenic ( female fetus--- old people sex, female weight lifter)  

Stanozolol

Anabolic steroid DHT derivative

Dutasteride

5a reducatase inhibitor (no DHT)

BPH, hair growth

adverse antiadrogenic

Mestranol

^ HDL, lowers LDL, blood clotting

Adverse: cigs + aging = clotting, cancers, gallstones

DES: In babies:  vaginal adenocarcinoma and in males hypospadia, cryptorchidism

SERM

partial agonist on bone

antagonist on breast,

agonist on endometrium

SERM

Blocks peripheral estrogen's negative feedback on GnRH, FS, LH

^ ovulation, multiple babies

Progestin

Norgestrel, Desogestrel

Precursor of androgen, estrogen, glucocorticoids

Adverse think PCOS: hair, acne, depress, DM like, ^LDL,lower HDL

cortisone ( 1:1)

short acting 1-12 hrs

Adverse of all glucocorticoids:

cushings ( ^ PEPCK* = gluconeogenesis oxaloacetate to phosphoenolpyruvate) , ACTH suppression --> adrenal cortical atrophy)

* glucagon, retinoic acid too

Triamcinolone (4:1 salt)

inter 12-36

Dexamethasone

glucocorticoid

long 36-55 hrs

Mineralcorticoid

some glucocorticoid

Dx of DM II

DM I trigger

MODY

control parameters

> 126 mg/dL on two separate occasion after overnight fast

> 200 mg/dL 2 hrs after 75 g oral glucose

DM 1: after coxsacie

MODY: mutations in glucokinase, insuline receptor, glucose transporter, nuclear transcription factors in beta cell gene expression

HB1c 7% or less, 150 mg/dl or less

Sodium Glucose cotransporter 2 inhibitor in PCT

Adverse: ^ UTI

Amylin analog

delays gastric emptying--> lower appetite

a-glucosidase inhibitor

Acarbose

DPP-4 inhibitors (causing ^ GLP-1)

-gliptin

Adverse: Pancreatitis

GLP-1 agonist

 SubQ

Liraglutide

^ I, lower Glucagon, delays gastric emptying

Adverse: Pancreatis*, ^ medullary carcinoman thyroid (MEN2, amyloid histo)

*Didanosine, stavudine, valproate, aspirginase

Thiazolidinediones

Rosiglitazone

PPAR-y agonist

lowers liver gluconeogenesis, similar to metformin

Adverse: Edema+ weight gain --> ^^ CHF, bladder cancer (pio), angina & MI (rosi)

Sulfonylureas 2nd gen

Glyburide,Repaglinide  Glimepiride, Glibenclamide

Glipizide: lower dose  in bad liver

Glyburide: lower in bad kidney

Repaglinide: no allergy

Chlorpropamide

(A,T,T)

Sulfonylureas 1st gen

Acetohexamide, tolbutamide, tolazamide, SIADH** in chlorpromide

High plasma protein binding

blocks ATP-dependent K channels* in beta cells--> ^ insulin which lowers glucagon

Adverse: Hypersensitivity (rash, sulfa, hematological toxicity) , hypoglycemia, weight gain

* opens: thiazide, diazoxide, minoxidil

** also carbamezapine, inhibited by Li

oral

No hypoglycemia or weight gain

^ GLUT4, lowers PEPCK through AMP-Kinase

Adverse: lowers absorption of folate, B12, lactic acidosis

Glulisine (shortest), Lispro, Aspart

O: 15 min

D: 3-4 hrs

MOA: tyrosine kinase--> PI-3 kinase or MAPK

muslce, adipose: ^ GLUT 4

liver, muslce: ^ FA synthesis, ^VLDL,^ LPL, ^ glycogen, ^ glycolysis lowers FA & AA --> ketones, lowers gluconeogenesis

**  M, B2 = ^ insulin release

a2= lowers insulin

Human insulin

(regular)

O: 30-60 mins

D: 6-8 hrs

Human (no allergy potential) NPH

O: 2-4 hrs

D: 10-20 hrs

no peaks

Glargine, Detemir

O: 1.5 hr

D: detemir 17 hrs, Glargine 24 hrs

T4

Permissive actions on B receptors (like cortisol)

Permissive action on ovarian cycle and spermatogensis

^ 02 consumption, ^ temp

^ gut motility and glucose absorption

Needed for carotene--> vit A

hypo:  hashimoto, amiodarone (hyper too), lithium)

Thyroid peroxidase inhibitors by inhibiting oxidation of Iodine to Iodide (1st step)

Propylthiouracil (prego): higher protein binding, also peripherally inhibits T4-->T3

