Inflammatory Response

-acute inflammation

-initial response to tissue injury

-Mediated by autocoid group

Histamine

serotonin

Bradyinin

Prostaglandins

Leukotrienes

Chronic Inflammation:

Release of additional mediators

Interleukins

GM-CSF

TNF

Interferons

PDFG

Cyclooxygenase pathway

-arachidonic acid (AA) converted to PG by COX

Lipoxygenase pathway

-AA converted to leukotrienes by lipoxygenase

COX-1: Constitutive, wide distribution

COX-2: expression is stimulus dependent, facilitates inflammatory response

Powerful chemotactic effect on

-eosinophils

-neutrophils

-macrophages

Promote bronchoconstriction

Alters vascular permeability

Neutrophils produce ROS

-membrane damaging

(Hydrogen peroxide, Hydroxyl radicals)

ROS + AA = chemotacticmetabolites

Goals (pain relief, arrest tissue damage)

Strategy (reduce inflammation)

Nonsteroidal anti-inflammatory drugs (NSAIDS): relieve pain (acute and chronic)

Glucocorticoids: chronic use toxicities

Slow-acting antirheumatic drugs

Disease modifying antirheumatic drugs (DMARDs)

NSAIDS

(general info & kinetic properties)

Suppress S/S of inflammation.

Antipyretic, Analgesic, original NSAID: ASA

-weak acids

-well absorbed

-highly metabolized

-renal and biliary excretion

-highly protein bound

• Inhibition of PG synthesis
• Decreases sensistivity of vessels to bradykinin and histamine
• Affect lymphokine production (reverse vasodilation)
• Inhibit platelet aggregation (Not for COX 2 selective agents)

Other mechanisms:

-chemotaxis inhibition

-down regulation of IL1

-Decrease production of ROS

-Interfere with Ca++ mediated intracellular events

All are gastric iritants (differeing degrees of irritation)

All can cause nephrotoxicity and/or hepatotoxicity

ASA

general info and history

Acetylsalicylic acid

"gold standard"

First documented use in 1763 (willow bard extracts- antiquity)

ASA:

Anti-inflammatory effects

Nonselective irreversible COX inhibitor

-inhibition of granulocyte adherence

-stabilized lysosomes

-inhibits migration of PMN and macrophages to sites of inflammation.

Mediated by cOX and IL-1 inhibition

dissipation of heat caused by vasodilation of peripheral vessels

Irreversible block of platelet cyclooxygenase (other NSAIDS are reversible block)

slight prolongation of bleed time

antiplatelet effect: 8-10 days

concern pre-surgery

Widely used, not for severe pain

(1200-1500mg TID)

Rheumatoid arthritis

Rheumatic fever

Fever

Clot prevention (81-325 mg/day)

Decrease incidence: Transient ischemic heart attacks, angina, coronary artery thrombosis

Lower incidence: Colon CA

Enteric coated: prevent tablet from dissolving in stomach, adequate absorption in small intestine

GI upset! (buffering may decrease)

~cause: irritaton of gastric mucosa, inhibition of GI protective PG

Increase incidence of gastric ulcers

Salicylism

-higher doses  -vomiting   -tinnitus    -decreased hearing   -vertigo

Increase liver enzymes      hepatitis      decreased renal function

bleeding                         rashes         asthma

Reye's syndrome

Mild: Respiratory alkalosis (increased respirations)

Moderate: Acidosis (SA derivatives, depression of resp. center)

Severe: restlessness, irritability fear or nervousness, dizziness, confusion, abnormally excited mood, hallucinations, LOC, fever, uncontrollable shaking, seizures, comiting, decreased urination, double vision

Mg⁺⁺ choline salicylate

Sodium salicylate

Salicylsalicylate (effective anti-inflammatory, less effective analgesia)

Less effective COX inhibitors

-good for some patients (asthma, bleeding tendencies, renal dysfunction)

No effect on "housekeeping" COX-1

-analgesia

-antipyretic

-anti-inflammatory

Fewer GI side effects (halved)

No impact on platelet aggregation

Selective COX-2 inhibitor

Sulfonamide (allergies)

Use:

-Rheumatoid arthritis                    -Osteoarthritis 

                      -Decrease ulcer incidence

Black box warning: increased risk of serious adverse CV events

FDA: adverse CV events related to all NSAIDS (except ASA)

Inhibits COX-2 over COX-1

Not as selective as other COX inhibitors

Fewer GI effects

Texicities similar to other NSAIDS

Decreases arachidonic acid availability

Anti-inflammatory, analgesic, and antipyretic

20% of patients have adverse GI effects

(decreased with misoprostal: Cytotec)

Less GI upset than ASA

(equivalent anti-inflammatory, analgesia)

Available OTC

Available oral, cream, gel, IV

Adverse effects and toxicity = NSAIDS

(agranulocytosis and aplastic anemia are rare)

Indomethacin:

general info

Potent COX inhibitor

May also inhibit Phospholipase A and C

Reduce PMN migration

Decrease T & B cell proliferation

Use:

-Rheumatism       -Gout       -Patient ductus arteriosus

Indomethacin:

uncommon conditions

Conjuctivitis (ointment)

Sweet's syndrome

Juvenile rheumatoid arthritis

Pleurisy

Nephrotic syndrome

Indomethacin:

Adverse reactions

1/3 of patients at higher doses

GI effects:

-abdominal pain

-diarrhea

-GI hemorrhage

-pancreatitis

Diflunisal (Dolobid): Rheumatoid arthritis, CA pain

Etodolac (Lodine): Post-op pain relief

Flurbiprofen (Ansaid): Racemic mixture, IV for minor ear, neck and nose surgery

Ketoprofen: Both COX and lipoxygenase, surprisingly no better than other NSAIDS

Ketorolac: analgesic post-surgery, increased peptic ulcer if use >5 days

Naproxen     Oxaproxin     Sulindac    Tolmetin

• COX-2 selective
• Weak PG inhibitor in peripheral tissues
• No significant anti-inflammatory effect
• PO or PR (newer IV formulation)
• Metabolized by hepatic enzymes (toxic to both liver and kidney)

• Equivalent to ASA as analgesic and antipyretic
• No effect on platelet aggregation
• Mild to moderate pain (HA, myalgia, postpartum)

allergic to ASA

asthmatics

hemophiloia

peptic ulcer

children

• Mild increase in hepatic enzymes
• Larger doses: dizziness, excitement, disorientation
• Fatal: 15gms, hepatotoxicity, ATN (renal)

• Therapy
• Sense of well being
• Specific receptors modulating synaptic transmission
• Drug effects elucidate disease mechanisms

• Different transmitters used in different areas
• Neuronal systems control broadly different functions
• Different signals:

EPSP (excitatory post synaptic potential,

IPSP (inhibitory post synaptic potential)

• Act as NTs for pain modulation
• Released during: pain, expectation of pain, excitement, certain foods, exercise, love, orgasm
• Types: Endorphins, Enkephalins, Dynorphins

Opium poppy Papaver somniferum

Serturner, a German pharmacist (1803), isolated a pure active alkaloid from opium and named morphine

Agonists, partial agonists, antagonists

Receptor specificity

μ (mu):

full agonists: morphine, fentanyl

partial agonists: codeine, oxycodone

antagonist: naloxone (narcan)

δ (delta)

Κ (kappa)

μ (mu)

Receptor functions & endogenous ligands

Supraspinal and spinal analgesia: sedation; inhibition of respiration; slowed GI transit; modulation of hormone and NT release

Endorphins>enkephalins>dynorphins

δ (delta)

Receptor function & endogenous ligands

Supraspinal and spinal analgesia; modulation of hormone and NT release

Enkephalins > endorphins and dynorphins

Κ (kappa)

Receptor function & endogenous ligand

Supraspinal and spinal analgesia; psychotommimetic effects; slowed GI transit

Dynorphins >> endorphins and enkephalins

A: Well absorbed (IM, SQ, Oral)

-nasal, patch- avoid first pass effect

-Codeine: low first pass metabolism

D: Highly perfused tissues- accumulation

-brain, heart, kidney, liver

-skeletal muscle-reservoir

M: Morphine: Phase 2 to active forms (M3G, M6G)

Esters (heroin): tissue esterases to morhine

Other-Phase 1 (CYP3A4, CYP2D6)

