Marc Imhotep Cray, M.D.                                BASIC PHARMACOLOGY:                 Pharmacokinetics and Pharmacody...
Marc Imhotep Cray, M.D.                          ( pKa : negative log of the ionization constant and is                   ...
Marc Imhotep Cray, M.D.      DRUG PERMEATION:             Partition Coefficient: The ratio of lipid solubility to aqueous...
Marc Imhotep Cray, M.D.      Routes of Administration:             ORAL                                                 ...
Marc Imhotep Cray, M.D.             Sites of Concentration: They can affect the Volume of              Distribution      ...
Marc Imhotep Cray, M.D.    Apparent          Apparent        #Liters % Total             Example,    Vd                   ...
Marc Imhotep Cray, M.D.             Enterohepatic Circulation: Drugs that are recycled through the              enterohep...
Marc Imhotep Cray, M.D.      PLASMA PROTEIN BINDING: Two main plasma proteins carry drugs      in the blood.              ...
Marc Imhotep Cray, M.D.                                      REDUCTIVE REACTIONS: Azo, Nitrile,                          ...
Marc Imhotep Cray, M.D.                                                  Glucocorticoids induce CYT-P450-3A4             ...
Marc Imhotep Cray, M.D.                                                  Penicillin-G is excreted by                     ...
Marc Imhotep Cray, M.D.                                         Cationic Transporter: Transports                         ...
Marc Imhotep Cray, M.D.                                               A plot of the log[conc] -vs- time                  ...
Marc Imhotep Cray, M.D.                                                     which is dependent on the                     ...
Marc Imhotep Cray, M.D.                                                                         Drug clearance of 660 ml/...
Marc Imhotep Cray, M.D.                                         There are no fluctuations with continuous                ...
Marc Imhotep Cray, M.D.                             : Dosage interval. The shorter the dosage      interval, the higher th...
Marc Imhotep Cray, M.D.                                       RENAL DISEASE: Renal disease means the drug is not cleared...
Marc Imhotep Cray, M.D.                                                    ClCr =Creatinine clearance of patient, and nor...
Marc Imhotep Cray, M.D.                                                                       beta-Arrestin Kinase (betaA...
Marc Imhotep Cray, M.D.             (E) NITRIC OXIDE:                      NO-Synthases:                               ...
Marc Imhotep Cray, M.D.                                    damage (free radicals) to neuron --->                          ...
Marc Imhotep Cray, M.D.      DOSE-RESPONSE CURVES:             Definitions:                        Affinity: A measure o...
Marc Imhotep Cray, M.D.             THERAPEUTIC INDEX = LD50 / ED50                    The ratio of median lethal dose t...
Marc Imhotep Cray, M.D.                                       The Emax does not change: maximum                          ...
Marc Imhotep Cray, M.D.      ADVERSE EFFECTS:             Drug Toxicity: Dose-dependent adverse response to a drug.      ...
Marc Imhotep Cray, M.D.                                     reproductive cancers in daughters born to                     ...
Marc Imhotep Cray, M.D.                             Alcohol can lead to facial flushing, or Tolbutamide                  ...
Marc Imhotep Cray, M.D.             Pharmacodynamic Tolerance: Cellular tolerance, due to down-              regulation o...