Adverse: maculopapular rash, agranulocytosis

Beta blocker and blocks deiodinase (t4-->T3)

inital drug for storm

Bisphosphonates (dronates)

analog of pyrophosphate--> Stabilize hydroxyapatite--> inhibit osteoclast

AdverseL Osteoneocrosis of jaw, GERD--> esophageal adenocarcinoma

Inhibits osteoclastic bone resorption

Intranasal spray

Postmenu osteoporosis, HyperCa of malignancy

PTH analog

 ^ osteoblast vs continous administration --> ^ osteoclast

^ osteosarcoma

May cause ^ Ca avoid glucocorticoids, thiazides

Against RANKL (osteoblast)  whch activates RANK on osteoclast

SubQ

mimicks osteoprotegerin ( ^ by estrogen)

all act on g protein

LOX: leukocytes, mast cells, DO-- think asthman, anaphy

LTB4 - NO chemo, LTC-D4: ^ permeability, ^ mucus

cox1: continuous production in most cells,

cox2: induced in sites of inflammation, brain, kidney, PGI2 made by cox2

SS (vessel, airways, uterus):

^ conc PGD2, PGE2, PGI2 = relax

low conc: TXA2, PGF2A, PGE2 = constriction

Platelet:

high: PGI2,PGD2, PGE2 =stable

low: TXA2, PGE2* = Agg

* fever

Eye: PGE, PGF lower intraocular pressure, ^ outflow

Aspirin

NSAIDs in general

Only NSAID that is irreversible of cox1,2 (acetylation of serine OH) & ETC uncoupler

300mg for pain, fever... grams for anti- inflamm

low: ^ uricemia

high: low urecemia bc damage to kidney

Toxicity:

uncouple--> ^ 02 consumption--> resp alkalosis--> ^ krebs--> ^ CO2--> >M acidosis

very low ATP--> NMJ depression--> low resp--> resp acidosis + M. acidosis --> Massive acidosis

Tx: drug is acid so alkalinize urine (acetazolamide)

Side effects:

       cox shutdown--> ^ LOX (avoid in asthmatics)

       Hypersensitivity

       Analgesic Nephropathy

       Salicylism ( tinnitus, vertigo, 1st sign)

       Reye: uncoupling--> multiple organ failure

Drug-drug:

    ^ bleeding with warfarin, ethanol

    sulfonylureas, warfarin --> ^ free conc

   Methotraxate not cleared by kidney

Ketorolac best analgesic

Indomethacin best anti-inflamm

Sulindac: easier on kidney, liver clearance

inhibits 5-LOX

asthma prophylaxis

Zafirlukast

 LTD4 receptor antagonist  ( mucus, permeability)

asthma prophylaxis

PGE1 analog

Alprostadil

NSAID ulcers, maintains PDA,

Abortion: mifepristone (anti-progestin)  + misoprostol

PGI2

Illoprost, Treprostinil

Pul HTN

PGF2a analog

--prost

glaucoma, brown iris

PGE2

Induce labor, abortion, hydatidiform mole,

COX-2 inhibitor

lowers PGI2 --> ^ MI, stroke

central COX inhibitor (safe even in gout)

analgesic, antipyretic only

Hepatotoxicity: 10 g or P450 inducer (34A) makes N-acetyl-p-benzoquinone imine (NAPQI) damage to liver

Tx: N- acetylcysteine (mucus lytic, Tx: hemo cystitis cyclophosphamide)

Histamine

H1 vs H2 vs H3 receptor

made from histidine, deactivated by MAOB

H1 (Gq) aka shock and anaphylaxis:

Broncho SS--> ^ Ca --> contract

P. nerves--> pain,  itch

AV node: lowers conduction

endo= ^ NO synthase, dilate, ^ Ca--> pericyte contraction, ^ permeability

CNS: wakefulness- pituitary, excites in cortex (reason for sedation and CNS depression with antihistamines)

H2: gastric parietal cells, cardiac, SS, mast cells

^ SA node firing, ^ contract of heart fast fibers

H3: presynaptic inhibition, lowers all neurotransmitters

H1 blocker

Antimuscarinic action: motion sickness, parkinson, EPS from antipsychotics, cold meds dry secretions

H1 blocker: allergy, rhinitis, urticaria, sleep

Loratadine, fexofenodine

dont corss BBB so not sedative, no muscarinic

2nd gene H1 blockers

Sucralfate

Stomach cytoprotectants ( 2more)

prodrug, needs acid to make bandaid

Bismuth Subsalicylate: same as above but not prodrug

Misoprostol: PGE1 (lowers acid, ^ HCO3, mucus)

Omeprazole + clarithromycin ( Macrolide with less GI upset) + amoxiciilin

Bismuth + metronidazole (metallic taste, no alcohol) + tetracycline

Antiacids

AlOH vs MgOH vs Ca-carbonate vs Na HCO3

chelates tetracyclines

Al: constipation

Mg: diarrhea

other too: may cause alkalosis

competitive H2 receptors antagonist

histamine is paracrine from enterochromaffine like cells

Nizatidine, Famotidine, Ranitidine

Cimetidine inhibites CYP450 and lowers androgen

PPI

irreversible H/K ATPase

DOC in severe GERD

Adverse:

 competes for CYP450 ( warfarine)

inhibits 2C19: ^ phenytoin

Induces 1A2: lowers imipramin, antipsychotics, theophylline

malabsorption of Fe, B12, ^ enteric, resp infections

G.I cells, neurons, platelets

Tryptophan, MAOB--> 5-hydroxyindole acetic acid 5-HIAA

5HT1a (Gi) - run of the mill anxiety

5HT2a (Gq)-  action of atypical antipsychotics

5ht3(Na/K channel)-  antiemetics

4 (Gs)