E: Mainly in urine

Bind to receptors in brain and spinal cord

modulation of pain

receptor effects:

-Reduce NT release (glutamate, ACh, NE, 5-HT, Substance P)

-Hyperpolarize postsynaptic neurons

Opioids: Pharmacodynamics

differential receptor effects

Mu: analgesia, euphoria, respiratory depression, dependence

Delta: analgesia, enhance mu effects

Kappa: analgesia, enhance mu effects

• analgesia: sensory and emotional aspects
• Euphoria (dysphoria)
• sedation
• respiratory depression (brainstem)
• cough suppression
• miosis (always - marker)
• increased muscle tone (trunk)
• N/V
• Hyperthermia (mu) or hypothermia (kappa)

Opioids:

CV and GI effects

CV:

most have no direct effects

bradycardia (CNS)

Meperidine (Demerol) - tachycardia

GI:

constipation (ENS) - marked, no tolerance

Opioids:

Other organ system effects

Kidneys: function depressed, increased retention

Uterus: may prolong labor

Flushing

Immune response: enhanced

Pain assessment

(opioids)

Pathology

Patient history

Duration

Severe, constant

Sharp, intermittent- not as effective

Terminal illness (fixed interval, sustained release)

Obstetrics- fetal monitoring

Renal or biliary colic

Acute Pulmonary Edema

(opioids)

Dyspnea from LVF

MOA:

-reduced anxiety

-reduced preload (↓ preload)

-reduced afterload (↓ PVR)

Loop diuretics

• Cough
• Diarrhea
• Shivering
• Anesthesia:

Pre-op anxiety or post-op pain

peri-op: anesthetic (fentanyl)

epidural

Opioid Toxicity:

Extension of therapeutic effects:

behavioral restlessness,    tremulousness, respiratory depression,    N/V,    increased ICP, constipation,    urinary retention,    postural hypotension (accentuated by hypovolemia),  itching around nose

 Tolerance:

~Fairly rapid
~multiple mechanisms (theories): receptor phosphorylation cAMP, internalization uncoupling with G-proteins

Dependence:

~Continuation despite negative effects
~Withdrawal symptoms

Stems from physical and chemical dependence

• Rhinorrhea
• Lacrimation
• Yawning
• Chills
• Hyperventilation
• Hyperthermia
• Mydriasis
• N/V
• Anxiety
• Hostility

~Drug OD: Naloxone (Narcan)

~Head injuries: Opioids may enhance resp. depression

~Impaired pulmonary function

~Pregnancy: fetal dependence

~Impaired hepatic or renal function

~Endocrine disease: prolonged or exaggerated response to opioids

~Mixing: pure agonists (morphine) with partial (pentazocine) reduces analgesia

Strong Agonists (opioids):

Phenanthrenes

~Use for severe pain

Morphine, hydromorphone

Heroin (diacetylmorphine)

(palliative care, UK)

[image]

Strong Agonists (opioids):

Phenylheptylamines

Methadone:

Chronic pain (morphine tolerance)

duration of analgesia: 4-6 hrs

long half-life: 25-50 hrs

CYP3A4

Opioid abuse

Strong Agonists (opioids):

Phenylpiperidine

Fentanyl:

Additionsl analogs (increased potency, rate)

Multiple routes of administration

Meperidine (Demerol):

antimuscarinic effects (tachycardia)

(-) inotrope,   seizures

usage decreasing due to side effects

~Phenanthrenes: Codeine, Oxycodone

More effective as combinations:

Oxycodone + acetaminophen = Percocet

Oxycodone + Aspirin = Percodan

~Phenylheptaylamines:

Propoxyphene (Darvon)

~Phenylpiperidines:

Loperamide (immodium): diarrhea, low incidence of abuse

Derivative of morphine:

Naloxone, Naltrexone

Completely and dramatically reverses opioid effects in 1-3 minutes (short duration, Nalaxone, effect may return)

Little effect in absence of agonist

90% of all drugs manufactured in the world are consumed by 10% of the American population

Today there are estimated 30 million chronic drug users in America

Most chronic abusers (addicts) started by using marijuana, alcohol, and tobacco in their youth

Schedule of Controlled Drugs

(general info & history)