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IVMS BASIC PHARMACOLOGY-General Principles, Pharmacokinetics and Pharmacodynamics Notes

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IVMS BASIC PHARMACOLOGY-General Principles, Pharmacokinetics and Pharmacodynamics Notes

  1. 1. Marc Imhotep Cray, M.D. BASIC PHARMACOLOGY: Pharmacokinetics and Pharmacodynamics PHARMACOKINETICS: what the body does to the drug PHARMACODYNAMICS: Study of what a drug does to the body ------------------------------------------------------------------------------------ HENDERSON-HESSELBACH EQUATION:  Weak Acid  pKa:  If its pKa < pH of the environment, then the conjugate base (anion) form of the species will predominate. Example = CH3COO-  If its pKa > pH of the environment, then the environment is more acidic, so its acidic (neutral) form will predominate. Example = CH3COOH  Weak acids tend to be absorbed in acidic environments, like the stomach.  Weak Base  pKa  If its pKa < pH of the environment, then the environment is more basic, so the species will remain in the neutral form. Example = NH3  If its pKa > pH of the environment, then the environment is more acidic, so it will give up its extra H+ to the base, and the base will exist in its cation form. Example = NH4+  Weak bases tend to be absorbed in basic environments, like the duodenum. Pharmacokinetics and Pharmacodynamics Page 1
  2. 2. Marc Imhotep Cray, M.D. ( pKa : negative log of the ionization constant and is equal to the pH at which a drug is 50 % ionized.)  Weak acids become highly ionized as pH increases,weak bases become highly ionized as pH decreases Pharmacokinetics and Pharmacodynamics Page 2
  3. 3. Marc Imhotep Cray, M.D. DRUG PERMEATION:  Partition Coefficient: The ratio of lipid solubility to aqueous solubility. The higher the partition coefficient, the more membrane soluble is the substance.  Kidney Glomeruli have the largest pores through which drugs can pass ------> drug filtration.  Blood Brain Barrier (BBB): Only lipid-soluble compounds get through the BBB.  Four components to the blood-brain barrier: 1. Tight Junctions in brain capillaries 2. Glial cell foot processes wrap around the capillaries 3. Low CSF protein concentration --> no oncotic pressure for reabsorbing protein out of the plasma. 4. Endothelial cells in the brain contain enzymes that metabolize, neutralize, many drugs before they access the CSF.  MAO and COMT are found in brain endothelial cells. They metabolize Dopamine before it reaches the CSF, thus we must give L-DOPA in order to get dopamine to the CSF.  Exceptions to the BBB. Certain parts of the brain are not protected by the BBB:  Pituitary, Median Eminence  Supraventricular areas  Parts of hypothalamus Meningitis: It opens up the blood brain barrier, due to edema. Thus Penicillin-G can be used to treat meningitis, despite the fact that it doesnt normally cross the BBB. Penicillin-G is also actively pumped back out of the brain once it has crossed the BBB. Pharmacokinetics and Pharmacodynamics Page 3
  4. 4. Marc Imhotep Cray, M.D. Routes of Administration:  ORAL  FIRST-PASS EFFECT: Alteration of drugs in liver via portal circulation. Some drugs have a high first-pass effect and thus a lower bioavailability. Know these:  Morphine  Imipramine  Propanolol  Gastric Emptying: Generally, anything that slows gastric emptying will slow the absorption of drugs.  Things that slow gastric emptying: Fats, acidic pH, bulk, anticholinergics, hypothyroidism, Al(OH)3  Faster gastric emptying is beneficial for the absorption of most drugs  Tetracycline chelates calcium and should therefore not be given with milk.  TOPICAL: Lipophilic drugs absorbed through skin.  Examples: Nicotine patch, nitroglycerine, scopolamine = for motion-sickness. VOLUME OF DISTRIBUTION: The apparent amount of volume that a drug seems to distribute to.  Pharmacokinetics and Pharmacodynamics Page 4
  5. 5. Marc Imhotep Cray, M.D.  Sites of Concentration: They can affect the Volume of Distribution  FAT: Drug concentrates in fat --> lower concentration of drug in the plasma --> high Vd  BONE: Drug concentrates in bone --> lower concentration of drug in the plasma --> high Vd  TISSUE: Drug concentrates in tissue--> lower concentration of drug in the plasma--> high Vd  PLASMA PROTEINS: Drug binds to plasma protein -- > higher concentration of drug in the plasma ---> low Vd.  The Vd is based on the total amount of drug in the plasma (not just the amount of free drug)  TRANSCELLULAR: Drug concentrates in non- plasma locations --> lower concentration of drug in the plasma --> high Vd  Pharmacokinetics and Pharmacodynamics Page 5