5HT blocker in all suntypes

Carcinoid syndrome

also give Octreotide (somatosatin: halts serotonin secretion)

5H3

antiemetic

5HT 1B/1D agonist (Gi)

vasocontriction

Presynaptic inhibitor of substance A, neurokinin A, CGRP

Tx: migraine

C/I: cardio or cerebrovascular disease

5-HT2 blocker

Prophylaxis Migraine - 2nd line ( retroperitoneal fibrosis)

partial agonist at a1, 5HT2 receptor

vasoconstric

Migraine

Adverse: ischemia, abortion

1st line prophylaxis of Migraine

BB, TCA, anti-seizures, Ca

Propanolol

Amitriptyline

Valproate, topiramate

Verapamil

Omalizumab

Zileuton- good for asthma induced by aspirin

Zafirlukast treat asthma too but associated with Churg Strauss

humanized IgE ( precents mast cell activation)

unresponsive asthma

Nedocromil

Prevents degranulation of mast cells: lowers Histamine, leukotrienes

OTC seasonal allergies

Phosphodiesterase ( ^ cAMP)

Any drug that targets bronchoconstriction = early response

antagonist of bronchonstrictive adenosine

Adverse: narrow therapeutic window, cardiac arrhythmias

2nd line asthma, apnea with prematurity

Ipratropium- short

Tiotropium- long

DOC in beta blocker induced bronchospasm

Betta 2 agonists for Asthma -2

short vs long acting

Acute Bronchoconstriction

Short:  Albuterol, Terbutaline

Prophylaxis of exercise induced asthma (must be in combo with steroid, solo can cause asthma attack)

Long: Salmeterol

Asthma Corticosteroids

Inhaled (3) vs Systemic (2)

early and late response

Inflammation, prevents B2 from desensitization

Chronic treatment

Inhaled: Budesonide, Beclomethasone, Fluticasone

Only to bring asthma under control

Systemic: Prednisone (O), Prednisolone (IV)

NSAID: Indomethacin, Naproxen, Sulindac

Colchicine: tubulin, neutrophil mobility, activity

Steroids : if allergic to NSAIDs

Xanthine oxidase inhibitors: Allopurinol*, febuxostat

* Steven-J, a prodrug .... Inhibits metabolism of 6-mercaptopurine (cancer)  and prodrug azathioprine (immunesupress)

Probenecid: inhibits reabsorption

Pegloticase: enzyme = uric acid--> allontoin , long term management of gout not responding to other therapiies

Infliximab: human  Ig-TNF-a

Adalimumab: human Ig-TNF-a

Etanercept: site for TNF receptor and has IgG Fc region

Reactivation fo HBV, TB

DMARDs

MTX

Hydroxychloroquine

Sulfasalazine

Leflunomide

Rituximab

Penicillamine

Auranofin

- MTX:

DHF reductase inhibitor, lowers BM

- Hydroxychloroquine:

lowers RF, acute phase proteins,cinchonism, G6PD hemolysis. use in malaria, SLE,

- Sulfasalazine

 lowers b cell, inhibits COX, G6PD hemolysis

- Leflunomide

inhibits dihydroorotate dyhydrogenase in mito--> low UMP--> no ribonucleotide synthesis , arrests in G1, BM supression and liver toxicity can be fatal

- Rituximab

 CD20, used in B cell leukemias.. Can reactivate HBV, JC ( progressive multifocal leukoencephalopathy)

- Penicillamine

 Chelator of metals inhibits metalloproteases, supresses T lymphocytes, used in wilson

- Auranofin

lowers lysosomal and macro function, skin rash and mouth sores

Immunosupression Drugs (anti-rejection drugs)

Cyclosporine

Tacrolimus

Sirolimus

Mycophenolate Motefil

Calcineurin cleaves P from NF-AT and frees it

- Cyclosporine:binds cyclophillin, inhibits de-P. no IL-2,y-IFN broken down by 3A4... nephro, neuro toxic, gingival hyperplasia ( Phenytoin, Ca channel dipines)

- Tacrolimus:  binds FK binding protein, inhibits de-P, used in Autoimmune

- Sirolimus/ rapamycin: Inhibits mTOR (in pathway involved in response to IL-2)   use in kidney transplant, coating cardiac stents, interstitial pneumonitis

- Mycophenolate Motefil: inhibits Inosine 5 monophosphate dehydrogenase --> no guanine, B,T cells cant use scavenger pathway, opp. infections