• Controlled Substances Act (1970)
• DEA, FDA, HHS
• Drugs placed in schedules based on potential for abuse
• Controversy
• Exclusions: tobacco, alcohol

Schedule 1: High abuse, no medical application

ie: heroin, GHB, marijuana

Schedule 2: High abuse, medical application

ie: Morphine, Amphetamines

Schedule 3: lower abuse, medical use

ie: Codeine (dose), ketamine, anabolic steroids

Schedule 4: Low abuse, medical use, low addiction

ie: Butorphanol (Stadol), Valium, Ambien

Schedule 5: Very low abuse, addiction, preparations of small amounts from other schedules (cough syrup with codeine)

ie: Pregabalin (Lyrica), Lomotil

Opioid Dependence

Dependence:

Physical dependence, withdrawal symptoms

Addiction:

Psychological dependence, strong feelings of euphoria or reward

~dopamine mesolimbic system

 ~Reward processing system (animal modes(

 ~Associate drug with effects:

learning system

addiction- maladaptive learning (drugs of abuse, compulsive disorders (gambling))

~Few patients desire opioid after drug withdrawal

~1/6 becomes addicted to cocaine

~Addiction factors: deredity, environmental cues

~Alter perception wihtout euphoria

~Little associated wiht mesolimbic dopamine system:

LSD: serotonin receptor

PCP, Ketamine: Dissociative, NMDA receptors

1. Initial use, experimentation
2. Repeated or regular use
3. Abuse
4. Dependence
5. Relapse

All increase dopamine in mesolimbic system

Classify based on targets:

GPCR

Iontropic receptors or ion channels

Monoamine transporters

Opioids: mu, kappa, delta

~Morphine, heroin, codeine, oxycodone, demerol

~strong tolerance and dependence

~withdrawal

~treatment:

OD: Naloxone

Substitution: Methadone

GPCR

~Euphoria, relazation

~Duration: 2-4 hours

~toxicity: visual distortion, drowsiness, impaired memory

~Medical use: ↑ appetite, ↓IOP, ↓nausea

~Dependence (2 out of 5):

withdrawal- agitation, insomnia

Gamma-hydroxybutyric acid (GHB)

GABA_B, GHB receptor

~Endogenous: metabolism of GABA

~"date rape drug": euphoria, social closeness, sedation, amnesia

~10-20 mg/kg dose, 20-30 minute effects

~Toxicity: respiratory arrest

~Medical use: insomnia

Nicotinic ACh receptors: Ionotropic

~High level of addiction

~common

~nAChRs on dopamine neurons

~cessation: nicotine patch, behavioral

~OD: Atropine

GABA_A: Ionotropic

~Librium, Valium, Halcion

~Sedative-hypnotics: followed barbs

~Schedule IV (4)

~Sedative, retrograde amnesia

~OD: seizures, coma

Many receptors (GABA_A, NMDA, 5-HT): Ionotropic

~Common

~Dopamine release?

~Dependence, withdrawal:

tremors, anxiety, N/V, delerium tremens

~Treatment: benzos, counseling

Phenyclidine (PCP)

Ketamine

NMDA Receptors: Ionotropic

Anesthetics

Hallucinogens

NMDA: Ionotropic

Huffing, bagging

Aromatic hydrocarbons

Brain lesions, coma, death

Monoamine transporters: Dopamine Transporter (DAT)

~Highly addictive (crack cocaine)- stimulant

~Peripheral effects:

NET, Na+ channels

Tachycardia, appetite suppression

~OD: Intercranial hemorrhage, MI, coma, death

Monoamine Transporters: Ionotropic

VMAT, NET, DAT

~Increase arousal, stimulant

~Euphoria

~Pill, smoke, injection

~Hypertension, tachycardia

~Neurotoxic

~"Meth Mouth"

Monoamine Transporters: Ionotropic:

SERT

~intimacy and empathy

~"Designer drug"

~hyperthermia

~dehydration?

~Serotonin syndrome

Morphology: Cocci, Bacilli, etc.

