General Pharmacology

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General Pharmacology

• Better living through pharmacology,
  pharmokinetics, and pharmodynamics,
• P. Andrews

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Case 1
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Case 1, cont.
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Case 1, cont.
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• CAREFUL AND JUDICIOUS USE OF MEDICATIONS CAN
  TRULY MAKE A DIFFERENCE

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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

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Things to know, cont.

• The Federal Food, Drug and Cosmetic act of 1938
• The Durham-Humphrey 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

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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

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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

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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-(1-piperidinyl)a
  ndrostan-16yl-1-methyl-, bromide.
• Molecular structure C34H57BrN2O4

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• Generic name
• Non-proprietary name
• FDA approved
• First manufacturer
• vecuronium bromide
• Trade (Proprietary) name
• Registered to a specific manufacturer
• Marsam Pharmaceuticals, Inc.
• Vecuronium TM
• Official name
• Assigned by USP
• Vecuronium Bromide USP

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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

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Drug Profiles

• Names
• Classification
• Mechanism of Action
• Indications
• Pharmacokinetics
• Side effects/ adverse reactions
• Routes of administration
• Contraindications
• Dosage
• How supplied
• Special considerations

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Legal stuff- Federal

• Protect the public
• Pure Food and Drug Act, 1906
• Improve quality and labeling of drugs
• Harrison Narcotic Act, 1914
• Regulating importation, manufacture, sale, use of
  opium, cocaine, derivatives
• Federal Food, Drug, Cosmetic Act, 1938
• Empowers FDA to enforce, set premarket safety
  standards

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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

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• 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

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Other regulations

• Prescription drugs
• Designated sufficiently dangerous to require
  supervision
• OTC
• Available in small doses present low risk

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General issues

• Drugs must be secured
• State laws vary generally set scope of practice
  for EMS
• Medical directors can delegate authority to
  paramedics

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Standards

• Assay
• Determines amount purity
• Bioequivalence
• Relative therapeutic effectiveness of chemically
  equivalent drugs
• Bioassay
• Attempts to ascertain drugs availability in
  biological model

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New Drug Development
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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

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• Understand pharmacokinetics, pharmacodynamics
• Have current references available
• Take careful drug histories
• Evaluate compliance, dosage, adverse reactions
• Consult with medical direction when appropriate

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SIX RIGHTS OF MEDICATION ADMINISTRATION

• Right medication
• Right dose
• Right time
• Right route
• Right patient
• Right documentation
• AND SEVEN Right to refuse

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Cells talk to each other

• Three distinct languages
• Nervous system
• neurotransmitters
• Endocrine system
• hormones
• Immune system
• cytokines

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In disease, all systems are affected

• The three systems cant 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

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Drug Class Examples

• Nitroglycerin
• Body system Cardiac drug
• Action of the agent Anti-anginal
• Mechanism of action Vasodilator
• Indications for nitroglycerin
• Cardiac chest pain
• Pulmonary edema
• Hypertensive crisis
• Which drug class best describes this drug?

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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

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Prehospital example Hyperglycemics

• Dextrose 50 and glucagon
• Both will raise blood glucose
• Mechanism of action
• 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?

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Sources of drug information

• AMA Drug Evaluation
• Physicians Desk Reference (PDR)
• Hospital Formulary
• Drug Inserts
• Other sources

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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

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• 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

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• Schedule V. Low potential for abuse, but have
  small quantities of narcotics
• Cough medicine (Vicks 44)

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Standardization of Drugs

• A necessity
• Techniques for measuring a drugs strength and
  purity
• Assay
• Bioassay
• The United States Pharmacopeia (USP)
• Official volumes of drug standards

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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 physicians license

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Special Considerations- Pregnant 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

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FDA Pregnancy Categories
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FDA Pregnancy Categories, cont.
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Special Considerations Pediatric patients

• Based on weight or BSA
• Length-based resuscitation tape (Broslows)
• Absorption of oral meds less due to differences
  in gastric pH, emptying time, low enzyme levels

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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

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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

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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

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Pharmacokinetics

• The study of the basic processes that determine
  duration and intensity of a drugs effect

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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

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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

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Absorption

• IM faster than SC
• Enteral administration must survive digestive
  process
• Enteric coating dissolve in duodenum
• Many drugs ionize
• Ionized drugs dont absorb across cell membranes
• Most drugs reach equilibrium
• pH affects ionization

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• Concentration affects absorption
• Loading dose maintenance dose
• Bioavailability
• Amount of drug still active after reaching target
  tissue

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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 cant cross
  membranes
• Changing blood pH can affect protein-binding
  action of drug.
• TCAs are strongly bound to plasma proteins.

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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.

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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?

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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?

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Case 2, cont.

• Tx
• Oxygen
• Ecg
• IV
• Sodium Bicarbonate 1 mEq/kg
• Rapid transport

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Case 2, cont.

• What does Sodium Bicarbonate do for this patient?
• What is her prognosis?

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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?

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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

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Other deposits

• Fatty tissue serves as drug reservoir
• Bones and teeth can accumulate drugs that bind to
  calcium
• Ie., tetracycline

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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

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Biotransformation, cont.

• Occurs in liver primarily
• Also occurs in kidney, lung, GI tract
• First-pass effect
• Some drugs cant be given orally

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Elimination

• Most drugs excreted in urine
• Some in feces or air
• Glomerular filtration
• 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

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Elimination, cont.

• Some drugs and metabolites are eliminated in
  expired air
• Breathalyzer
• Feces, sweat, saliva, breast milk

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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

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• 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.

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Two functional divisions of autonomic nervous
system

• Parasympathetic - Vegetative functions - feed or
  breed
• Sympathetic - Fight or Flight

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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.