  6. 6. Marc Imhotep Cray, M.D. Apparent Apparent #Liters % Total Example, Vd Vd in 70kg Body Explanation man Weight (L / kg) Plasma 0.045 3L 4.5% Plasma-Protein-bound Water L/kg drugs, and large drugs that stay in plasma. Concentrates in blood and thus has a small Vd. Example = Heparin Extracellular 0.2 14 L 20% Large water soluble Water L/kg drugs. Example = Mannitol Total Body 0.6 42 L 60% Small water soluble Water L/kg drugs; rapid equilibration between body compartments. Example = Ethanol Tissue >0.7 L/kg >42 L ----- Drugs that bind to tissue Concentration Example = chloroquine, which intercalates with DNA intracellularly. Vd may be greater than TBW volume, hence some drug must be bound to plasma. This is very common and occurs with many drugs. Pharmacokinetics and Pharmacodynamics Page 6
  7. 7. Marc Imhotep Cray, M.D.  Enterohepatic Circulation: Drugs that are recycled through the enterohepatic circulation will have a lower concentration of drug in the plasma, and therefore a higher V d. Pharmacokinetics and Pharmacodynamics Page 7
  8. 8. Marc Imhotep Cray, M.D. PLASMA PROTEIN BINDING: Two main plasma proteins carry drugs in the blood. alpha1-Acid Glycoprotein ALBUMIN OROSOMUCOID Negatively Charged, hence it Positively Charged, hence it binds primarily to weak binds primarily to weak acids. bases. Negative acute-phase Positive acute-phase protein: its synthesis protein: its synthesis decreases during time of increases during times of body insult. body insult. Examples: Phenytoin, Examples: Quinidine, Salicylates Propanolol BIOTRANSFORMATION: Alteration of drugs by the liver. Drugs can be metabolized from active to inactive, or from inactive to active. Generally drugs are made more hydrophilic by the process.  PHASE I: Mixed-Function Oxidases, formed by microsomes made out of SER folded over on itself.  Cytochrome-P450 Enzyme Complex: Has four required components in order to work.  Cytochrome-P450 Enzyme  Cytochrome-P450 Reductase  O2  NADPH: NADPH is the only energy source. No ATP is required!  Phase I enzymes perform multiple types of reactions:  OXIDATIVE REACTIONS: on drugs, such as Aromatic hydroxylation, aliphatic hydroxylation, N-dealkylation, O- dealkylation, S-dealkylation, N-Oxidation, S-Oxidation, Desulfuration. Pharmacokinetics and Pharmacodynamics Page 8
  9. 9. Marc Imhotep Cray, M.D.  REDUCTIVE REACTIONS: Azo, Nitrile, Carbamyl  HYDROLYTIC REACTIONS: Ester hydrolysis, Amide hydrolysis.  PHASE II: Drug Conjugation. usually to glucuronides, making the drug more soluble. CYTOCHROME-P450 COMPLEX:  There are multiple isotypes.  CYT-P450-2 and CYT-P450-3A are responsible for the metabolism of most drugs.  CYT-P450-3A4 metabolizes many drugs in the GI- Tract, where it decreases the bioavailability of many orally absorbed drugs.  INDUCERS of CYT-P450 COMPLEX: Drugs that increase the production of Cyt-P450 enzymes.  ANTICONVULSANTS:Phenobarbitol,Phenytoin,Ca rbamazepine induce CYT-P450-3A4  Phenobarbitol, Phenytoin also induce CYT-P450- 2B1  Polycyclic Aromatics (PAH): Induce CYT-P450- 1A1 Pharmacokinetics and Pharmacodynamics Page 9
  10. 10. Marc Imhotep Cray, M.D.  Glucocorticoids induce CYT-P450-3A4  Chronic Alcohol, Isoniazid induce CYT-P450-2E1. This is important as this drug activates some carcinogens such as Nitrosamines.  Chronic alcoholics have up-regulated many of their CYT-P450 enzymes.  INHIBITORS of CYT-P450 COMPLEX: Drugs that inhibit the production of Cyt-P450 enzymes.  Acute Alcohol suppresses many of the CYT-P450 enzymes, explaining some of the drug-interactions of acute alcohol use.  Erythromycin, Ketanazole inhibit CYT-P450-3A4.  Terfenadine (Seldane) is metabolized by CYT-P450-3A4, so the toxic unmetabolized form builds up in the presence of Erythromycin. The unmetabolized form is toxic and causes lethal arrhythmias. This is why Seldane was taken off the market.  Chloramphenicol, Cimetidine, Disulfiram also inhibit CYT-P450s. EXCRETION:  KIDNEY  GLOMERULAR FILTRATION: Clearance of the apparent volume of distribution by passive filtration.  Drug with MW < 5000 ------> it is completely filtered.  Inulin is completely filtered, and its clearance can be measured to estimate Glomerular Filtration Rate (GFR).  TUBULAR SECRETION: Active secretion.  Specific Compounds that are secreted:  para-Amino Hippurate (PAH) is completely secreted, so its clearance can be measured to estimate Renal Blood Flow (RBF). Pharmacokinetics and Pharmacodynamics Page 10