Arrangement

Metabolism: Aerobes vs. Anaerobes

Staining Characteristics: Gram, AF

Gram negative:

Additional outer membrane

contains lipopolysaccharide (LPS)

PCN: prevents peptidoglycan synthesis

Lysozymes: digests peptidoglycan

Protein synthesis

Sedimentation rate:

-70S (eukaryotes are 80S)

-subunits of 30S and 50S

-Eythromomycin and Streptomycin bind to 70S

Hemolysis patterns

Spore Forming

Aerotolerance

Surface antigens (Group A and B Strep)

Ability to invade tissues: bypass host defense, OIP-mycobacterium, viruses

Ability to produce toxin: endotoxin, exotoxin

Selective Toxicity

Spectrum of Activity

Modes of Action

Side effects

Resistance of Microorganisms

Inhibiting cell wall synthesis selectively damages bacterial and fungal cells

PCN and Cephalosporin: B-lactam ring

the B-lactam ring attaches to the enzymes that cross link peptidoglycans and prevent cell wall synthesis

Clinical use:

PCN

Gram (+) cocci:

Group A strep (throat)

Group B prophylaxis

Viridans strep endocarditis

Enterococcal UTI

Anaerobes

Dental procedure prophylaxis

Aspiration pneumonia

Used against beta-lactamase producing streptococci

Methicillin

Nafcillin

Isozazol penicillins

Greater activity against Gram (-) bacteria

(penetrate outer membrane)

Ampicillin/Amoxicillin

Pipercillin

Available with beta-lactamase inhibitor (clavulanic acid, sulbactam)

-Hypersensitivity:

most common drug allergy

can cross react with similar antibiotics

-Allergic reactions:

anaphylactic shock (0.05%)

skin rash (<1%)

oral lesions

hemolytic anemia

interstitial nephritis

-GI upset

N/V

1930's: Sulfonamides

1940's PCN

1960's: MORE PCN

1970's: Spectinomycin

-More resistant to b-lactamase

-Broader spectrum

-First generation:

better gram (+) activity

Cephalexin (Keflex), cefazolin

Uses: UTI, Staph, Alternative to PCN (less allergy)

Beta-lactam (more beta-lactamase resistant)

Very expensive

Wide spectrum of activity

Penetrate CNS

DOC for enterobacter

Imipenem, Meropenem

Resistant to beta-lactamase

Alternative to PCN resistant bacteria (MRSA)

"Drug of last resort"

10% of adverse rxns

irritating to tissues

chills/fever

ototoxicity, nephrotoxicity

"red neck" syndrome

Polypeptide ATBs (polymyxins)

Act as detergents

Bind to phospholipids

Especially effective against gram-negative bacteria which have an outer membrane

selective toxicity

attach bacterial cells without significantly damaging animal cells

70S ribosomes (humans are 80S)

-subunits, 30S, 50S

Streptomyces,  Bacteriostatic

Pharmacokinetics: readily absorbed, widely distributed

Have the widest spectrum of activity of any ATB

however, they destroy the normal intestinal microbiota and often produce severe GI disorders

-GI: Anorexia, N/V/D, stimulate gut motility

-bone

-liver: acute cholestatic hepatitis (hypersensitivity)

-kidney

-Drug interactions: inhibitor of CYP 450 enzymes

Protype drug: Erythromycin

(streptomyces erythreus)

Semi-synthetic derivatives: Clarithromycin (Biaxin) and Azythromycin (Zithromax(

 Chemistry: macrolide ring

-Usually plasmia mediated

reduced permeability

active efflux

esterases that hydrolyze macrolides

modification of ribosome binding site

Drug of choice: corynebacterial infections (diptheria)

Chlamydial infections (respiratory, neonate, ocular, genital)

Aminoglycosides (streptomycin)

Clindamycin (anaerobes)

Chloramphenicol (serious toxicities)

Streptogramins

Oxazolidinones (Linezolid- MRSA, VRE)

Hallucinogens

LSD, mescalin, psilocybin: 5HT_2A agonist:

Natural and synthetic

No dependence/addiction

Duration: 6-12 hours

Inability to make rational judgements

differences between the enzymes used by bacterial and animal cells

Rifamycin family bind to a bacterial RNA polymerase

Inhibit DNA gyrase (bacterial)

Excellent gram (-) activity

Good Gram (+)

Types:

Cipro, Levaquin, Floxin

UTI, RTI

Bone and joint infections

ADR

competitive inhibition

incorporated into important molecules

Structurally similar to PABA (synthesis of folic acid)

Pneumocystis, toxoplasmosis (conjunction with trimethoprim (Bactrim, Septra))

Toxicity: allergenic, may precipitate in urine, hematopoetic disturbances

Imidazoles: creams for cell membrane inhibition (ketoconazol)

Polyenes: Amphotercin and Nystatin- systemic infections

Dermatophytes: Griseofulvin (oral), Lamisil (topical)

Antiviral agents

Purine/Pyrimidine analogs (disrupt viral DNA replication (Acyclovir, AZT)

Relenza, Tamiflu (prevent influenze entering or exiting cell)

Cells infected with viruses produce proteins- interferons

Quinidine- malaria (second generation compounds)

Metronidazole (Flagyl):

Giardia, Trichomonas

Many side effects: birth defects, cancer, black hairy tongue

Comcomitant disease states?

Prior adverse drug reactions?

Impaired elimination or metabolism?

Age? 

Pregnancy status?

Genetics?

Most infections- presribe antibiotics

Severe infections: C&S:

culture tubes-aerobic and anaerobic

isolation

identification

antibiotic sensitivity

anaerobe culture

beta-lactamase assay

synergy studies

PCR identification of strain

Multiple antibiotics given together can have synergistic effect:

PCN damages cell wall, Streptomycin penetrates better

Antaonism:

Tetracyclines inhibit growth

PCN requires growth for effectiveness

Endo    crine   System

"inside"  "secrete"            

Odd organ system

Endocrine glands usually not connected

Secrete chemical messages called hormones to target cells

ie: pineal gland, hypotlamus, pituitary gland, thyroid gland, parathyroid gland, thymus gland, adrenal glands, pancreas, ovary, testis

4 structural groups:

Amino acid based (amino acid derivatives, peptides and proteins (polypeptides))

Steroids (cholesterol based)

Fatty acid derivatives (eicosanoids)

Consists of two major types of secretory tissues which reflects its dual function

-Exocrine (digestive enzymes)

-Endocrine: islets of Langerhans

control centers for blood glucose

(insulin from beta cells,

Glucagon from alpha cells)

Elevated Blood Glucose

Four types:

Type 1: insulin dependent (IDDM)

Type 2: Non-insulin dependent (NIDDM)

Type 3: other causes elevated blood glucose (pancreatitis, drug therapy)

Type 4: gestational

-Destruction of beta cells

-Severe or absolute insulin deficiency

-Immune (most common)

-Idiopathic

-Clinical manifestations: hyperglycemia

80-90% of the function of the insulin secreting beta cells in the islet of Langerhans is lost

-Polydipsia, polyuria, polyphagia, wt. loss, and fatigue

-Require insulin replacement (DKA)

"Adult Onset Diabetes"

Genetic-environmental interaction

Metabolic syndrome

Combination of relative deficiency of insulin secreation with tissue insulin resistance

Exercise, lose weight, medication

Manifestations: recurrent infections, vision problems, neuropathy

dehydration: nonketotic hyperosmolar coma

-Hyperglycemia and nonenzymatic glycosylation

-Hyperglycemia and polyol pathway:

Sorbitol and fructose increase IC osmotic pressure (attracts water, leading to cell injury)

-Evident in the eye lens, nerves, RBCs

-Protein kinase C (enzyme inappropriately activated by hyperglycemia)

-Microvascular disease (retinopathy, diabetic nephropathy)

Gestational: Hormones block- insulin release

7% of US pregnancies

Higher birthweight

Resolves after pregnancy

(increase risk for 2nd pregnancy, increase risk for Type 2 DM)

Diagnosis:

Fast blood glucose, glucose tolerance test

Monitoring:

Self: glucose POC, HgB A1C, insulin

Insufficiency of ADH-Posterior Pituitary

-Polyuria and polydipsia

-Partial/total inability to concentrate the urine

-Neurogenic (insufficient amounts of ADH)

-Nephrogenic (inadequate response to ADH)

↑ADH = SIADH

↓ADH = Diabetes Insipidous

Beta cells:

