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Pharmacokinetics

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Title: Pharmacokinetics


1
Pharmacokinetics
  • Pharmacokinetics describes the movement of a drug
    from consumption (entry) to elimination
    (removal). What the body does with the drug
  • Pharmacodynamics describes how the drug works at
    the target tissue. What the drug does to the
    body.

2
Routes of administration
  • The route of administration is determined
    primarily by the properties of the drug and the
    therapeutic objective. There are two major
    routes of administration enteral parenteral.
  • Enteral
  • Oral most common route, most complicated, most
    variability first pass metabolism in both the
    intestine and liver, gastric emptying
    variability, acid lability, enteric coating, etc.
  • Sublingual Absorption directly into the systemic
    circulation, rapid onset and avoids first pass
    metabolism in the liver and intestine and the
    acidic stomach.
  • Rectal (just like sublingual) but safer
  • Parenteral
  • IV avoids first pass effects, it allows the most
    control over the circulating level of agent it
    is invasive, requires intravenous access once
    given IV drugs are difficult to remove (emesis,
    charcoal).
  • IM
  • Subcutaneous
  • Other
  • Topical
  • Transdermal allows systemic distribution (vs.
    topical),
  • Inhalation
  • Intranasal

3
Paracetamol Absorption by various routes
4
Absorption of Drugs
  • A) Transfer of drug from the GI tract
  • Passive diffusion is driven by the concentration
    gradient. Diffusion depends on lipid solubility,
    hydrophilic drugs enter via aqueous channels.
    Some passive transport involves a carrier protein
    (facilitated diffusion).
  • Active transport involves a specific carrier
    protein. Drugs resembling natural metabolites
    are often transported via this energy dependent
    mechanism.
  • Receptor mediated endocytosis

5
Absorption of Drugs
  • B) Effect of pH on drug absorption
  • Most drugs are weal acids or bases
  • Acid HA?H A-
  • Base B H ? BH
  • Passage of an uncharged drug through a membrane,
    movement of drug across the membrane is
    proportional to the concentration of charged and
    uncharged drug. Manipulation of the pH on either
    side can promote drug movement.
  • Antacids, metabolic acidosis alkalosis may
    alter the ratio of charged and uncharged drugs
    leading to altered absorption.

6
  • C) Physical factors influencing absorption
  • Blood flow to the absorption site
  • Total surface area available for absorption
  • Contact time with the absorptive surface

7
Bioavailability
  • A)Bioavailability is the fraction of administered
    drug that reaches the systemic circulation this
    is expressed as the fraction of drug in the
    systemic circulation to drug administered
  • B) Factors influencing bioavailability
  • 1st pass hepatic metabolism
  • Drug solubility
  • Chemical instability
  • Nature of drug formulation

8
Drug Distribution
  • Drug distribution is the process by which a drug
    reversibly leaves the plasma and enters the
    extracellular fluid to reach cells and tissues.
    This process depends on
  • Blood flow to tissue
  • Capillary permeability
  • Drug solubility
  • Degree of drug binding to plasma and tissue
    proteins Albumin is the major drug binding
    entity and acts as a reservoir of drug.

9
Volume of Distribution
  • A hypothetical volume of fluid into which a drug
    is distributed, its a useful to consider in
    predicting effective drug dosages.
  • Once absorbed into the plasma a drug can be
    distributed to one of three (or all three)
    distinct fluid compartments.
  • Plasma compartment (6 body mass).
  • Extracellular fluid (20 body mass).
  • Total body water (60 body mass.
  • Vd vol. of distribution
  • Vd D/C D dose
  • C plasma concentration
  • Vd has an important influence on the half-life of
    a drug because action elimination usually
    depends on the amount of free drug at the cell.

10
  • Binding of Drugs to Plasma Proteins
  • Drugs bound to plasma proteins, usually albumin,
    are inactive, only free drug can exert its effect
    and be eliminated.
  • Binding capacity of Albumin
  • Drugs bind reversibly to albumin, binding
    capacity may be low (11) or high (51).