  11. 11. Marc Imhotep Cray, M.D.  Penicillin-G is excreted by active secretion. Probenecid can be given to block this secretion.  Anionic System: The anionic secretory system generally secretes weak ACIDS:  Penicillins, Cephalosporins  Salicylates  Thiazide Diuretics  Glucuronide conjugates  Cationic System: The cationic secretory system generally secretes BASES, or things that are positively charged.  Ion-Trapping: Drugs can be "trapped" in the urine, and their rate of elimination can be increased, by adjusting the pH of the urine to accommodate the drug. This is useful to make the body get rid of poisons more quickly.  To increase excretion of acidic drugs, make the urine more basic (give HCO3-)  To increase excretion of basic drugs, make the urine more acidic.  BILIARY EXCRETION: Some drugs are actively secreted in the biliary tract and excreted in the feces. Some of the drug may be reabsorbed via the enterohepatic circulation.  Transporters: The liver actively transporters generally large compounds (MW > 300), or positive, negative, or neutral charge.  Anionic Transporter: Transports some acids, such as Bile Acids, Bilirubin Glucuronides, Glucuronide conjugates, Sulfobromophthalein, Penicillins  Neutral Transporter: Transports lipophilic agents, such as:  Steroids  Ouabain Pharmacokinetics and Pharmacodynamics Page 11
  12. 12. Marc Imhotep Cray, M.D.  Cationic Transporter: Transports positively charged agents, such as n- Methylnicotinamide, tubocurarine.  Charcoal can be given to increase the fecal excretion of these drugs and prevent enterohepatic reabsorption.  Cholestyramine can be given to increase the rate of biliary excretion of some drugs. PHARMACOKINETICS: what the body does to the drug  ORDERS of EXCRETION:  ZERO-ORDER EXCRETION: The rate of excretion of a drug is independent of its concentration.  General properties:  dC/dt = -K  A plot of the drug-concentration -vs- time is linear.  The half-life of the drug becomes continually shorter as the drug is excreted.  Examples:  Ethanol is zero-order in moderate quantities, because the metabolism system is saturated. The rate of metabolism remains the same no matter what the concentration.  Phenytoin and Salicylates follow zero-order kinetic at high concentration.  FIRST-ORDER EXCRETION: The rate of excretion of a drug is directly proportional to its concentration.  General properties:  dC/dt = -K[C] Pharmacokinetics and Pharmacodynamics Page 12
  13. 13. Marc Imhotep Cray, M.D.  A plot of the log[conc] -vs- time is linear. slope of the line = -Kel / 2.303  The half-life of the drug remains constant throughout its excretion Equation:  HALF-LIFE: The half-life is inversely proportional to the Kel, constant of elimination. The higher the elimination constant, the shorter the half-life.   COMPARTMENTS:  One-Compartment Kinetics: Kinetics are calculated based on the assumption that the drug is distributed to one uniform compartment.  One compartment kinetics implies that the drug has a rapid equilibrium between tissues and the blood, and that the release of the drug from any tissues is not rate- limiting in its excretion.  One-compartment kinetics also assumes that the drug is distributed instantaneously throughout the body. This is only true for IV infusion.  Multi-Compartment Kinetics: Most drugs follow multi-compartment kinetics to an extent.  Biphasic Elimination Curve: Many drugs follow a biphasic elimination curve -- first a steep slope then a shallow slope.  STEEP (initial) part of curve --- > initial distribution of the drug in the body.  SHALLOW part of curve ---> ultimate renal excretion of drug, Pharmacokinetics and Pharmacodynamics Page 13
  14. 14. Marc Imhotep Cray, M.D. which is dependent on the release of the drug from tissue compartments into the blood.  CLEARANCE: The apparent volume of blood from which a drug is cleared per unit of time.  CLEARANCE OF DRUG = (Vd)x(Kel)  The higher the volume of distribution of the drug, the more rapid is its clearance.  The higher the elimination constant, the more rapid is its clearance.   This is based on the Dilution Principle:  (Conc)(Volume)=(Conc)(Volum e)  Total Amount=Total Amount  MEANING: In first-order kinetics, drug is cleared at a constant rate. A constant fraction of the V d is cleared per unit time. The higher the K el, the higher is that fraction of volume.  Drug Clearance of 120 ml/min --> drug is cleared at the same rate as GFR and is not reabsorbed. Example = inulin Pharmacokinetics and Pharmacodynamics Page 14