GABA

&

Its Receptors

Makes: L-glutamic acid decarboxylase: glutamate + B6

Breaks: GABA transaminase: glutamate + succinic

Channel: 2 a, 2b, 1 y (2 gaba bind at a-b, BZ at a-y, Barbiturate at B)

GABA-A (GABA-C same): ligang gated, Cl in (BZ, barbs)

GABA-B: Gi (lowers cAMP), ^ K out, Ca in (baclofen)

Benzodiazepine Profile

Antagonist?

allosteric at GABA-A, increases frequency (potentiation 0+1=2)

subunits:

a1,a5: sedation, ataxia, amnesia

a2,a3: anxiolysis, anti seizure

Acitve metabolites through 3A4, 2C19

Flumazenil antagonist: cant antagonize alcohol or barbiturates

Short Acting

Anxiolytic 2

vs

Sedative

Benzo 1

TOM

Midazolam: anterograde amnesia, induce anesthesia

Oxazepam

vs

Triazolam

Intermediate

Anxiolytic 3

vs

Sedative 2

Benzo

TALE

Alprazolam- Only one used in Anxiety associated with depression

Lorazepam- anterograde amnesia, status epilepticus

Chlordiazepoxide

vs

Temazepam

Estazolam

Long acting

Anxiolytic 3

vs

Sedative 2

Benzo

DCC FQ

Diazepam- status epilepticus

Clonazepam

Clorazepate

vs

Flurazepam

Quazepam

not benzo but reverse by flumazenil

parasomnia

Phenobarbital

(T, P

Primidone and phenobarbital: anticonvulsant

Thiopental : anesthetic

Pentobarbital: induce coma

Seizures

Increase DURATION of opening, block complex I of ETC

1st line neonates

cardioresp depression

Inducers of CYP450

Primidone is metabolized to phenobarbital and phenylethylmalonamide--all are anticonvulsants= severe sedation

partial agonist 5HT1A

Anxiolytic

C/I: with MAO inhibitors

agonist melatoning receptor Gi

no dependence

sleep

Tonic Clonic (grand mal)

DOC

Phenytoin*

Carbamazepine*

Valproic Acid*

Ethosuximide*

Valproic acid

Lamtrigine

Lorazepam

Diazepam: acute

Phenytoin/fosphenytoin: prophylaxis

DOC for prophylacxis of status elipticus

DOC tonic clonic

blocks inactivated Na voltage channels (like 1b)

Zero order Kinetics at therapeutc range

inducer of CYP450

Gingival hyperplasia, Hirsutism, SLE-like, fetal hydantoin syndrome, pseuolymphoma (cleft lip/palate, heart, microcephaly, no nails)megaloblastic anemia,

Interfers with folate, VitD

bipolar

DOC: trigeminal neuralgia, simple, complex, tonic clonic

blocks inactivated Na channels

Neural tube defects, SIADH, Steven-J, Aplastic anemia

DOC tonic clonic

bipolar, prophylaxis of migraine, myoclonic

MOA: inhibits GABA transaminase (vigabatrin) , Inhibits inactivated voltage gated Na channels, inhibits histone deacetylase inhibits T type Ca channels,

Not inducer of P450, inhibits 2C9

Alopecia, pancreatitis, thrombocytopenia, ^ Bleed time, neural tube defects

DOC Absence seizures only  (burst of thalamic activity, during seizure nothing can arouse them except smell)

T type Ca channel blocker

adverse EFGHIJ

all and absences seizures

bipolar

Blocks voltage gated Na channels

Anticonvulsant, prohylaxis of migraine

blocks Na channels, ^ GABA action

carbonix anhydrase inhibitor

Kidney Stones

Phentermine(amphetamine) /topiramate: 1st drug for Obesity

antiepileptic

NMDA blocker

Inhaled General Anesthetic

Very high MAC: weak

B/G: .45 small so fast onset/recovery

not metabolized (breath out)

displaces 02, diffusional hypoxia

gas trapped in cavity no malg hyperthermia

Methoxyflurane vs vs halothane vs enflurane

sevoflurane

Inhaled general anesthetic

MAC is small

 All malignant hyoerthermia

Methoxyflurane: nephrotoxcity  

Halothane: Hepatotoxicity

enflurane: seizures

IV general Anesthetic

All IVpreps include:sedate= midazolam or Dexmedetomidine (a2 agonist, CNS depress), Dry secretion = atropine

"milk"

Potentiates GABA-a

Propofol infusion syndrome:

Rhabdomyolysis--> renal fail--> metabolic acidosis, hyperK--> cardio collapse

Methohexital

THIOPENTAL

IV general Anesthetic

All IVpreps include:sedate= midazolam or Dexmedetomidine (a2 agonist, CNS depress), Dry secretion = atropine

Potent, ^ lipid, redistribution, rapid

lowers intracranial pressure, GABAa enhancer ( duration)

Noncompetitive antagonist of NMDA glutamate receptor

Phencyclidine

Dissociative anesthetic

Adverse: vivid dreams and hallucination

^ intracranial pressure,

 ^ BP, HR

IV general anesthetic ( Fentanyl also in this class, not below comments)

10% adrenal suppression ( cushing syndrome Tx)

Local Anesthetics

PK?