11
  • Phase I reactions
  • These reactions convert lipophilic molecules to
    more polar molecules by unmasking a polar
    functional group (-OH, -NH2, etc.). Phase I
    reactions may increase, decrease or leave
    unchanged a drugs pharmacologic activity, these
    metabolites may be toxic.
  • Phase I reactions most often involve the
    Cytochrome P450 system (MFO)
  • Drug O2 NADP H?Modified drug H2O
    NADPH
  • Phase II reactions
  • These are conjugation reactions. Phase I
    reactions are frequently unable to create a
    hydrophilic enough molecule for renal excretion.
  • Phase II reactions involve conjugation with
    glucuronic acid, sulfuric acid, acetic acid or an
    amino acids. This usually creates a water
    soluble inactive molecule. Glucuronidation is the
    most common.

12
Enterohepatic Circulation
Renal Drug Interactions
Bile salts produced in the liver serve to aid in
digestion. 95 of bile acids are reabsorbed in
the ileum, each bile salt is cycled 20 times
before eventually being excreted. Some drugs also
undergo enterohepatic circulation resulting in
prolonged exposure and the production of
potentially toxic metabolites during multiple
passes through this pathway.
Bacterial population
13
Pharmacodynamics what drugs do to you
  • Most drugs exert their effects by binding to
    receptors the pharmacologic effect is mediated
    through drug/receptor binding.
  • Receptors may be
  • Enzymes
  • Structures (nucleic acids)
  • Membrane receptors
  • The drug-receptor complex formation leads to a
    biologic response, the magnitude of the response
    is proportional to the number of drug-receptor
    complexes.
  • Drug receptor ? drug-receptor ? biologic
    effect
  • Receptors have specificity, they bind a
    specifically shaped molecule (or part of a
    molecule) but this specificity is not absolute.
    The binding of ligand to receptor results in some
    change within the cell (transduction). The
    consequences of these changes (or lack of
    changes) results in the pharmacologic effect of
    the drug.

14
Receptor Desensitization
  • To protect the cell from potential damage from
    extensive stimulation receptors are desensitized
    so that more ligand is required for the same
    response (tachyphylaxis).
  • One mechanism involves receptor mediated
    endocytosis of chronically activated receptors
    endocytosed receptors may be degraded or recycled
    to the cell membrane after a delay (insulin).
  • Graded dose response
  • As the drugs concentration increases the
    magnitude of the pharmacologic effect increases.
    The relationship between dose and response is
    continuous more drug ? more response.
  • Eventually a plateau is attained when
  • 1. All receptors are occupied
  • 2. For receptors with a large spare population
    maximal cellular response is attained.

15
  • 1. Potency This measures the amount of drug
    necessary to produce an effect of a given
    magnitude. A significant contributing factor to
    potency is the affinity of a drug for the
    receptor.
  • 2. Efficacy This is dependent on the number of
    drug-receptor complexes formed and the efficiency
    of coupling of receptor activation to cellular
    response. The maximal effect is greater for more
    efficacious drugs

16
  • Agonists bind to a receptor and produces a
    biologic effect that mimics the response of the
    endogenous ligand.
  • Antagonists antagonists bind to the same
    receptor as agonists but are unable to elicit
    transduction. This binding occupies the receptor
    preventing the binding of the endogenous ligand
    or agonists thus blocking the drugs effect
    (binding may be at the natural ligand binding
    site or a different site).
  • Competitive inhibition When agonists bind
    reversibly
  • Noncompetitive inhibition binding to a
    non-agonist site that blocks agonist activity
  • Uncompetitive Irreversible binding (rare)
  • Functional (Physiologic) antagonism When a drug
    binds to a separate receptor but the response
    opposes the response to an agonist (Epinephrine
    bronchial ß2 receptors histamine bronchial H1
    histamine receptors

17
  • A) Therapeutic Index The therapeutic index of a
    drug is the ratio of the dose that produces
    toxicity to the dose that produces the desired
    response
  • Therapeutic Index TD50/ED50
  • TD50 toxic dose in 50 of patients
  • ED50 effective dose in 50 of patients
  • The therapeutic index is a sign of a drugs safety

