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General Pharmacology Better living through pharmacology, pharmokinetics, and pharmodynamics, P. Andrews Case # 1 Case 1, cont. Case 1, cont. CAREFUL AND JUDICIOUS USE OF MEDICATIONS CAN TRULY MAKE A DIFFERENCE Things to know about drugs Pharmokinetics Pharmodynamics Generic names Trade names Schedules of drugs FDA approval process The Harrison Narcotic act of 1914 Enteral drug administration Parenteral drug administration Mechanism of action Route of administration Pure food and drug act of 1906 Things to know, cont. The Federal Food, Drug and Cosmetic act of 1938 The DurhamHumphrey Amendments to the 1938 Act The Controlled Substance Act of 1970 OTC medications Bioequivalence Six rights of medication administration Absorption Bioavailability Biotransformation First-pass effect More things to know! Blood-brain barrier Placental barrier Oxidation Hydrolysis Elimination Agonist Antagonist Agonist-antagonist Extrapyramidal symptoms Idiosyncratic response Tolerence Side effect Cumulative effect Synergism Potentiation Onset of action Therapeutic index Half-life Minimum effective concentration Historical trends Ancient health care Herbs & minerals - 2,000 BC Pharmacology by end of Renaissance; separate from medicine Vaccinations 1796 (Smallpox) Insulin, Penicillin early 20th century Modern health care Human insulin tPA Pharmacology Chemical name Precise description chemical composition and molecular structure Vecuronium Bromide: Chemical compound: piperidinum, 1-[(2, 3, 5, 16, 17)-3, 17-bis (acetyloxy)-2-(1piperidinyl)androstan-16yl]-1-methyl-, bromide. Molecular structure C34H57BrN2O4 Generic name – Non-proprietary name FDA approved First manufacturer Trade (Proprietary) name Registered to a specific manufacturer vecuronium bromide Marsam Pharmaceuticals, Inc. Vecuronium TM Official name Assigned by USP Vecuronium Bromide USP Drug Sources Plants Atropine – Deadly nightshade plant Morphine – Opium plant Digitalis – Foxglove Animals and Humans Insulin Glucagon Minerals Calcium chloride Sodium Bicarbonate Magnesium Sulfate Synthetics Bretylium tosylate Lidocaine Procainamide Drug Profiles Names Classification Mechanism of Action Indications Pharmacokinetics Side effects/ adverse reactions Routes of administration Contraindications Dosage How supplied Special considerations Legal stuff - Federal Protect the public Pure Food and Drug Act, 1906 Harrison Narcotic Act, 1914 Improve quality and labeling of drugs Regulating importation, manufacture, sale, use of opium, cocaine, derivatives Federal Food, Drug, Cosmetic Act, 1938 Empowers FDA to enforce, set premarket safety standards More Federal stuff Durham-Humphrey Amendments, 1951 Prescription drug amendments, 1938 act; requires written or verbal prescription from physician to dispense some drugs Created OTC category Comprehensive Drug Abuse Prevention & Control Act, 1970 (Controlled substance act) Replaces Harrison Narcotic Act Establishes 5 schedules of drugs Prohibits refilling of Rx for Schedule II drugs, & requires original Rx to be filled within 72 hours Other regulations Prescription drugs Designated sufficiently dangerous to require supervision OTC Available in small doses; present low risk General issues Drugs must be secured State laws vary; generally set scope of practice for EMS Medical directors can delegate authority to paramedics Standards Assay Bioequivalence Determines amount & purity Relative therapeutic effectiveness of chemically equivalent drugs Bioassay Attempts to ascertain drugs availability in biological model New Drug Development You Are Responsible! Know precautions and contraindications Practice proper technique Know how to observe and document effects Establish and maintain professional relationships with other health care providers Understand pharmacokinetics, pharmacodynamics Have current references available Take careful drug histories Evaluate compliance, dosage, adverse reactions Consult with medical direction when appropriate SIX RIGHTS OF MEDICATION ADMINISTRATION Right medication Right dose Right time Right route Right patient Right documentation AND SEVEN – Right to refuse Cells talk to each other Three distinct languages Nervous system Endocrine system neurotransmitters hormones Immune system cytokines In disease, all systems are affected The three systems can’t exist without each other The actions of one impact the actions of the others I.e., stress (nervous system) disrupts endocrine system which may respond with glucocorticoid production = suppressed immune response Drug Class Examples Nitroglycerin Indications for nitroglycerin Body system: “Cardiac drug” Action of the agent: “Anti-anginal” Mechanism of action: “Vasodilator” Cardiac chest pain Pulmonary edema Hypertensive crisis Which drug class best describes this drug? Another way to classify drugs Mechanism of Action Drugs in each category work on similar sites in