  15. 15. Marc Imhotep Cray, M.D.  Drug clearance of 660 ml/min --> drug is cleared at the same rate as RPF and is actively secreted, and not reabsorbed. Example = PAH  BIOAVAILABILITY: The proportion of orally-administered drug that reaches the target tissue and has activity.    AUCORAL = Area under the curve. The total amount of drug, through time, that has any activity when administered orally.  AUCIV = Area under curve. The total amount of drug, through time, that has any activity when administered IV. This is the maximum amount of drug that will have activity.  100% Bioavailability = A drug administered by IV infusion.  BIOEQUIVALENCE: In order for two drugs to be bioequivalent, they must have both the same bioavailability and the same plasma profile, i.e. the curve must have the same shape. That means they must have the same Cmax and Tmax.  Cmax: The maximum plasma concentration attained by a drug-administration.  Tmax: The time at which maximum concentration is reached.  REPETITIVE DOSES:  FLUCTUATIONS: Drug levels fluctuate as you give each dose. Several factors determine the degree to which drug levels fluctuate. Pharmacokinetics and Pharmacodynamics Page 15
  16. 16. Marc Imhotep Cray, M.D.  There are no fluctuations with continuous IV infusion.  Slow (more gradual) absorption also reduces fluctuations, making it seem more like it were continuous infusion.  The more frequent the dosing interval, the less the fluctuations. Theoretically, if you give the drug, say, once every 30 seconds, then it is almost like continuous IV infusion and there are no fluctuations.   Steady-State Concentration (CSS): The plasma concentration of the drug once it has reached steady state.  It takes 4 to 5 half-lives for a drug to reach the steady state, regardless of dosage.  After one half-life, you have attained 50% of CSS. After two half-lives, you have attained 75%, etc. Thus, after 4 or 5 half-lives, you have attained ~98% of CSS, which is close enough for practical purposes.  If a drug is dosed at the same interval as its half-life, then the CSS will be twice the C0 of the drug.  If you have a drug of dose 50 mg and a half-life of 12 hrs, and you dose it every 12 hrs, then the steady-state concentration you will achieve with that drug will be 100 mg/L.   D: Dose-amount. The higher the dose amount, the higher the Css. Pharmacokinetics and Pharmacodynamics Page 16
  17. 17. Marc Imhotep Cray, M.D. : Dosage interval. The shorter the dosage interval, the higher the Css  F: Availability Fraction. The higher the availability fraction, the higher the Css  Kel: Elimination Constant. The higher the elimination constant, the lower is the Css  Vd: Volume of Distribution. A high volume of distribution means were putting the drug into a large vessel, which means we should expect a low Css.  Cl: Clearance. The higher the drug-clearance, the lower the Css.   If you know the desired steady-state concentration and the availability fraction, then you can calculate the dosing rate.  LOADING DOSE: When a drug has a long half-life, this is a way to get to CSS much faster.  Loading Dose = twice the regular dose, as long as we are giving the drug at the same interval as the half-life.   INTRAVENOUS INFUSION: The CSS is equal to the input (infusion rate x volume of distribution) divided by the output (Kel)   R0 = the rate of infusion.  Vd = the volume of distribution, which should be equal to plasma volume, or 3.15L, or 4.5% of TBW.  Kel = Elimination Constant  Loading Dose in this case is just equal to Volume of distribution time the Css : Pharmacokinetics and Pharmacodynamics Page 17
  18. 18. Marc Imhotep Cray, M.D.   RENAL DISEASE: Renal disease means the drug is not cleared as quickly ---> the drug will have a higher CSS---> we should adjust the dose downward to accommodate for the slower clearance.  If the fraction of renal clearance is 100% (i.e. the drug is cleared only by the kidneys), then you decrease the dosage by the same amount the clearance is decreased.  For example: If you have only 60% of renal function remaining, then you give only 60% of the original dose.  If the fraction of renal clearance is less then 100%, then multiply that fraction by the percent of renal function remaining.  For example: If you have only 60% of renal function remaining, and 30% of the drug is cleared by the kidney, then the dose adjustment = (60%)(30%) = 20%. The dose should be adjusted 20%, or you should give 80% of the original dose.  G =The percentage of the original dose that we should give the patient. If G = 60%, then we should give the patient 60% of the original dose.  f =The fraction of the drug that is cleared by the kidney. If f is 100%, then the drug is cleared only by the kidney. Pharmacokinetics and Pharmacodynamics Page 18
