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Lecture 1 Pharmacodynamics =What Does the Drug Do to the Body ~Pharmacological Effects ~Physiological Effects

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Lecture 1 Pharmacodynamics =What Does the Drug Do to the Body ~Pharmacological Effects ~Physiological Effects LADME=what does the body do to the drug? = Pharmacokinetics Lecture 1 Pharmacodynamics =what does the drug do to the body ~Pharmacological effects ~Physiological effects Pharmacokinetics in your life What happens to a drug after its administration? A young child given an IM injection might ask : "How will that 'ouch' get from there to my sore throat"? LADME D 1. Liberation =releasing The answer to this question is the basis of 2. Absorption pharmacokinetics, i. e., how drugs move around the body A M and how quickly this movement occurs. E 3. Distribution During this semester many of the processes which control 4. Metabolism the absorption, distribution, metabolism, and excretion of drugs will be discussed. L 5. Excretion Getting drug from one site to another Disposition of drug in the body A D L IV= No A M E 1 one, two, and three compartment models Many of the processes involved in drug movement around the body are NOT saturated at normal therapeutic dose levels, making plasma concentration vs. time much simplified Parameters to be measured in 2 compartment model Rate for absorption Two compartment model often has wider application Common parameters of a blood time curve Therapeutic Range (window, index) All drugs are poisons Only proper administration determines whether a compound is beneficial or not The amount of drug administered and the resulting concentration in the body determines whether a drug is beneficial or detrimental The ideal range of drug concentrations within the body is referred as Therapeutic range (TR) or therapeutic window or therapeutic index (TI) 2 Therapeutic Range of a drug in Plasma Drug concentration vs. Drug effect TD50 TI = ED50 So, The larger the TI the ??? Drug entered ~~ Drug leaved Plasma concentrations achieved can be controlled by the rate of drug absorption Dose (absorbed) must match the rate the drug is metabolized + eliminated Absorption too fast, resulting in dosing interval?? Toxic level TR Sub-therapeutic 1 < 3 3 > 2 3 = 3 The goal of drug therapy: to maintain drug concentration in the TR Components of therapeutic administration Dose Unit: mass mg, g (tablet, capsule, mL) Dose: Amount of drugs administered at one time mass/body weight mg/kg, mg/lb (mg/mL) Loading Dose: Dosage (dosing) Interval: Time between A dose to quickly raise drug conc to therapeutic range. administration of separate drug doses Used in critical condition: ex. life threatening infections, shock Route of administration: Means by which the drug Maintenance dose: is given Dose required to maintain therapeutic concentration established by loading dose 3 Dosage Interval What is the difference ?? A. 300 mg s.i.d. Vs. B. 100 mg t.i.d Total Daily dose: Patient compliance: Therapeutic effect: Possible toxicity Route of administration Parenteral: beside the intestine Less fluctuation Intra arterial (IA) Intra vascular (IV) IV Bolus=single large volume IV infusion=slowly dripped over sec, min or hr Larger fluctuation thus overpass toxic level IV Bolus b = slow release formulation, vs. showed lower peak and IV infusion slower elimination Think about it! Route of administration-Parenteral Subcutaneous (SC), Intramuscular (IM) and Intravenous (IV) The difference between IA vs. IV? •Which one is more predictable in distribution? for drugs that are poorly absorbed form the GI tract •Which one is more likely to cause (local) tissue toxicity? for agents that are unstable in the GI tract •Which one is more quickly to effect? •Which one would have higher plasma concentration? ensure active drug absorption more rapid/predictable than oral administration •Hint: Routes of choice for uncooperative or unconscious patients 4 Route of administration-Enteral Route of administration-Enteral Oral Rectal Most pharmaceutical companies aim for this –it’s the most convenient and most economical Strategic placement: placement low in rectum, where Factors that determine drug effect following oral veins drain into systemic circulation without passing absorption: through the liver, thus first pass metabolism by the liver Rate & absorption extent by GI tract can thus be bypassed Absorption site (=mainly small intestine, larger surface area) Sublingual Drug ionization state: non-ionized (lipid-soluble) forms are more favorably absorbed Placement under the tongue allows some drugs to diffuse First-Pass Effect into the capillary network and therefore to enter the Drugs absorbed from the GI tract pass through the portal systemic circulation directly, enabling the drug to bypass venous system to the liver, resulting in low systemic the liver and avoid inactivation by hepatic metabolism. circulation due to