General Pharmacology Better living through pharmacology, pharmokinetics, and pharmodynamics, P....
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Transcript of General Pharmacology Better living through pharmacology, pharmokinetics, and pharmodynamics, P....
General Pharmacology
Better living through pharmacology, pharmokinetics,
and pharmodynamics,P. Andrews
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 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
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-(1-piperidinyl)androstan-16yl]-1-methyl-, bromide.
Molecular structure C34H57BrN2O4
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
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
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
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 Determines amount & purity
Bioequivalence Relative therapeutic effectiveness of
chemically equivalent drugs Bioassay
Attempts to ascertain drugs availability in biological model
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
neurotransmitters Endocrine system
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
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?
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
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?
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 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
FDA Pregnancy Categories
A Adequate studies have not demonstrated a risk to the fetus
B 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 Animal studies have demonstrated adverse effects, but there are no adequate studies in pregnant woman
D Fetal risk has been demonstrated; in certain circumstances, benefits could outweigh risks
X 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 transportmovement 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 protein-binding 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?
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 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
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 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
C e ntra l N erv ou s S ys tem
S o m a tic N e rvo u s S ys temV olu n ta ry co n tro l
R e cep to rs:A lph a 1 a nd 2B e ta 1 a nd 2
N e uro tra n sm itte rs:N orep ine ph rine
E p ine ph rine
S ym pa the tic"F igh t o r F lig h t"
N e uro tra n sm itte r:A ce tylcho line
P a ra sym pa the tic"F e ed an d B ree d"
A u to n om ic N erv ou s S ys tem
P e rip he ra l N e rv o us S ystem
N e rvo us S ys tem
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
C e ntra l N erv ou s S ys tem
S o m a tic N e rvo u s S ys temV olu n ta ry co n tro l
R e cep to rs:A lph a 1 a nd 2B e ta 1 a nd 2
N e uro tra n sm itte rs:N orep ine ph rine
E p ine ph rine
S ym pa the tic"F igh t o r F lig h t"
N e uro tra n sm itte r:A ce tylcho line
P a ra sym pa the tic"F e ed an d B ree d"
A u to n om ic N erv ou s S ys tem
P e rip he ra l N e rv o us S ystem
N e rvo us S ys tem
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
1) Brain sends out the response via nerve paths
2) Nerve moves the response: depolarization
3) Depolarization stimulates norepinephrine sacks• Sacks move to the end of the nerve and
dump out their contents
23
4) Norepinephrine travels across the synapse• Attaches to a receptor on the organ, organ
responds to the signal
5) Norepineprhine detaches and is deactivated• 2 options: destroy it or move it back into its sack
23
4
5
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
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) 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
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
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 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
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
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 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
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
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 it’s minimum effective concentration
Minimum effective concentration Level of drug needed to cause a given effect
Duration of action How long the drug remains above it’s minimum effective
concentration Termination of action
Time from when a drug drops below minimum effective concentration until it’s eliminated
Therapeutic index 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!
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