18
Kinetics of Drug Metabolism
  • 1st Order Kinetics
  • The rate of drug metabolism is proportional to
    the concentration of free drug, a constant
    fraction is metabolized per unit time
  • Zero-order kinetics
  • A few drugs (ASA, ETOH, Phenytoin) saturate their
    catabolic pathways at therapeutic levels. Their
    rate of elimination is constant and t1/2 is
    dependent on drug concentration

19
Botanicals
  • Echinacea (E. purpurea)
  • May decrease the incidence /or duration of URI
    symptoms when used prophylactically or with early
    symptoms.
  • Caution indicated when used by those with hyper-
    or hypo- immune function.
  • Garlic (Allium sativum)
  • Active agent is alliin, converted to allicin
    when clove is disrupted (allinase).
  • Allicin spontaneously degrades to diallyl
    disulfide compounds, these are heat labile.
  • Cardiovascular effects
  • 5 reduction in total cholesterol (HMG-CoA
    reductase inhibition)
  • Decreased atherosclerotic plaque volume
  • Decreased SBP DBP
  • Anti-platelet effects
  • Ginkgo (Ginkgo biloba)
  • Some protective effect in animal models of
    ischemia
  • Increased pain-free walking in mild-moderate PVD
  • No effect in preventing the onset of Alzheimers
    disease in a large RPCT.

20
  • Milk Thistle (Silybum marianum)
  • Silymarins (silybin, silychristin, silydianin)
  • In animal models it limits hepatotoxicity from a
    variety of toxins
  • Anti-neoplastic effects in-vitro in some human
    tumor cell lines.
  • St. Johns Wort (Hypericium perforatum)
  • Hypericin, hyperforin
  • In-vitro causes reuptake inhibition for 5-HT, NE
    DA.
  • Efficacious in mild to moderate depression,
    concerns over self treatment. Combined with
    prescription reuptake inhibitors may cause
    adverse effects.
  • Induces photosensitivity in some.
  • Saw Palmetto
  • 5a-reductase inhibitor (blocks testosterone ?
    DHT)
  • More effective than placebo for symptoms of mild
    to moderate BPH symptoms.
  • Does not interfere with PSA monitoring.

21
Heavy Metals
  • Arsenic
  • Natural contaminant of drinking water
  • Organic arsenic found in seafood is easily
    excreted and has minimal toxic potential.
  • Wood preservatives may be a common source (dont
    make picnic tables with pressure treated wood).
  • Impairs cellular respiration
  • Pathognomonic skin changes in subacute
    chronic exposure
  • Encephalopathy, respiratory failure, ARF, CV
    instability
  • Lead
  • CDC recommends universal screening, average
    levels decreasing
  • Pediatric sensitivity normochromic normocytic
    anemia, encephalopathy, cognitive dysfunction, GI
    symptoms, renal disease
  • Reproductive fertility issues.
  • Mercury
  • 3 types
  • Elemental quicksilver, inhalation, flu-like
    symptoms, erethism, Parkinsonian symptoms.
  • Inorganic batteries, corrosive, absorbed across
    the GI tract, GI symptoms, ARF, erethism, CV
    collapse

22
  • Organic seafood, recommended limited intake of
    certain sea food in pregnant, lactating women and
    children. CNS effects, maternal exposure
    producing CP-like syndrome, seizures, MR.
  • Cadmium (Zinc)
  • Absent in neonates (does not cross placenta and
    not excreted in breast milk)
  • BBB intact to Cd no encephalopathy
  • Stored in kidney, liver and testis
  • Sources
  • Cigarettes 1º 2º smoke
  • Cereal grains from herbicides, concentrated in
    the germ
  • Root vegetables
  • Water pipes leached by soft water
  • Acts like zinc
  • Enzyme cofactors
  • Produces free radicals
  • Acute exposure URI
  • Chronic exposure- renal hypertension, renal
    lithiasis leading to renal failure