extensive hepatic metabolism Route of administration-Others How can drugs be administered Transdermal Allows sustained, therapeutic plasma levels injections Avoids first pass effect Simple and high patient compliance Nasal Route for peptides (degraded by gastric pH if taken orally) and to avoid first pass metabolism Inhalation Choice for anesthetic agents and bronchodilators. (allows for high drug concentrations locally, not systemically). Conjunctival and intrathecal Eye drops and injection into the subarachnoid space via a lumbar puncture needle. How can drugs be administered How can drugs be administered skin or mucosa skin or mucosa-continued fentanyl patch 5 Comments on routes of administration Common routes of drug administration Bioavailbility Advantage Disadvantage Effect of administration routes Effect of administration routes Administration route affects speed and extent of absorption extentSpeed = = how how high fast drugto reach conc. equilibrium in plasma in can plasma reach No absorption phase=100% absorption I.V. e c n n o IM o r c e Faster absorption and t a s o m higher plasma conc. t s s a e l by IM vs SC SC P T Movement of Drugs Movement of Drugs Cellular membrane structure "How does the medicine know where to go". Drug distribution is directed by the physicochemical properties of the drug and the physiology of the body membranes and fluids. 6 Absorption mechanisms- passive diffusion Passive diffusion Does not involve a carrier, is not saturable, shows low structural Prerequisite: Drug has to be in solution specificity Passive diffusion Fick’s Law describes passive movement down concentration gradient The mechanism by which the majority of drugs gain access to the body Facilitate transport Water-soluble drugs penetrate the cell through aqueous channels Active transport Charged drugs will be influenced by membrane potentials Convective transport Lipid-soluble drugs readily move across most biological membranes Ion-pair transport Factors affecting the Passive diffusion: Pinocytosis (exception) A lipid:aqueous drug partition coefficient The ionization state Spontaneous movement of solutes from high to low concentration The pH and the drug pKa (determining the drug’s ionization state) follows: Fick’s Law of Diffusion Fick’s Law of Diffusion Passive diffusion To describe the passive flux of molecules down a conc gradient Does not involve a carrier, is not saturable, shows low structural specificity Fick’s Law describes passive movement down concentration gradient The mechanism by which the majority of drugs gain access to the body Water-soluble drugs penetrate the cell through aqueous channels Charged drugs will be influenced by membrane potentials Lipid-soluble drugs readily move across most biological membranes α lipophilicity and membrane area Factors affecting the Passive diffusion: Since under usual conditions: 1/α membrane thickness Lipid:Aqueous drug partition coefficient The ionization state The pH and the drug pKa (determining the drug’s ionization state) ∴ Diffusion rate α drug concentration Absorption mechanisms-facilitated transport Passive diffusion vs. Facilitated diffusion Facilitated transport (diffusion) 1. Does Not 1. Does Not need energy, need energy, Similar to Active transport: 2. Work with 2. Work with conc. gradient conc. Gradient Carrier mediated Can be competitive 3. Carrier Can be saturable mediated 4. Saturable Does Not need energy, work with conc. gradient 7 Absorption mechanisms-active transport Absorption mechanisms Active transport Against conc. gradient, do not stop at equilibrium, cause intracellular accumulation Active transport vs Diffusion Examples : Na, K Amino acids may be saturable Vitamins Against conc. gradient Depending on Sugars transporting carrier or Needs energy (ATP) Hormones enzyme Can be competitive Larger drugs May be saturable Absorption mechanisms-convective transport Absorption mechanisms Pinocytosis Convective transport Ion-pair transport Absorption thru (Endocytosis) pores (7-10 A), for MW up to 400 Fatty acids Diffusion controlled, Vit. A,D,E,K Driven by Parasite eggs conc. gradient Vit B12 complex Both ions and Not so important neutral molecules can pass, for drugs To form uncharged complex Particles or droplets engulfed Depending on size (∵size restriction) to pass membrane Not important for drug absorption Summary –factors affecting drug movement A. Charge (= polarity = affected by environmental pH) B. Lipophilicity (fat loving) C. Concentration gradient D. Molecular size E. Temperature of cellular environment Lecture 2 F. Thickness of membrane Small, lipophilic drug with high concentration gradient, moves the best 8 Drug administered in solid form must completely A= Drug absorption dissolve before they can be absorbed Absorption: Uptake of a drug into the systemic circulatio = from site of administration to systemic circulation (blood stream) Lipid membrane Break into smaller
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