PD?

adjuncts needed?

esters vs Amides

Weak bases need alkaline solution--> binds from within, as a cation on inactivated Na channels

From increasing size, myelination:

C fibers--> Ao--> Ay--> AB--> Aa

 Pain--> temp--> touch--> pressure--> motor

X-caine vs x-i-x-caine  ( amides, i before caine)

plasma esterases (genetic poly, looks like PABA so hypersensitivity) vs Liver P450

Add vasoconstriction ( epinephrine a1, high dose, a2: spinal anesthesia lowers substance P release)

a2: Dexmedetomidine, clonidine

Cocaine doesnt need it has NE reuptake blockade can causes ischemia, HTN

saxitoxin (marine toxins)

block the activated Na channel ( 1A like)

ciguatoxin

binds w/in channel, prevents Na inactivation

hallucinations

Mivacurium

vs

Atracurium

Non depolarizing neuromuscular blockers

Pancuronium( antimuscarinic),Vecuronium longer acting

competitive antagonists at muscle nicotinic ACh receptor

acts on skeletal muscles only (not cardiac)

reversed with neostigmine

Mivacurium: shortest, plasma esterases, can release histamine

Atracurium: intermediate, spontanous inactivation to laudanosine--> lowers threshhold for seizures

Succinylcholine

Train of Four pattern?

Neuromuscular blockers (depolarizing)

agonist of nicotinic receptors also at ANS ganglia, muscarinic receptors (so aka ACh)

depolarized ( augmented by AChE inhibitor)--> Desensitization (antagonized by AChE inhibitor)

Avoid with peeps with poor cholinesterase metabolism

TOF ratio= 1 no drug or phase 1 of depolarized

TOF ratio: < 1= non depolarizing block or phase 2

Baclofen

vs

Dantrolene

Spasmolytic drugs (depresses CNS)

GABAb agonist = K in

vs

Binds Ryanodine receptor channel (RyR1)  blocking Ca release from sER in muscle, no effect on heart or smooth muscle (RyR2) , used in Malignant hyperthermi*

* AD mutation of RyR1 or Ca cant get back in sER--> massive contraction, lactic acidosis

Opiod Peptides, receptors

supraspinal vs spinal

tolerance exceptions?

W/D?

Acute vs long term W/D treatment

u (mu most numerous), k, o

all Gi

Receptor on neuro body ( K out) vs presynaptic (block ca released, no exocytosis, no NE, substance P)

Spinal:  inhibition of ascending pathways at dorsal horn

Supraspinal: Stimulation of modulatory descending pathway at Midbrain periaqueductal gray

No tolerance to miosis and constipation

negative reinforcement addiction (removal = hell)

W/D: due to ^ NE, substance P = agitation, pupil dilation, tachy, HTN, diarrhea, central originating pain

Acute: Methadone, Clonidine (lowers ANS)

Chronic: methadone, Buprenorphine w/ naloxone

Morphine

(prototype since potency: 1)

Resp depression: knocks out pCO2 in CNS, PNS pO2 sense low oxygen and maintain breathing, giving 02 to some one opiods--> resp depression

Opiod OD triad: coma, resp down, pinpoint pupils

vessel: vasodilation& venodilation, in peripheral due to histamine(flushing, pruritus) , in CNS due to ^ CO2--> ^ ICP

Morphine uses: pulmonary Edema (low preload), MI, diarrhea,

 G.I : constipation, give methylnatrexone, less peristalsis but more spasms (biliary colic)

cough suppression (Dextromethorphan: opiod like OTC)

^ ADH, ^prolactin, ^ GH, lowers LH

Merperidine

potency: .3

mu agonist

stong antimuscarinic: tachy, no GI,GU spasms, no miosis (addict in plain sight)

Methadone

mu agonist (slow kinetics)

blocks NMDA

Additive resp depression w/ heroin

( just recognize all ---hydrocodones, oxymorphones as mu agonists and abused)

Alfentanil

Fentanyl

Remifentanil

Sufentanil

mu agonist

anasthetics

Codeine

Tramadol

agonist, considered partial bc its weak

analgesia w/ NSAIDs

antitussive

Tramadol: blocks reuptake of NE, 5HT ( seizures)used in neuropathic pain

Loperamide

Dextromethorphan

Nalbuphine

Butorphanol

OTC opiods

Loperamide: diarrhea

Dextromethorphan: antitussive

Partial mu agonist and K receptor( dysphoria) antagonist  

Nalbuphine

Butorphanol

Pentazocine

Naloxone

vs

Naltrexone

vs

Methylnaltrexone

IV

vs

oral, long acting in alcohol and opiate (lowers craving)

vs

cant cross to brain, SubQ for constipation due to opiod

Alvimopan (oral)

Parkinsons

Levodopa/Carbidopa

Entacapone

Selegiline

Bromocritine

Benztropine

Amantadine

Levodopa/Carbidopa:

  precursore of dopamine/ peripheral carboxylase inhibitor

Entacapone:

  COMT inhibitor (catechol-methyltransferase)

Selegiline:

 MAOB inhibitor

Bromocritine:

 D2 agonist (hyperprolactemia,acromegaly)

Pramipexole, Ropinirole, Rotigotine 

 D3 agonist, antioxidant, antidepressant effects, also treats restless leg syndrome

Benztropine, Trihexyphenidyl

 muscarinic antagonists (lower tremor, rigidity)

Amantadine

 antiviral, ^ synthesis, release of DA, inhibits reuptake, inhibits muscarinic receptors

Dopamine pathways in CNS

Nigrostriatal

Mesolimbic/cortical

Tuburoinfundibular

Nigrostriatal (pars compacta)

  - Output to striatum, D1 (gs) stimulates direct, D2(Gi) inhibits indirect , ACh (Gq) stimulates indirect..

Mesolimbic (reward, impusliveness) /Mesocortical (emotions, motivations)

 - same changes seen in addiction and schizophrenia

 - agonist: psychosis, euphoria   antagonist: opposite

Tuburoinfundibular

 - DA: lowers prolactin, GnRH, GH

 - antagonist: bitch tits with milk

3 Theories on schizophrenia

Dopamine

Serotonin

Glutamate

Symptoms:

 (+) ^^DA in Mesolimbic : out to get me, hallucinations, (-) low DA in Mesocortex: fuck off, shitty speech, no emotion

Theories

Dopamine:

 less DA synthesis or release in limbic and cortex casues ^^ in DA receptors .. Typicals antagonis D2,D1 do nothing for (-) symptoms

 Serotonin:

  - 5HT inhibits DA release through 5HT2A receptors that are found in different densities.. Antagonism ^ DA and has the following effect:

   -  nigrostriatal: lowers extrapyramidal symptoms

   - Tuberoinfundibular: lowers hyperprolactemia

   - Mesocortical: improves (-) symptoms

   - Mesolimbic: D2 receptors >>> 5HT2A receptors so dont matter

   - Atypicals are weak D2 antagonist and strong 5HT2A blockers

Glutamate

 - NMDA receptors on GABA when stimulated suppress the brain.. Schizophrenia have shitty NMDA .. Future drugs

Chlorpromazine

(prototype)

Blocks D2 receptors everywhere

Mesocortical: worse (-) symptoms

Mesolimbic: helps (+) symptoms

Tuberoinfundibular: ^ eating, bitch tits + milk

Nigrostriatal: ^ extrapyramidal symptoms (all give antimuscarinic w/ exceptions)

  -- early:

     - Acute dystonic: sustained contractions, twitching

     - parkinsons

     - akathisia: restlessness (crackhead, Tx: Benzo)

     - Neuroleptic malignant syndrome: catatonia, ^ fever, cardiodysfunction, myoglobinemia (Tx: halt medication, dantrolene, bromocriptine)

  --Late: (mo-> yrs):

     - Perioral tremors:

     - Tardive dyskynesia: irreversible, atypical dont cause this, due to ^ reg of D2 receptors

Adverse:

  Antimuscarinic: Coma,convulsion,cardiotoxicity(torsades)

  A1 antagonist: orthostatic hypotension, sexual dys

  H1 antagonist: sedation, weight gain

Thioridazine

Fluphenazine

Haloperidol

Pimozide

Typical Antipsychotics

Thioridazine: strongest antimuscarinic (torsades)

Fluphenazine- depot form

Haloperidol- IV used in acute psychosis, mania

Pimozide- tourette syndrome, tic disorders  

Clozapine

Olanzapine

Risperidone

Aripiprazole

Qutiapine

Ziprasidone

Atypical Antipsychotics

rule of thumb: Antagonist 5HT2A>> D2 (nigrastrital), antimuscarinic (seizures, dry mouth)

- Clozapine:  strong antagonists D4 (Mesolimbic). Agranulocytosis, hypersalivation, no EPS

- Olanzapine: only 5H2A, not as effective on (+),no D4

- Risperidone: a1 blocker

- Aripiprazole: D2 & 5HT1A (anxiety) partial agonist

     - also used for mania, autism

- Quetiapine: strong H1, a1 antagonism, no antimuscarinic

- Ziprasidone: blocks all DA, 5HT receptors and blocks 5HT, NE reuptake ---- powerful antidepressant

Depression

role of neuroendocrine factors

&

Depression Hypothesis

Amine

Neurotrophic

Amine:

brain lacks amines: NE, 5HT, DA

Neurotrophic:

stress, pain--> lowers BDNF--> atrophy of cingulate (emotion, attention),  hippocampus, Meds ^ BDNF

Neuroendocrine factors:

Depression is seen in: ^cortisol, low estrogen, low testosterone, abnormal thyroid