the body and will have similar specific effects/side effects Beta blockers: metoprolol ACE inhibitors: lisinopril Alpha blockers: prazosin Calcium-channel blockers: verapamil Example: beta blocker actions and impacts Suppress the actions of the sympathetic nervous system Prehospital administration of epinephrine may not produce as dramatic effects with a patient taking a drug in this class Prehospital example: Hyperglycemics Dextrose 50% and glucagon Mechanism of action Both will raise blood glucose Glucagon: hormone that works in the liver to convert stored chains of carbohydrate to glucose Dextrose 50%: ready-made simple sugar that is ready to enter into the cell Which drug is considered first-line for hypoglycemia? Why? What are some limitations for glucagon in the presence of severe hypoglycemia? Sources of drug information AMA Drug Evaluation Physician’s Desk Reference (PDR) Hospital Formulary Drug Inserts Other sources Controlled substances Schedule I. High potential for abuse; no accepted medical indications Heroin, LSD, Crack, Marijuana Schedule II. High potential for abuse, but have accepted medical indications Morphine, Meperidine, Dilaudid, Oxycodone, Cocaine, Codeine, Opium, Methadone Schedule III. Less potential for abuse, and accepted medical indications Tylenol #3, Vicodin Schedule IV. Low potential for abuse, but may cause physical or psychological dependence. Diazepam, lorazepam, Phenobarbital Schedule V. Low potential for abuse, but have small quantities of narcotics Cough medicine (Vicks 44) Standardization of Drugs A necessity Techniques for measuring a drug’s strength and purity Assay Bioassay The United States Pharmacopeia (USP) Official volumes of drug standards Medical Control Medication administration is ALS skill Medical Director Actively involved in and ultimately responsible for all clinical and patient care. We are extension of physician’s license Special ConsiderationsPregnant patients Evaluate benefit vs. risk to fetus FDA has a scale (A,B,C,D,X) to indicate drugs that may have documented problems Many drugs are unknown to cause problems Drugs may cross placental barrier or through lactation FDA Pregnancy Categories A B Adequate studies have not demonstrated a risk to the fetus Animal studies have not demonstrated a risk to the fetus; no adequate studies in humans OR Adequate studies in pregnant women have not demonstrated a risk to fetus in first and last trimester BUT animal studies show adverse effects FDA Pregnancy Categories, cont. C D X Animal studies have demonstrated adverse effects, but there are no adequate studies in pregnant woman Fetal risk has been demonstrated; in certain circumstances, benefits could outweigh risks Fetal risk has been demonstrated. This risk outweighs any possible benefit to mother. Avoid using in pregnant patients. Special Considerations – Pediatric patients Based on weight or BSA Length-based resuscitation tape (Broslow’s) Absorption of oral meds less due to differences in gastric pH, emptying time, low enzyme levels Pediatrics, cont. Unexpected toxicity common in topically applied meds Drugs that bind to protein have higher availability Neonates have much higher % of extracellular fluid – may require higher doses Lower metabolic rate & hepatic system ; higher risk for toxicity Special Considerations - Geriatric patients MULTIPLE MEDS A PROBLEM Physiological effects of aging can lead to altered pharmacodynamics and pharmacokinetics. Absorb oral meds slower Distribution altered Lipid soluble drugs have greater deposition Drug action delayed or prolonged Pharmacology The study of drugs and their interactions with the body Drugs do not confer any new properties on cells or tissues – only modify or exploit existing functions Given for local or systemic action Pharmacokinetics The study of the basic processes that determine duration and intensity of a drug’s effect Transport Active transport Requires energy to move a substance ATP ADP Sodium – potassium pump Facilitated diffusion Binds with carrier protein, configuration of cell membrane changes, allows large molecule to enter body I.e., Insulin increases glucose transport from 10-20 fold Transport, cont Passive transport movement of substance without energy Diffusion Movement of solute in solvent Osmosis Movement of solvent Filtration Molecules move across membrane down pressure gradient Absorption IM faster than SC Enteral administration; must survive digestive process Enteric coating; dissolve in duodenum Many drugs ionize Ionized drugs don’t absorb across cell membranes Most drugs reach equilibrium pH affects ionization Concentration affects absorption Loading dose – maintenance dose Bioavailability Amount of drug still active after reaching target tissue Distribution Some drugs bind to proteins in blood and remain for prolonged period Therapeutic effects due to unbound portion of drug in blood Drug bound to plasma proteins can’t cross