  19. 19. Marc Imhotep Cray, M.D.  ClCr =Creatinine clearance of patient, and normal clearance. The ratio is the percent of normal kidney function remaining.  Renal disease increases the time to reach steady-state concentration. Renal Disease ---> longer half-life ---> longer time to reach steady-state. PHARMACODYNAMICS: Study of what a drug does to the body METABOTROPIC RECEPTOR-COUPLING MECHANISMS:  SPECIFIC G-RECEPTORS Gs Stimulates adenylate cyclase (cAMP) Gi Inhibits adenylate cyclase alpha2-Receptors have Gi ---> inhibit post-synaptic adrenergic neurons Gq Stimulates Phospholipase- alpha1-Receptors have Gq --> Ca+2 C (IP3/DAG) in smooth muscle Go Inhibits Ca+2 channels Gi Opens K+ channels  (A) cAMP PATHWAY (beta-Adrenergic)  HORMONE RECEPTORS: beta-Adrenergic, GH, most hypothalamic and pituitary hormones.  Signal Transduction Pathway:  Adenylyl Cyclase ---> cAMP ---> PKA ---> phosphorylate target protein.  Phosphodiesterase then cleaves cAMP - --> 3,5-AMP  The GTP on the G-Protein spontaneously cleaves back to GDP, to inactive the G- Protein.  Xanthines: Caffeine inhibits phosphodiesterase ---> cAMP.  Desensitization: Pharmacokinetics and Pharmacodynamics Page 19
  20. 20. Marc Imhotep Cray, M.D.  beta-Arrestin Kinase (betaARK) is activated by tonically high cAMP levels. cAMP phosphorylates betaARK to activate it.  betaARK phosphorylates the regulatory domain of the target receptors ---> prevent cAMP activation.  (B) PHOSPHO-INOSITOL PATHWAY (alpha-Adrenergic)  HORMONE-RECEPTORS: alpha-Adrenergic  Signal Transduction Pathway:  Phospholipase-A2 cuts apart PIP2 ---> IP3 + DAG  IP3 goes to Rough-ER where it opens calcium channels ---> Ca+2  DAG phosphorylates PKC, a calmodulin- kinase, which then phosphorylates the target protein, whenever Ca+2 (from IP3) is available. +2  Ca is then sequestered back into the Rough-ER by active transport.  (C) STEROID RECEPTORS:  HORMONES: Cortisol, sex steroids, Thyroid Hormone, Aldosterone  Signal Transduction:  Heat-shock proteins normally bind to the nuclear receptor to hold it inactive.  The hormone (Cortisol, Sex Steroids, Tyrosine) bind to the nuclear receptor, releasing the heat shock protein.  The hormone-receptor complex then binds to DNA to effect transcription.  Cortisol stimulates Lipocortin ---> inhibit Phospholipase-A2 ---> inhibit synthesis of prostaglandins ---> anti-inflammatory properties.  (D) TYROSINE-KINASE RECEPTORS  Hormones: Insulin, IGF, EGF  Pathway: auto-phosphorylation of tyrosine ---> phosphorylate target protein. Pharmacokinetics and Pharmacodynamics Page 20
  21. 21. Marc Imhotep Cray, M.D.  (E) NITRIC OXIDE:  NO-Synthases:  Constitutive NO-Synthase: Present in most cells, and is responsible for ACh- activated smooth muscle relaxation.  Inducible NO-Synthase: Induced by cytokines to cause acute vasodilation.  NO Functions:  Forms free radical intermediates in PMNs and macrophages. IONOTROPIC RECEPTOR-COUPLING MECHANISMS:  (A) GABA RECEPTOR: -  RECEPTOR MECHANISM: In the CNS, it is a Cl channel. GABA binds ---> Cl- comes into neuron ---> hyperpolarization ---> Inhibitory effects in CNS.  Barbiturates (Phenobarbitol): It binds at an allosteric site to increase the effectiveness of GABA. It is GABAergic, but it is not a GABA agonist, because it does not bind to the same site as GABA.  Benzodiazepines (Diazepam, Valium): It binds at a separate site than the barbiturates, but it is still GABAergic and binds at an allosteric site.  Picrotoxin: GABA Antagonist, it antagonizes GABA, causing excitability in the CNS. Thus it is a convulsive agent.  (B) NMDA RECEPTOR: N-Methyl-D-Aspartate  MECH: It binds excitatory neurotransmitters, glutamate and aspartate. It lets in Ca +2 (primarily) and also Na+.  Alzheimers Disease: The NMDA receptor may play a role in the pathogenesis of Alzheimers Disease. +  Leaky NMDA Channels ---> Na comes in the neuron ---> water follows Na+ ---> reversible cell damage to neurons (hydropic swelling). +2  Leaky NMDA Channels ---> Ca builds up in neuron ---> irreversible, oxidative Pharmacokinetics and Pharmacodynamics Page 21