23
Air Pollutants
  • Byproducts of the incomplete combustion of
    hydrocarbon fuels or contaminants
  • Implicated in the etiology of respiratory
    diseases, cancer, CV disorders
  • Pre-existing respiratory CV disorders increase
    risk
  • Synergy in effects among agents
  • CO
  • Binds to Hgb gt200 X O2
  • Red dead
  • HA, N, V (flu-like syndrome), confusion,
    decreased VA, CV instability, coma seizure,
    death.
  • Delayed encephalopathic effects which may not
    remit.
  • Higher metabolic rate indicates greater
    sensitivity (kids and pets).
  • Hyperbaric oxygen chamber for CNS or CV symptoms,
    gt25 COHgb
  • Sulfur Dioxide
  • Sulfur dioxide forms sulfurous acid on contact
    with moist membranes
  • Irritant, most deleterious in upper airway,
    bronchospasm

24
  • Nitrogen oxides
  • Deep lung irritant, pulmonary edema acutely
    followed by pulmonary fibrosis of bronchioles.
  • Ozone
  • Mucous membrane and lung irritant.
  • Produces free radicals
  • Direct and secondary lung injury resulting in
    chronic bronchitis, bronchioloits and emphysema.
  • Particulate matter
  • Most important predictor of the type severity
    of pathology related to particle size smaller
    size tends to be more injurious.
  • Cyanide
  • HCN is a common product of combustion of
    plastics/petrochemical polymers.
  • Impairs cytochrome oxidase function leading to
    cellular hypoxia
  • CO cyanide concomitant exposure is common,
    suspect in CO poisoning that does not respond
    to 100 oxygen.

25
  • Hydrogen Sulfide
  • Rotten egg smell, rapid onset olfactory fatigue
  • Upper airway pulmonary irritant
  • Natural sources
  • Cytochrome oxidase inhibitor
  • Knockdown effect, single breath at 750-1000ppm
    can cause unconsciousness and respiratory
    depression.
  • Chloramine
  • Bleach ammonia combination
  • Contact with mucous membranes produces
    hypochlorous acid, ammonia gas and oxygen free
    radicals.
  • Pulmonary irritation, fatalities have resulted
    from exposures in enclosed areas (BRs).

26
Pesticides
  • Organochlorine pesticides- block axonal
    transmission via Na channels
  • Organophosphates and carbamates block synaptic
    transmission through Achesterase inhibition.
  • OCs- DDT, lipid soluble, Cl stabilizes
  • Banned in 1st world, used in 3rd world
    (effective, safe, cheap)
  • OPs carbamates
  • Lower ecological toxicity, higher human toxicity
  • Reversible Achesterase inhibition (Ops age)
  • OP Carbamate Exposure
  • SLUDGE plus cramps, fasiculations and seizures if
    severe death

27
Ethanol
  • Peak plasma levels 30 minutes after ingestion
    (binge risk)
  • 90 metabolized in liver
  • Metabolic pathway is usually saturated
    (zero-order kinetics)

1. Alcohol dehydrogenase liver, brain stomach
(gt in ?), excess NADH promotes liver damage. 2.
MEOS Cytochrome P450 isoenzyme, inducible,
produces tolerance, excess NADPH promotes liver
damage, promotes metabolism of other drugs. 3.
Aldehyde dehydrogenase inhibited by disulfiram.
28
  • Effects of ETOH
  • Acute
  • CNS Low dose-disinhibition, anxiolytic, impaired
    judgment
  • Moderate dose-dysarthria, dyscoordination
  • High dose-emesis, stupor, coma, respiratory
    depression, death
  • Cardiac ? contractility
  • Smooth muscle relaxation, vasodilatation
  • Chronic
  • Liver GI Oxidative stress (?ed reducing
    equivalents), cirrhosis, steatosis, hepatitis,
    pancreatitis
  • CNS Withdrawal (agitation, seizures, DTs)
  • Toxicity- distal neuropathy, ataxia, dementia,
    demyelination
  • Cardiovascular
  • Cardiomyopathy- most common non-ischemic cause,
    blocks effects of therapeutic agents
  • Arrthymias- associated with intoxication
    (especially binge) withdrawal
  • Hypertension- 5 of hypertensives, the most
    common remediable cause
  • Anemia nutritional deficiency, chronic GI loss
  • Electrolyte abnormalities