membranes Changing blood pH can affect proteinbinding action of drug. TCA’s are strongly bound to plasma proteins. Case #2 You are dispatched to a report of a possible suicide attempt. You arrive to find a 50 year old woman CAO PPTE. She is crying, and says that she wants to die. She admits to taking pills about ½ hour pta. PMH: Vascular H/A. Her B/P is 140/90, P 100, RR 28, Skin PWD, PERL. BBS =, clear. Wt. ~ 60 kg. Case # 2, cont. You continue assessing her while your partner goes to check the trash containers in the house. He returns with an empty bottle of desipramine. The label shows that the Rx was filled yesterday, and there were 50 tablets of 100 mg ea. What is the total dose she probably ingested? Case # 2, cont. You put her on the ecg monitor, and note that her QRS is widening. Her heart rate is now 110, her B/P is 110/64, RR 28, and she is c/o dry mouth and blurred vision. What medication will you give her? Case # 2, cont. Tx: Oxygen Ecg IV Sodium Bicarbonate 1 mEq/kg Rapid transport Case #2, cont. What does Sodium Bicarbonate do for this patient? What is her prognosis? Drugs bind to proteins Albumen is one of the chief proteins in the blood available for binding with drugs. When a pt. Is malnourished, albumen is low. What significance does this have re; drug therapy? The blood – brain barrier Tight junctions of capillary endothelieal cells in CNS form a barrier Only non-protein-bound, highly lipid-soluble drugs can enter CNS Placental barrier similar Other deposits Fatty tissue serves as drug reservoir Bones and teeth can accumulate drugs that bind to calcium Ie., tetracycline Biotransformation Drugs are metabolized – broken down into metabolites Transforms drug into more or less active metabolite Make drug more water soluble to facilitate elimination Protein-bound drugs are not available for biotransformation Biotransformation, cont. Occurs in liver primarily Also occurs in kidney, lung, GI tract First-pass effect Some drugs can’t be given orally Elimination Most drugs excreted in urine Glomerular filtration Some in feces or air A function of glomerular filtration pressure (BP and kidney blood flow) Active transport system; requires ATP Tubular secretion Urine pH affects reabsorption in renal tubules Elimination, cont. Some drugs and metabolites are eliminated in expired air Breathalyzer Feces, sweat, saliva, breast milk Autonomic Nervous System Responsible for control of involuntary actions. Exit the central nervous system and enter structures called the autonomic ganglia nerve fibers from CNS interact with nerve fibers from the ganglia to target organs Pre-ganglionic nerves - exit CNS and terminate in autonomic ganglia Post-ganglionic nerves - exit ganglia and teminate in target tissues No actual connection between nerve cells - a synapse The space between nerve cell and target organ is a neuroeffector junction. Neurotransmitters - specialized chemicals to conduct impulse Neurotransmitters released from pre-synaptic neurons and act on post-synaptic neurons or target organ. Two functional divisions of autonomic nervous system Parasympathetic - Vegetative functions feed or breed Sympathetic - Fight or Flight the two neurotransmitters of the autonomic nervous system Acetylcholine -used in pre-ganglionic nerves of the sympathetic system and in pre and post-ganglionic nerves of the parasympathetic system Norepinephrine - the post-ganglionic neurotransmitter of the sympathetic nervous system. Cholinergic synapses - use acetylcholine as neurotransmitter Adrenergic synapses - use norepinephrine as neurotransmitter Sympathetic nervous system stimulation Sweating Peripheral vasoconstriction Increased blood flow to skeletal muscle Increased HR and cardiac contractility Bronchodilation Energy Reduced blood flow to abdominal organs Decreased digestion Relaxation of bladder smooth muscle Release of glucose stores Also stimulation of the adrenal medulla - release of hormones norepinephrine and epinephrine Adrenergic receptors norepinephrine crosses synaptic cleft and interacts alpha 1-peripheral vasoconstriction, mild bronchoconstriction, stimulation of metabolism alpha 2-inhibitory - prevent overrelease of norepinephrine in synapse beta 1 - increased heart rate, cardiac contractility, automaticity, conduction beta 2 - vasodilation, bronchodilation Dopaminergic receptors Sympathomimetics not fully understood - believe to cause dilation of renal, coronary, cerebral arteries meds that stimulate the sympathetic nervous system Sympatholytics inhibit the sympathetic nervous system Nervous System Central Nervous System Peripheral Nervous System Somatic Nervous System Voluntary control Autonomic Nervous System Sympathetic "Fight or Flight" Neurotransmitters: Norepinephrine Epinephrine Receptors: Alpha 1 and 2 Beta 1 and 2 Parasympathetic "Feed and Breed" Neurotransmitter: Acetylcholine Parasympathetic nervous system Acetylcholine release - very short-lived