Proform, Activated in granules

C-peptide: no known function

Species differences

Constituitive, low level release

Insulin secretagogues:

glucose (mannose, fructose)

amino acids

hormones

fatty acids

SNS (bet adrenergic)

Drugs- sulfonylureas, isoproterenol, ACh can release secretion of insulin

-Tyrosine kinase receptor

-Multiple effects:

membrane translocation of GLUT

increased glycogen formation

activation of multiple transcription factors

insulin

Leptin

SNS (alpha adrenergic)

Chronically high glucose

Drugs: diazoxide, phenytoin, vinblastine, colchicine

Rapid acting: Lispro, Aspart

Short acting (Regular): Novolin, humulin

Intermediate acting: Neutral protamine Hagedorn, isophane

Long acting: Glargine, detemir

SQ injection- hypodermic needle

Portable pen injectors

Continuous SC insulin infusion devices (CSII):

requires sterile change every 2-3 days

best for "tight" insulin control

Inensive: IDDM: tight control,

basal + bolus (calculated)

Conventional: SSI

Illness: DKA, hyperosmolar hyperglycemic syndrome

Complication of treatment:

S/S: anxiety, blurred vision, palpitations, shaky, slurred speech, sweating

Treatment: glucose/simple sugars 3-4 tabs, 1/2 can of soda

Glucagon injections: 1 mg IM/IV/SQ may repeat in 20 mins prn

Biguanides

Insulin Secretagogues

Incretin-based therapies

Amylin Analogs

Bile Acid Sequestrant

Thiazolidinediones

First line therapy (NIDDM)

Reduction in hepatic glucose production (metformin/Glucophage)

500 mg prandial

GI toxicities

Bind to K+ channels: Rectifier current, binding causes depolarization

Classes: Sulfonylureas, Meglitinide, Phenylalanine derivatives

Decrease insulin resistance (PPAR mediated)

Increase insulin signal transduction

Risk of MI:

increase with insulin, nitrates

Avandia-Rosiglitazone

Block digestion of complex carbs

Beneficial in Pre-diabetes

Prominent GI effects:

Flatulence, diarrhea, abdominal pain

large cation exchange resins-not absorbed

Bind bile acids0 prevent reabsorption

GI upset

Amylin also released by beta cells (suppresses glucagon release)

Decrease circulating glucose

Concomitant with insulin

Incretins: GI hormones

Glucagon-like polypeptide-1 (GLP-1) Agonists

dipeptidyl Peptidase-4 (DPP-4) Antagonists

Biguanide

Biguanide + insulin OR Biguani de + Decretagogue

Biguinide + 2-3 other classes

Intensive Insulin Therapy

Low-carb, low fat, calorie-restricted diet

Patients with type 2 DM have an LDL goal <100 mg/dL

wt. loss

First line therapy; statins

Fiber, Omega-3 fatty acids

Adjunctive therapies for DM:

CV disease/HTN

Antiplatelet agents

SBP goal <130

ACE-II inhibitor is first line:

Renal protective

ARBs

Consider starting daily low dose ASA (81 mg/day) to prevent ischemic events

Formula for BMI

weight distrubution

concern over "central Obesity"

1. Nutrient and Energy model: Metabolism, appetite regulation, energy expenditure

2. Genetics

3. Behavioral and cultural factors

1. Diet Therapy

2. Increased Physical Activity

1. SNRI's - Pristique, Symbalta, Sibutramine

2. Orlistat - lipase inhibitor, decreases absorption of dietary fat ( 120 mg PO TID)

1. outer protein coating

2. Lipid core

inhibits VLDL secretion, which decreases production of LDL

Increases HDL

Incorporates into NAD

LDL -40%

HDL +10%

Triglycerides ↓

LDL -20%

HDL + 25%

Triglycerides ↓↓

LDL -10%

HDL +15%

Triglycerides ↓↓

LDL -20%

HDL +5%

Tryglycerides (-)

LDL -20%

HDL +5%

Triglycerides (-)

1) Crystal Violet: all cells turn purple

2) Iodine: all purple iodine acts as mordant to set stain

3) Decolorize with alcohol:

Gram (+): purple (because of the thick wall, not all the color is washed out)

Gram (-): turns clear

4)Safranin wash:

Gram (+): stays purple

Gram (-): turns pink