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• Cholinergic synapses - use acetylcholine as
  neurotransmitter
• Adrenergic synapses - use norepinephrine as
  neurotransmitter

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Sympathetic nervous system stimulation

• Sweating
• Peripheral vasoconstriction
• Increased blood flow to skeletal muscle
• Increased HR and cardiac contractility
• Bronchodilation
• Energy

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• 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

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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

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• Dopaminergic receptors
• not fully understood - believe to cause dilation
  of renal, coronary, cerebral arteries
• Sympathomimetics -
• meds that stimulate the sympathetic nervous
  system
• Sympatholytics
• inhibit the sympathetic nervous system

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• Beta Blocker

• Sympathomimetics

Non-Specific Beta Agonist
Beta-2 Agonist
Adrenergics
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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

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• Parasympatholytics
• Anticholinergics
• block the actions of the parasympathetic nervous
  system
• Atropine
• Parasympathomimetics
• Cholinergics
• Stimulate the parasympathetic nervous system

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• Beta Blocker

• Sympathomimetics

Non-Specific Beta Agonist
Beta-2 Agonist
Adrenergics
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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
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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

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Parasympathomimetics
Parasympatholytics

• Cholinergics

• Anticholinergics

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Autonomic Nervous System Sympathetic Receptor
Site Action
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• 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

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3
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• 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

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2
3
4
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Drug Routes

• Enteral
• Oral (PO)
• Orogastric/Nasogastric (OG/NG)
• Sublingual (SL)
• Buccal
• Rectal (PR)

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Drug routes, cont. Parenteral

• Subcutaneous (SC, SQ, SubQ)
• Inhalation/
• Nebulized
• Topical
• Transdermal
• Nasal
• Instillation
• Intradermal

• Intravenous (IV)
• Endotracheal (ET)
• Intraosseous (IO)
• Umbilical
• Intramuscular (IM)

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Drug forms

• Liquid (solute - solvent) - Solution
• Tinctures drug extracted chemically with
  alcohol.
• Suspensions - liquid preparations dont remain
  mixed
• Spirits Volatile chemicals dissolved in alcohol
• Gaseous Oxygen, Nitrous Oxide

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• Emulsions oily substance mixed with a solvent
  that wont 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

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Drug storage

• Properties may be altered by environment.
• Temperature
• Light
• Moisture
• Shelf-life

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Pharmacodynamics

• Most drugs bind to a receptor
• Protein molecules
• Can be stimulated/inhibited by chemicals
• Each receptors 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 sites
  shape determines receptivity to chemicals

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• Drugs pharmacodynamics involves its efficacy
• Generally, drugs either stimulate or inhibit the
  cells 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

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• 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

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Second messenger

• Calcium or cyclic adenosine monophosphate (cAMP)
• Most common second messenger
• Activates other enzymes cascading
• Number of receptor sites on target cell
  constantly changes
• Receptor proteins destroyed during function
• Reactivated or remanufactured
• Down regulation
• Binding of a drug or hormone that causes number
  of receptors to decrease

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Agonists and Antagonists

• Agonist
• bind to receptor and cause a response
• Antagonist
• 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

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Antagonists

• Lock and key key fits but wont 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

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• Drugs that change physical properties
• Osmotrol
• Drugs that chemically bind with other substances
• Isopropyl alcohol denatures proteins on surface
  of bacterial cells
• Drugs alter a normal metabolic pathway
• Anticancer, antiviral drugs

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Response to drug administration

• We must carefully weight risk vs benefit!
• Allergic reaction
• Hypersensitivity
• Idiosyncrasy
• Effect unique to person not expected
• Tolerence
• Decreased response to drug after repeated
  administration

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• 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

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• Drug dependence
• Pt becomes accustomed to drug will suffer
  withdrawal symptoms
• Drug interaction
• Effects of one drug alters response to another
  drug
• Drug antagonism
• Effects of one drug blocks response to another
  drug
• Summation
• Additive effect two drugs that both have same
  effect are given together

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• Synergism
• Two drugs that have the same effect are given
  together and produce a response greater than the
  sum of their individual responses
• Potentiation
• One drug enhances the effect of another
• Interference
• One drug affects the pharmacology of another drug

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Drug response relationship

• Plasma level profiles
• Length of onset, duration, termination of action,
  minimum effective concentration and toxic levels
• Onset of action
• A medication reaches its minimum effective
  concentration
• Minimum effective concentration
• Level of drug needed to cause a given effect

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• Duration of action
• How long the drug remains above its minimum
  effective concentration
• Termination of action
• Time from when a drug drops below minimum
  effective concentration until its eliminated
• Therapeutic index
• Ratio of a drugs 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

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What alters drug response?

• Age
• Body mass
• Sex
• Environmental
• Time of administration
• Pathologic state
• Genetic factors
• Psychological factors

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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.

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• What is your DDX?
• As you continue your assessment, you notice fresh
  needle tracks on his arms.
• What is happening?

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• 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

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• What do you think his prognosis is?
• What does Naloxone do?
• What is its half-life?
• Why is this important?
• Why do you want to assess his CBG?

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Be cautious know when to be aggressive!

• Once youve given a drug, you cant take it back
  make sure youre right!

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• Using your field-guide, Drug book, and a PDR for
  information
• GROUP EXERCISE!

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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

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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

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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.

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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

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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

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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

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• Prefrontal lobes anticipate the future, make
  plans, realize our mortality
• The cerebellum
• Under cortex
• Source of athletic grace

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The sensory (peripheral) system

• Sends constant information back to brain
• I.e., pressure, position, temperature

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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

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