deactivated by chemical acetylcholinesterase Parasympathetic actions Pupils constrict Secretions by digestive glands Increased smooth muscle activity along digestive tract Bronchoconstriction Reduced heart rate and contractility Parasympatholytics Anticholinergics block the actions of the parasympathetic nervous system Atropine Parasympathomimetics Cholinergics Stimulate the parasympathetic nervous system Nervous System Central Nervous System Peripheral Nervous System Somatic Nervous System Voluntary control Autonomic Nervous System Sympathetic "Fight or Flight" Neurotransmitters: Norepinephrine Epinephrine Receptors: Alpha 1 and 2 Beta 1 and 2 Parasympathetic "Feed and Breed" Neurotransmitter: Acetylcholine The Parasympathetic NS What organs will help out the typical couch potato? Digestion Slow heart rate Smaller bronchioles Pupil size Normal or constricted This system works best at rest Couch Potato Over-stimulation of the Parasympathetic NS A little is a good thing, but too much stimulation of this system leads to trouble Very slow heart rates Bronchoconstriction Major gastrointestional actions Vomiting Diarrhea Autonomic Nervous System Sympathetic Receptor Site Action 1) 2) 3) Brain sends out the response via nerve paths Nerve moves the response: depolarization Depolarization stimulates norepinephrine sacks • Sacks move to the end of the nerve and dump out their contents 2 3 4) 5) Norepinephrine travels across the synapse • Attaches to a receptor on the organ, organ responds to the signal Norepineprhine detaches and is deactivated • 2 options: destroy it or move it back into its sack 5 2 3 4 Drug Routes Enteral Oral (PO) Orogastric/Nasogastric (OG/NG) Sublingual (SL) Buccal Rectal (PR) Drug routes, cont. Parenteral Intravenous (IV) Endotracheal (ET) Intraosseous (IO) Umbilical Intramuscular (IM) Subcutaneous (SC, SQ, SubQ) Inhalation/ Nebulized Topical Transdermal Nasal Instillation Intradermal Drug forms Liquid: (solute - solvent) Solution Tinctures: drug extracted chemically with alcohol. Suspensions - liquid preparations don’t remain mixed Spirits: Volatile chemicals dissolved in alcohol Gaseous – Oxygen, Nitrous Oxide Emulsions: oily substance mixed with a solvent that won’t dissolve it. (oil and vinegar). Elixirs: Drug in an alcohol solvent. (Nyquil) Syrups: Drug dissolved in sugar and water (cough syrup). Solids: capsule, tablet, lozenge, powder Topical use: ointment, paste, cream, aerosol Drug storage Properties may be altered by environment. Temperature Light Moisture Shelf-life Pharmacodynamics Most drugs bind to a receptor Protein molecules Can be stimulated/inhibited by chemicals Each receptor’s name generally corresponds to the drug that stimulates it Affinity Force of attraction between a drug and a receptor Different drugs may bond to same receptor site, but strength of bond may vary – binding site’s shape determines receptivity to chemicals Drug’s pharmacodynamics involves its efficacy Generally, drugs either stimulate or inhibit the cell’s normal actions. Efficacy and affinity not directly related Drug A causes a stronger response than drug B Drug B binds to the receptor site more strongly than drug A When drug binds to receptor, chemical change occurs Drugs Interact with receptor and result in desired effect Interact with receptor and cause release/production of a second compound Second messenger Calcium or cyclic adenosine monophosphate (cAMP) Number of receptor sites on target cell constantly changes Most common second messenger Activates other enzymes; cascading Receptor proteins destroyed during function Reactivated or remanufactured Down regulation Binding of a drug or hormone that causes number of receptors to decrease Agonists and Antagonists Agonist Antagonist bind to receptor and cause a response Binds to receptor but does not cause it to initiate the expected response Agonist-Antagonist Do both Nubain; stimulates opioid agonist analgesic properties but partially blocks respiratory depression Antagonists Lock and key – key fits but won’t open the lock Competitive antagonist Drug binds and causes the expected effect and also blocks another drug Noncompetitive antagonist Drug binds and causes a deformity of binding site that prevents an agonist from fitting and binding Naloxone Drugs that change physical properties Drugs that chemically bind with other substances Osmotrol Isopropyl alcohol – denatures proteins on surface of bacterial cells Drugs alter a normal metabolic pathway Anticancer, antiviral drugs Response to drug administration We must carefully weight risk vs benefit! Allergic reaction Idiosyncrasy Hypersensitivity Effect unique to person; not expected Tolerence Decreased response to drug after repeated administration Cross tolerence Tolerence for a drug that develops after administration of a different drug Tachyphylaxis Rapidly occuring tolerance to a drug Decongestants, bronchodilators Cumulative effect Increased