29
  • FAS- IUGR, microcephaly, impaired intellect,
    facial malformations, jt. abnormalities. FAE-
    cognitive impairment (mild-severe) appears dose
    dependent.
  • Immune System- increased in liver pancreas,
    decreased in lung and gut
  • Carcinogenesis
  • ETOH-Drug interactions
  • CNS depressants synergistic (BZDs)
  • Hepatic metabolism (P450 induction, inhibition)
  • ETOH in common OTCs
  • Cough cold preparations (5-10)
  • Mouthwashes (Listerine has 27)
  • Flavor extracts contain 10-35 ethanol

30
Toxic Alcohols
  • Methanol-sterno, windshield washing fluid
  • Same metabolic pathway as ETOH, toxic agent is
    formic acid (characteristic visual obscuration
    snow storm, bradycardia, acidosis, seizures,
    coma).
  • Ethylene glycol- antifreeze, wine adulterant
  • Initial metabolism the same as ETOH, major toxic
    agent is oxalic acid forms Calcium oxalate in
    renal tubules leading to renal failure.
  • Treatment Alcohol dehydrogenase has a higher
    affinity for ETOH, toxic agents produced are
    adequately handled in small amounts. Fomepizole
    blocks alcohol dehydrogenase.

31
Spiders, Snakes Animal Toxins
  • Snake bites- not all bites of venomous snakes
    inject venom
  • Pit Vipers- rattle snakes, cotton mouth,
  • Local damage- proteolytic enzymes,
    anti-coagulants
  • Pain local damage, can have systemic effects
    (small body mass), rhabdomyolysis, renal failure,
    resp. distress, coagulopathy
  • Coral Snakes
  • Neurotoxin (paresthesias, weakness, CN
    abnormalities, fasiculations, lethargy,
    respiratory paralysis, death)
  • Often mild local findings
  • Beware of dead snakes

32
  • Spiders
  • Loxosceles-bite usually involves crushing the
    spider
  • Digestion externale (local necrosis, hemolysis,
    coagulopathy, mirco-thrombosis
  • Immediate local response may progress to local
    tissue necrosis over several days, may mimic 3rd
    degree burn, decubitis ulcer
  • Lactrodectus-
  • Potent neurotoxin causes uncontrolled release of
    Ach NE
  • Often minor local reaction
  • NM symptoms 30 min 6 hrs
  • Local muscle spasm, cramps, fasiculations,
    weakness, hypertension

33
Fish Toxins
  • Ciguatera Fish Poisoning (Ciguatera toxin)
  • The most common nonbacterial fish-borne
    poisoning Gambierdiscus toxicus is the
    dynoflagellate responsible for producing
    ciguatera toxin.
  • Sources
  • Amberjack, barracuda, dolphin fish, grouper, sea
    bass, sturgeon fish, eel, red snapper, Spanish
    mackerel.
  • Toxicity This toxin is heat stable and
    unaffected by cooking temperature or stomach
    acid. It is lipid soluble and does not affect
    taste, color or odor of the fish. Larger fish
    tend to have larger toxin loads.
  • The mechanism involves direct stimulation of
    voltage gated Ca2 channels, phospholipase C and
    nonselective cation channels.
  • The toxin exhibits both bioaccumulation
    biomagnification
  • Presentation
  • Onset of symptoms 1 hour -3 days after ingestion,
    neurologic symptoms may persist for months.
  • GI, arthralgia, myalgia, vertigo, CN palsies,
    hallucinations, seizures, coma.
  • CV instability (?HR, ?BP, arrhythmias)
  • Resp. bronchospasm, respiratory failure

