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 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

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

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?

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 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

•“Sympathomimetics”

“Adrenergics”

• “Beta

Block

er”

Beta-2 Agonist”

“Non

-Spec

ific B

eta

Agonist

”

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

•“Sympathomimetics”

“Adrenergics”

• “Beta

Block

er”

Beta-2 Agonist”

“Non

-Spec

ific B

eta

Agonist

”

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

“Parasy

mpathomimetic

s”

“Parasympatholytics”

• “A

nticho

liner

gics

”

• “Cholinergics”

Autonomic Nervous System Sympathetic Receptor Site Action

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

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) 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!

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