effectiveness when a drug is given in several doses Drug dependence Drug interaction Effects of one drug alters response to another drug Drug antagonism Pt becomes accustomed to drug; will suffer withdrawal symptoms Effects of one drug blocks response to another drug Summation Additive effect; two drugs that both have same effect are given together Synergism Potentiation Two drugs that have the same effect are given together and produce a response greater than the sum of their individual responses One drug enhances the effect of another Interference One drug affects the pharmacology of another drug Drug response relationship Plasma level profiles Onset of action Length of onset, duration, termination of action, minimum effective concentration and toxic levels A medication reaches it’s minimum effective concentration Minimum effective concentration Level of drug needed to cause a given effect Duration of action Termination of action Time from when a drug drops below minimum effective concentration until it’s eliminated Therapeutic index How long the drug remains above it’s minimum effective concentration Ratio of a drug’s lethal dose for 50% of population to its effective dose for 50% of population Half-life Time the body takes to clear one half of the drug What alters drug response? Age Body mass Sex Environmental Time of administration Pathologic state Genetic factors Psychological factors Case # 3 You are dispatched to a report of a 30 y/o male not breathing. You arrive on scene to find a male, wt ~ 150 lb, supine on the sidewalk outside REI. Bystanders tell you he just sat down, and then slumped over about 2 minutes pta. He is unresponsive, apneic, and has a carotid pulse. His pupils are pinpoint, and his skin is warm, pale, cyanotic at lips and nailbeds. What is your DDX? As you continue your assessment, you notice fresh needle tracks on his arms. What is happening? Your treatment of choice includes: Oxygen via BVM ecg Naloxone, IV or IM ET if no response Restrain and transport CBG enroute Repeat Naloxone Thiamine if available What do you think his prognosis is? What does Naloxone do? What is it’s half-life? Why is this important? Why do you want to assess his CBG? Be cautious – know when to be aggressive! Once you’ve given a drug, you can’t take it back – make sure you’re right! Using your field-guide, Drug book, and a PDR for information – GROUP EXERCISE! The nervous system master system Makes thought and movement possible Axons and dendrites are the wiring – neurons send and receive messages Axons carry messages from neurons Dendrites receive messages Neurons produce chemical messenger molecules and secrete them into the synapse Neurotransmitters lock onto receptors on dendrites of neurons upstream or downstream The nervous system master system, cont. Neuronal communication is based on the shape of neurotransmitters and receptors Key & lock – must fit receptor sites Insertion of neurotransmitter sets off a chain reaction; Sodium and chloride outside the membrane enters the cell through channels Potassium exits the cell through its channel = wave of energy; at the end of the energy sweep, calcium enters axon and pushes neurotransmitters out of their storages into other synapse Spinal cord Most primitive structure of nervous system Carries messages back and forth Also contains reflex arcs – pain response Under control of brain stem, cerebellum, basal ganglia, & cerebral cortex. The brain stem Tops off spinal cord and sends messages to provide most basic functions; breathing, vasoconstriction, cardiac action Reticular activating system rises up from brain stem Rouses us into consciousness Limbic system Acts as gatekeeper of memory Food, sex, fight & flight The brain stem, cont. Twin hippocampal structures are responsible for encoding new memory Amygdalae – on each side of the limbic system; react to threatening stimuli with fear The thalamus – in the center of the limbic system; aids in memory – stores memory for ~ 3 yrs, then other structures take over The brain stem, cont. Hypothalamas – monitors and controls hormonal activities Maternal bonding, etc Oversees endocrine functions Serves as connection between mind and body Cortex – wraps around limbic structures Rises up from thalamus & is folded & wrinkled Conscious control over movement, sensory interpretation, speech, cognitive function Prefrontal lobes – anticipate the future, make plans, realize our mortality The cerebellum Under cortex Source of athletic grace The sensory (peripheral) system Sends constant information back to brain I.e., pressure, position, temperature The motor system Somatic system Long single axons to specific skeletal muscles Can override the autonomic system Autonomic system Controls vegetative function Divides into sympathetic & parasympathetic systems Uses two neurons – preganglionic neurons & postgangleonic neurons Sympathetic & parasympathetic systems are a TEAM