34
Fish Toxins
  • Scrombroid Fish Poisoning (Scombrotoxin)
  • Dark meat fish (high levels of histadine) tuna,
    mahi-mahi, bluefish, sardines
  • Normal bacterial flora allowed to grow by
    improper storage convert histadine to histamine.
    Consumption of histamine results in mild
    systemic reaction (flushing, angioedema,
    tachycardia, HA, N, V, may induce
    bronchoconstrictive effect.
  • Responds to antihistamines
  • Tetrodotoxin
  • Puffer fish (fugu)
  • Impairs axonal and synaptic transmission
  • Perioral paresthesias, muscular paralysis,
    respiratory paralysis, death
  • No antitoxin

35
  • Angina
  • Stable
  • Unstable
  • Variant (Prinzmetal) angina
  • Anti-anginal drugs
  • Organic nitrates (NTG, Isosorbide dinitrate,
    etc.)
  • Mechanism
  • ? venous tone (? preload)
  • ? arterial tone (?afterload)
  • 1 2 result in ? O2 demand
  • Coronary artery vasodilation
  • Tolerance develops rapidly
  • Side effects
  • Sublingual NTG should cause a headache (if not
    its not dilating)
  • Potentially bad combination with ED drugs
    (Viagra, Cialis, etc.)

36
  • Beta- Blockers (block beta-adrenergic receptors)
  • Beta 1-antagonists
  • Mechanism
  • ? HR
  • ?contractility
  • ? PVR
  • Lack of selectivity (ß1 vs. ß2, big problem for
    asthmatics)
  • Abrupt withdrawal creates big problems
  • Ca2 Channel Blockers
  • Lower myocardial O2 demand by ? BP, ?CO ?
    contractility
  • Nice table on anti-anginals and concomitant
    diseases

37
  • Anti-hyperlipidemics
  • It is desirable to have low LDL, TG total
    cholesterol but a high HDL.
  • Cholesterol levels are determined by endogenous
    synthesis and dietary intake.
  • For any drug treatment to be successful it must
    be accompanied by dietary changes
  • Many cholesterol lowering drugs have secondary
    benefits.
  • Treatment options
  • Mild-moderate elevations ? lifestyle
    modifications
  • LDL gt 160 mg/dl with 1 ASCVD (atherosclerotic
    cardiovascular disease) risk factor ? drugs
  • LDL gt 130 mg/dl with 2 ASCVD risk factors ? drugs
  • Hypertriglyceridemia
  • Niacin
  • Fibric acid derivatives
  • Anti-lipoprotein therapy
  • ? lipoprotein production (these carry TG
    cholesterol)
  • ? lipoprotein degradation
  • ? cholesterol absorption (ezetimibe)
  • ? cholesterol excretion (bile acid binding resins)

38
  • STATINS HMG CoA reductase inhibitors
  • Lower cholesterol levels
  • Stabilize atherosclerotic plaques
  • Improve coronary endothelial function
  • Inhibit platelet thrombus formation
  • Anti-inflammatory
  • Recommended for
  • Patients with CAD without hyperlipidemia
  • Men with CAD
  • Patients with average cholesterol levels without
    known CAD
  • Adverse reactions are rare but serious
  • Many of the beneficial effects are independent of
    lower cholesterol levels

39
  • Anti-hypertensives
  • Lowering BP prevents vascular damage associated
    with high BP, and the sequelae of that vascular
    damage.
  • ? BP is asymptomatic until a complication (MI,
    stroke, renal failure, etc,) develops.
  • 1/3rd of known ?BP is poorly controlled.
  • Diuretics
  • Short term ? in intravascular volume (this may
    even increase BP)
  • Long term ? in PVR
  • Thiazides- ? Na reabsorption,
  • Loop diuretics- ? Na, K Cl- reabsorption,
    function via renal PG synthesis
  • K sparing diuretics

40
  • ß-Blockers
  • ?BP by ?CO (?hr ?contractility) and ?CNS
    sympathetic output (? rennin release
    ?aldosterone release).
  • ß1 selective blockers best at ?BP without side
    effects of ß2 blockade (bronchiole smooth muscle
    contraction)
  • All ß-Blockers bind to both 12 receptors to some
    extent ß1 agents loose their selectivity as
    their dose increases.
  • Acute withdrawal of ß-Blockers can be fatal.
  • Ca2 Channel Blockers Second line therapy for
    most hypertensives unless there is some
    mitigating circumstance that precludes ß-Blocker
    use (asthma, DM, PVD, angina) but these are
    negative inotropes just like ß-Blockers.