  22. 22. Marc Imhotep Cray, M.D. damage (free radicals) to neuron ---> permanent damage and cell death.  MK-801 is an NMDA Receptor Blocker that has been tried as experimental treatment for Alzheimers. But it doesnt work because it has a stimulatory effect on the hippocampus, causing hallucinations, similar to taking phencyclidine (PCP).  (C) ACETYLCHOLINE NICOTINIC RECEPTOR: + +  MECH: It is a Na channel. When 2 AChs bind, Na comes in, depolarizing the membrane.  Desensitization: If you let ACh hang around long enough (such in the presence of cholinesterase inhibitors), then some of the ACh-receptors will convert to a high-affinity state, and the ACh will stay locked onto the receptors.  RESULT: Fewer receptors are available --- > AChs effect is therefore antagonized --- > depolarization blockade.  This explains the way in which cholinesterase inhibitors cause paralysis.  Succinylcholine binds to the ACh with a higher affinity than ACh.  Early on, you will see fasciculations, as it has its stimulatory effect on ACh.  After that you see paralysis. Succinylcholine becomes an ACh antagonist, as all the receptors convert to the high-affinity state, and the molecule locks on. Pharmacokinetics and Pharmacodynamics Page 22
  23. 23. Marc Imhotep Cray, M.D. DOSE-RESPONSE CURVES:  Definitions:  Affinity: A measure of the propensity of the drug to bind with a given receptor.  Potency: A potent drug induces the same response at a lower concentration. A potent drug has a lower EC50 value.  Efficacy: The biologic response resulting from the binding of a drug to its receptor. An efficacious drug has a higher Emax value.  Partial Agonist: A compound whose maximal response (Emax) is somewhat less than the full agonist.  GRADED-RESPONSE CURVE: A plot of efficacy (some measured value, such as blood pressure) -vs- drug concentration.  EC50 = The drug concentration at which 50% efficacy is attained. The lower the EC50, the more potent the drug.  Emax = the maximum attained biological response out of the drug.     QUANTAL DOSE-RESPONSE CURVE: A graph of discrete (yes-or-no) values, plotting the number of subjects attaining the condition (such as death, or cure from disease) -vs- drug concentration.  ED50: The drug-dosage at which 50% of the population attains the desired characteristic.  LD50: Lethal-Dose-50. The drug-dose at which 50% of the population is killed from a drug. Pharmacokinetics and Pharmacodynamics Page 23
  24. 24. Marc Imhotep Cray, M.D.  THERAPEUTIC INDEX = LD50 / ED50  The ratio of median lethal dose to median effective dose.  The higher the therapeutic index, the better. That means that a higher dose is required for lethality, compared to the dose required to be effective.  MARGIN OF SAFETY = LD1 / ED99  The ratio of the dosage required to kill 1% of population, compared to the dosage that is effective in 99% of population.  The higher the margin of safety, the better.  COMPETITIVE INHIBITORS: They bind to the same site as the endogenous molecule, preventing the endogenous molecule from binding.  The DOSE-RESPONSE CURVE SHIFTS TO THE RIGHT in the presence of a competitive inhibitor.  The EC50 is increased: more of a drug would be required to achieve same effect. Pharmacokinetics and Pharmacodynamics Page 24
  25. 25. Marc Imhotep Cray, M.D.  The Emax does not change: maximum efficacy is the same, as long as you have enough of the endogenous molecules around.  The effect of a competitive inhibitor is REVERSIBLE and can be overcome by a higher dose of the endogenous substance.  The intrinsic activity of a competitive inhibitor is 0. It has no activity in itself, but only prevents the endogenous substance from having activity.  Partial Agonist: A substance that binds to a receptor and shows less activity than the full agonist.  At low concentrations, it increases the overall biological response from the receptor.  At high concentrations, as all receptors are occupied, it acts as a competitive inhibitor and decreases the overall biological response from the receptor.  NON-COMPETITIVE INHIBITORS: They either (1) bind to a different (allosteric) site, or (2) they bind irreversibly to the primary site.  The DOSE RESPONSE CURVE SHIFTS DOWN in the presence of a non-competitive inhibitor.  The EC50 is increased: more of a drug would be required for same effect.  The Emax decreases: The non-competitive inhibitor permanently occupies some of the receptors. The maximal attainable response is therefore less.  The intrinsic activity of the non-competitive inhibitor is actually a negative number, as the number of functional receptors, and therefore the maximum attainable biological response, is decreased.  Pharmacokinetics and Pharmacodynamics Page 25