Tranylcypromine

Selegilline

Phenelzine

Isocarboxazid

irreversible MAOi

needs washout period if starting SSRI

Tranylcypromine: nonselective

Selegilline: MAOb, skin patch, ^ DA

Phenelzine: nonselective 

Isocarboxazid: nonselective

ATYPICAL ANTIDEPRESSION  

MAOI

A vs B

diet drug restrictions

enzymes on outer mitochondrial membrane

A: neurons, liver, GI all neurotransmitters

B: neurons, platelets (DA, phenylethylamine = amphetamine actions)

Diet tyramine: soy sauce, sauerkraut, liver & meats, fava beans, alcohol, cheese

Tyramine displaces DA, NE, EP from vesicles

Drugs:

^ NE: TCA, a1 agonists (cold medications)

^5HT: St. johns wort, Dextromethorphan, meperidine, TCA

Imipramine

Clomipramine

Amitriptyline

Amoxapine

Desipramine

TCA

block NE, 5HT reuptake

block a1, M, H1

metabolized by P450

Antagonism with a2 agonists (lowers NE lower Bp)

Imipramine: 5HT> NE, enuresis (lowers REM)

Clomipramine:  5HT>NE, OCD

Amitriptyline: 5HT=NE, neuropathic pain, migraine

Amoxapine: NE> 5HT, DA, psychotic depression

Desipramine: NE> 5HT, cocaine craving & W/D

SSRI adverse

&

Serotonin syndrome, Tx?

GI: N/V, diarrhea

anorgasmia

CNS stimulate: insomnia, axiety ( intially give benzo)

platelets: ^ bleeds

Serotoning syndrom: rigidity, ^ temp, ANS dysfunction, myoclonus, coma Tx: Benzo, cyproheptadine (antagonist) or chlorpromazine

Fluoxetine*

Paroxetine

Sertraline

Citalopram

Fluvoxamine*

Escitalopram

Powerful P450 inhibitors

Fluoxetine: 3A4 ( BZ/alprazolam, carbamazepine)

Sertraline: minimal inhibition

Citalopram: no inhibition

Fluvoxamine: 1A2 (TCA)

Paroxetine: 2D6 most potent, strong antimuscarinic, only one with no metabolite

Escitalopram

Venlafaxine

Duloxetine

Milnacipran

SNRI

Duloxetone, milnacipran : fibromyalgia  (also pregabalin)

depression, neuropathic pain

Nefazodone

Trazodone

Serotonin 2A antagonists* and reuptake inhibitors

SARIs

inhibits a1 (hypotension, arrhythmias, priapism

* (-) symptoms of mesocortex

NaSSA

a2 antagonism: ^ NE synthesis, release

NE acitvate a1 in locus coeruleus --> ^ 5HT release

BLOCKS:

 - 5-HT2c, H1: weight gain (used in anorexia nervosa)

 - 5HT2A: no sex dysfunction

 - 5HT3: no N/V, GI

 - all available 5HT acts on 5HT1A ( anxiolytic like buspirone)

atypical antidepressant

^DA, NE (blocks reuptake and enhance release)

smoking cessation too

Bipolar I vs II vs III

Hospital acute Tx?

I: depressive, manic

II: depressive + hypomanic (cyclothymic)

III: Mania when treated with antidepressant for a depressive episode

Tx: Clonazepam

Lithium

(behaves like Na)

alternative in Prego?

blocks inosine 5'- monophosphatase--> lowers inositol --> lowers Gq

stabilizes inactive trimeric G protein of Gs, Gi

inhibits PKC (synaptic plasticity)

Vd: 60% of weight

Competes with Na for reabsorption in PCT, small amount in DCT ( triamterene, amiloride* ^ clearance)

Diuretics decrease clearance

NSAIDs, ACE ^ reabsorption

Side effects due to depolarization: tremors (propranolol)

Side effects due to G protein:

  - ADH binds V2 receptors (Gs): polyuria, polydipsia* dont give thiazide ( Tx: Diabetes insipidus, would lower clearance)  

  - TSH binds (Gs): hypothyroid

  - glucose intolerance, leukocytosis

Teratogenic: Ebstein anomaly ( tricuspid leaflet points towards apex), large atrium, small ventricle, WPW

Lamotrigine

antipanic: Gabapentin, clonazepam

Valproate

Carbamazepine

Lamotrigine

Quetiapine, Olanzapine, Risperidone, Aripiprazole

Amphetamine

MethylPhenidate

Atomoxetine

Cocaine

Bath Salts

Stimulants

Nacolepsy, Obesity, obstructive sleep apnea, ADHD

Amphetamine, Methylhenidate:

^ release of DA,NE, 5HT, block reuptake

Anxiety, HR,HTN, Mydriasis

Atomoxtine:

 - NE reuptake inhibitor

 -  Suicidal ideation, no abuse no W/D

Cocaine:

 - Blocks DA, NE, 5HT reuptake no effect on mobile pool

 - also blocks vol Na channel

Bath salts:

 - act like cocaine, amphetamine

 - violent, HTN,HR, hallucinations, seizures, rhabdomyolysis--> ARF... supportive

CB1 vs CB2

Receptors both Gi

THC: CB1>CB2 agonist

endogenous from membrane phospholipids

Methotrexate

5-flurouracil

Cytarabine

Mercaptopurine

Antimetabolites, S phase

Methotrexate

  - inhibits DHF redutase ( T,A,G), leucovorin

  - NSAIDS, penicillin ^ toxicity

5-flurouracil (IV) capecitabine (oral)

  - - thymidylate synthase after activation to FdUMP

   - hand foot syndrome, neurotox

Cytarabine

   - (-) DNA polymerase after its -P- and incorporated lookes like cytosine

Gemcitabine:

  - (-) DNA pol, (-) ribonucleotide reductase

Mercaptopurine

  - Activated by HGPRTase to monoP

  - (-) PRPP amidotransferase (Rate lining in de novo purine)

   - immunesuppression (azathioprine is prodrug)

Cyclophosphamide

Cisplatin

Carmustine

Lomustine

Alkylating Agents (N7 guanine is most common site), ^ risk of leukemia, lymphoma

Not cell cycle specific

Cyclophosphamide

  - hemorrhagic cystitis due to acrolein, MESNA

  - If cystitis already give N- acetylcysteine

Cisplatin

  - Nephrotoxocity ( give amifostine), Severe N/V ( ondansetron), ototoxicity, P. neuropathy

Carmustine

  - Interstitial pneumonitits

Vinblastine

Vincristine

Paclitaxel

Irinotecan

Topotecan

Etoposide

Vinblastine, Vincristine

  - M phase, inhibts microtubule polymerization, arrest in metaphase, P. neuropathies, no BMS with vincristine

Paclitaxel

  - Mphase, stabalizes microtubules, arrest in prophase, P. neuropathies,

Irinotecan

  - Sphase, inhibits topoisomerase I

Etoposide

   - sphase, inibits topoisomerase II

Actinomycin D

Bleomycin

Daunorubicin

Doxorubicin

Antitumor antibiotics

Actinomycin D, a-manitin

  - (-) RNA polymerases, blocks transcription

Bleomycin

  - G2 specific, binds iron--> ^ ROS, pulmonary fibrosis

Daunorubicin, Doxorubicin

  - intercalates DNA, ^ ROS, blocks topoisomerase II

  - Red-orange urine, Cardio: acute= arrhythmia, chronic: dilated

  - Dexrazoxane chelates iron

Tamoxifen

Fulvestrant

Anostrozole

Hormonal therapy cancer

Tamoxifen, Toremifene

   - SERM, (-) at ER in breast, (+) everywhere else

   - ^^ endometrial carcinoma, osteoporosis, lowers Cholesterol, LDL

Fulvestrant

  - pure ER antagonist and ^ degration of receptor

Anostrozole

   - competative inhibitor of aromatase

Exemestane

  - irreversible aromatase

Rituximab

Trastuzumab

Cetuximab

Imatinib

Gefitinib

Eriotinib

Kill by ADCC, complement, induce apoptosis

Cancer antibodies

Rituximab

  - CD20, NHL, CLL (wegener, mico polyangiitis, ITP, R.A)

Trastuzumab

  - ErbB2 of EGF receptor, (+ metastatic breast, gastic, gastroesophageal adenocarcinoma)

Cetuximab

  - ErbB1 of EGF receptor in meatastatic colorectal cancer)

Imatinib

  - TK, bcr-abl (CML: 9,22), c-kit (G.I stromal), PDGFR (^ EO syndrome)

Gefitinib: ErbB1  non small cell lung cancer  

Eriotinib: same as above

Sorafenib, Sunitinib: many TK

Alemtuzumab

 - CD52(lymphocytes, PMN) , CLL,

Bevacivumab

 - VEGF, toxicity: HTN, CHF, proteinuria, G.I hemmorrhage

 - metastatic colorectal, non-small cell lung cancer, erbB2 (-) breast cancer

anticancer

Need asparagine--> aspartate + Ammonia

Toxicity due to lower protein synthesis: low insulin, less clotting factors, pancreatitis ( valproate, didanosine, stavudine)

AML-M3 expresses vit-A receptor

forces differentiation of promyelocytes--> myelocytes--> metamyelocytes--> Bands--> PMN

Retinoic Acid syndrome: fever, dyspnea, effusions (lung, pleural, pericardial), mental confusion

Anticancer

S-phase

Inhibits Ribonucleotide Reductase (no ribnucleotide--> deoxyribonucleotide)

Binds 20S core of 26S proteasome

^ I-kB (inhibitor of NF-kB--> ^ cyclins, bcl-2,VEGF etc)

Temsirolimus

Everolimus

mTOR inhibitors

inhibits PI3 kinase which activates mTOR

Leuprolide

Degarelix

Flutamide

Leuprolide, Goserelin, Triptorelin

  - GnRH analog, block surge

Degarelix

  - GnRH antagonist

 Flutamide

   - Competitive antagonist