41
  • ACE-inhibitors
  • Block angiotensin I ? angiotensin II conversion
  • Angiotensin II causes
  • Vasoconstriction
  • Aldosterone secretion
  • ADH secretion
  • Thirst
  • Direct Na and water retention
  • These agents also block degradation of bradykinin
  • Angiotensin II receptor blockers block all 2
    above but not 3

42
Anxiolytics Hypnotics
  • All anti-anxiety agents have sedative properties,
    many are anti-convulsants. Short acting agents
    produce anterograde amnesia.
  • BZDs (benzodiazepines)
  • Open GABA receptor Cl- channels (? Cl- entry)
    hyperpolarization of the neuron inhibits action
    potential generation
  • a2 GABA receptor agonists produce antianxiety
    effects muscle relaxant effects (via action at
    spinal cord level)
  • a1 GABA receptor agonists produce sedation,
    amnesia and anticonvulsant effects
  • BZDs used for insomnia tend to lack active
    metabolites (except flurazepam (Dalmane)). Why?
  • Tolerance dependence develop quickly to BZDs.
  • Withdrawal syndrome
  • Very safe, fatal overdoses always involve a
    combination with another CNS depressant (ETOH,
    Barbiturates, Narcotics, etc.) The safety of
    BZDs compared to barbiturates has eliminated
    barbiturate use except for seizures.

43
  • Non-BZD agents used for hypnotic effects, all
    have short t1/2
  • Ambien
  • Sonata
  • Lunesta the only sedative shown to be effective
    for 6 months, others create tolerance after 2
    weeks and become ineffective for insomnia.
  • BZD Antagonist
  • Flumazenil reverses all BZD effects, very short
    t1/2 so treatment of overdose may require
    multiple administrations. This agent will produce
    an acute withdrawal syndrome

44
  • Insulin Oral hypoglycemics
  • DM complications
  • Macrovascular PVD, CAD, Cerebrovascular
    disease
  • Microvascular Neuropathy, Nephropathy,
    Retinopathy
  • Strict control (Glucose 120-150) is associated
    with more frequent hypoglycemic episodes but
    clearly significantly delays the onset severity
    of DM complications.
  • Insulin release ? glucose ? ? ATP ? Blocks K
    leak from cell ? Cell depolarizes? Ca2 influx ?
    Insulin release from vesicles and ? insulin
    production
  • Insulin The goal of insulin therapy is to mimic
    both the basal and post-prandial release of
    insulin this requires insulins with variable
    onsets and durations of effect.

45
  • Oral Hypoglycemics
  • Insulin sensitizers Biguanides (Metformin)
  • Insulin secretogogues
  • Sulfonylureas (tolbutamide, glyburide, glypizide)
  • Meglitinide analogues
  • Glycosidase inhibitors block carbohydrate
    degradation in the gut so slows decreases
    absorption, obvious side effects. Acarbose.
  • Incretin therapy (Januvia) a new approach
  • Peptide hormones released into the gut lumen when
    carbohydrate is consumed stimulate the release of
    insulin and block glucagon release, this is why
    oral glucose raises blood glucose levels faster
    than IV glucose.
  • Januvia blocks the enzyme that degrades incretins
    in the gut so they have a longer duration of
    action.

46
  • Anti-inflammatory Agents
  • Role of prostaglandins in normal and abnormal
    function.
  • Aspirin as a prototype
  • NSAIDs have fewer common side effects
  • COX-1 COX-2 enzymes
  • COX-1 COX-2 inhibitors

47
  • Just say know?
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