  26. 26. Marc Imhotep Cray, M.D. ADVERSE EFFECTS:  Drug Toxicity: Dose-dependent adverse response to a drug.  Organ-Directed Toxicity:  Aspirin induced GI toxicity (due to prostaglandin blockade)  Epinephrine induced arrhythmias (due to beta-agonist)  Propanolol induced heart-block (due to beta-antagonist)  Aminoglycoside-induced renal toxicity  Chloramphenicol-induced aplastic anemia.  Neonatal Toxicity: Drugs that are toxic to the fetus or newborn.  Sulfonamide-induced kernicterus.  Chloramphenicol-induced Grey-Baby Syndrome  Tetracycline-induced teeth discoloration and retardation of bone growth.  TERATOGENS: Drugs that adversely affect the development of the fetus  Thalidomide:  Antifolates such as Methotrexate.  Phenytoin: Malformation of fingers, cleft palate.  Warfarin: Hypoplastic nasal structures.  Diethylstilbestrol: Oral contraceptive is no longer used because it causes Pharmacokinetics and Pharmacodynamics Page 26
  27. 27. Marc Imhotep Cray, M.D. reproductive cancers in daughters born to mothers taking the drug.  Aminoglycosides, Chloroquine: Deafness  Drug Allergy: An exaggerated, immune-mediated response to a drug.  TYPE-I: Immediate IgE-mediated anaphylaxis.  Example: Penicillin anaphylaxis.  TYPE-II: Antibody-Dependent Cellular Cytotoxicity (ADCC). IgG or IgM mediated attack against a specific cell type, usually blood cells (anemia, thrombocytopenia, leukopenia).  Hemolytic anemia: induced by Penicillin or Methyldopa  Thrombocytopenia: induced by Quinidine  SLE: Drug-induced SLE caused by Hydralazine or Procainamide.  TYPE-III: Immune-complex drug reaction  Serum Sickness: Urticaria, arthralgia, lymphadenopathy, fever.  Steven-Johnson Syndrome: Form of immune vasculitis induced by sulfonamides. May be fatal.  Symptoms: Erythema multiforme,arthritis,nephritis,CN S abnormalities,myocarditis.  TYPE-IV: Contact dermatitis caused by topically- applied drugs or by poison ivy.  Drug Idiosyncrasies: An unusual response to a drug due to genetic polymorphisms, or for unexplained reasons.  Isoniazid: N-Acetylation affects the metabolism of isoniazid  Slow N-Acetylation: Isoniazid is more likely to cause peripheral neuritis.  Fast N-Acetylation: Some evidence says that Isoniazid is more likely to cause hepatotoxicity in this group. However, other evidence says that age (above 35 yrs old) is the most important determinant of hepatotoxicity. Pharmacokinetics and Pharmacodynamics Page 27
  28. 28. Marc Imhotep Cray, M.D.  Alcohol can lead to facial flushing, or Tolbutamide can lead to cardiotoxicity, in people with an oxidation polymorphism.  Succinylcholine can produce apnea in people with abnormal serum cholinesterase. Their cholinesterase is incapable of degrading the succinylcholine, thus it builds up and depolarization blockade results.  Primaquine, Sulfonamides induce acute hemolytic anemia in patients with Glucose-6-Phosphate Dehydrogenase deficiency.  They have an inability to regenerate NADPH in RBCs --> all reductive processes that require NADPH are impaired.  Note that this is Acute Hemolytic Anemia, yet it is not classified as an allergic reaction -- it is an idiosyncrasy when caused by sulfonamides or primaquine. Other anemias are Type-II hypersensitivity reactions.  G6PD deficiency is most prevalent in blacks & semitics. It is rare in caucasians & asians.  Barbiturates induce porphyria (urine turns dark red on standing) in people with abnormal heme biosynthesis.  Psychosis, peripheral neuritis, and abdominal pain may be found. TOLERANCE  Pharmacokinetic Tolerance: Increase in the enzymes responsible for metabolizing the drug.  Warfarin doses must be increased in patients taking barbiturates or phenytoin, because these drugs induce the enzymes responsible for metabolizing warfarin. Pharmacokinetics and Pharmacodynamics Page 28
  29. 29. Marc Imhotep Cray, M.D.  Pharmacodynamic Tolerance: Cellular tolerance, due to down- regulation of receptors, or down-regulation of the intracellular response to a drug.  Tachyphylaxis: When using indirect agonists, which stimulate the endogenous substance, this occurs when you run out of the endogenous substance and therefore see the opposite effect, or no effect at all.  Tyramine can cause depletion of all NE stores if you use it long enough, resulting in tachyphylaxis.  Physiologic Tolerance: Two agents yield opposite physiology effects.  Competitixve Tolerance: Occurs when an agonist is administered with an antagonist.  Ex.: Naloxone and Morphine are chemical antagonists, and one induces tolerance to the otherFurther Study of Basic Medical Pharmacology:PHAR - CH02 Pharmacokinetic Basis of Therapeutics andPharmacodynamic Principles-ANDREW M. PETERSON Pharmacokinetics and Pharmacodynamics Page 29

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