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

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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.

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• 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.

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• 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
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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.

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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.

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• 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

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• 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

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• 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

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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

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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.

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• 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.

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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

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• 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

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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

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• 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.

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• 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).

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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

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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.
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• 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

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• 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

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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.

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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

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• 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

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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

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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

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• 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.)

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• 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

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• 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)

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• 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

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• 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

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• 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.

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• 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

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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.

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• 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

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• 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.

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• 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?