nervous system pharmacology -...

Nervous System

Pharmacology

Paramedic Program

Autonomic Nervous System

• Effects of many drugs depend on:

– Which branch of ANS they act on

– Whether the ANS branch is stimulated or inhibited

by drug therapy

Copyright © 2007, 2006, 2001, 1994 by Mosby, Inc., an affiliate of Elsevier Inc.


• CNS

– Brain

– Spinal cord

• PNS

– Cranial and spinal nerves and their branches

– Connects all parts of body to CNS


Types of Nerve Fibers

• Visceral afferent (sensory)– Convey impulses from internal organs to CNS

• Visceral efferent (motor)– Convey impulses from CNS to internal organs, glands, and smooth and

cardiac muscle

• Somatic afferent (sensory)– Convey impulses from head, body wall, and extremities to CNS

• Somatic efferent (motor)– Convey impulses from CNS to striated muscles



• Peripheral nervous system provides a double

set of nerve fibers:

– Sympathetic (adrenergic)

• Exit from thoracic and lumbar regions

– Parasympathetic (cholinergic)

• Exit from cranial and sacral portions


Overview of Nervous System


Pre- and Postganglionic Neurons

• A two-neuron chain exists in a series between

the CNS and effector organs

– Preganglionic neuron located in the CNS

• Passes between CNS and ganglia

– Postganglionic neuron located in the periphery

• Passes between ganglia and effector organ


Acetylcholine (ACh)

• Neurotransmitter

– At junction between preganglionic fiber and

synapse

– At junction between postganglionic fiber and

effector cell

– Fibers that release ACh are known as cholinergic

fibers

• All preganglionic fibers of autonomic division

• All postganglionic fibers of parasympathetic division


Norepinephrine

• Neurotransmitter between sympathetic

postganglionic fiber and effector cell

• Adrenergic fibers

– Release norepinephrine

– Most postganglionic neurons of the sympathetic

division are adrenergic


Nerve Impulse Transmission

• Acetylcholine combines with cholinergic

receptors

– Nicotinic

• Excitatory response

– Muscarinic

• Excites or inhibits



• Norepinephrine combines with alpha and beta

receptors in effector organs

– Binds to and activates both types of receptor

molecules

• More affinity for alpha receptors



• Epinephrine is an adrenergic substance:

– Produced by adrenal medulla

– Nearly equal affinity for both receptors

– In tissues containing alpha- and beta-receptor

cells, one type is more abundant

– Has a dominating effect


Classifications

• Cholinergic (parasympathomimetic)

• Cholinergic blocking (parasympatholytic)

• Adrenergic (sympathomimetic)

• Adrenergic blocking (sympatholytic)


Narcotic Analgesics & Antagonists

• Narcotic analgesics relieve pain, antagonists

reverse effects of these narcotic drugs

• Pain has two components:

– Nerve pathway & the brain

– Emotional response to pain

• Anxiety, previous pain experience, age, gender, culture

Types of Pain

• Acute: sudden onset usually subsides with treatment (AMI,

appendicitis)

• Chronic: persistent / recurrent pain that is difficult to treat

(Cancer, arthritis)

• Referred: visceral pain felt at a distant site from its origin

• Somatic: from skeletal muscles, ligaments, vessels or joints

• Superficial: from skin or mucus membrane

• Visceral: ‘deep’ pain from smooth muscle or organ system.

May be difficult to localize, dull ache pain

Opiates

• Opiates are drugs contain or extracted from

opium

• Opioid is a synthetic drug used to bind with

opioid receptors in the brain. They are similar

to opium or morphine.

Opiates

• Morphine

• Hydomorphone (Dilaudid)

• Meperidine (Demerol)

• Methadone

• Oxycodone (OxyContin, Percodan, Tylox,

Percocet)

• Hydrocodone (Lortab)

• Propoxyphene (Darvon, Dolene)

Opiates

• Some effects of opioid analesics

– N&V

– Urinary retention

– Constipation

– Cough reflex suppression

– Orthostatic hypotension

– Respiratory depression

– CNS depression

Morphine Sulfate

• Class: Narcotic analgesic

• Actions: naturally occurring narcotic analgesic. Causes

feelings of euphoria and well-being, alters reaction to pain,

mild vasodilation causing decreased pre-load & after-load.

Also decreases oxygen demand by myocardium

• Indications: moderate to severe pain, mild to moderate

CHF, myocardial chest pain

Morphine Sulfate

• Contraindications: allergy to opiates, decreased LOC,

hypotension, ICP, respiratory depression, convulsive

disorder, ingested poisoning, undiagnosed abdominal &

intracranial conditions.

• Side Effects: respiratory depression, hypotension,

localized allergic reaction with IV administration, N&V,

constipation, addiction

• Dosage: Adults: 2-10mg IVP slowly over 1-2 minutes,

repeated q hr as needed. Pediatrics: 0.05-0.1 mg/kg IVP

slowly may be repeated q 1-4 hr as needed

Meperidine Hydrochloride

• Demerol

• Class: Narcotic Opiate

• Actions: Synthetic opiate with actions on opiate receptor

sites of the brain similar to morphine. Related low, medium,

and high doses of the drug mirror analgesic responses as MS.

• Indicaitons: Moderate to severe pain, such as trauma,

medical, or surgical pain. Has minimal to no antidiarrheic or

antitussive acitons.

Meperidine Hydrochloride

• Contraindications: Known hypersensitivity to drug,

seizure disorders, undiagnosed abdominal or intracranial

pathologies

• Side effects: Similar to Morphine, but localized reaction

may be more severe. Tends to cause increased euphoria.

• Dosage: – Adult: 25-100mg slow IVP over 1-2 min q 3-4 hrs as needed.

– Pediatric: 0.5-1.0 mg IVP slow over 1-2 min q 3-4 hrs as needed.

– Supplied as 25mg, 50mg, 75mg, 100mg syringes.

Hydromorphone hydrochloride

• Dilaudid

• Class: narcotic opiate

• Actions: Semisynthetic derative similar to morphine but is

8-10 times more potent analgesic effect. Has more rapid

onset, shorter duration, and is less hypnotic and lessens

tendency to produce N&V

• Indications: Moderate to severe pain (trauma, medical or

surgical). Also used to control persistent nonproductive

cough.

Hydromorphone hydrochloride

• Contraindications: known sensitivity, intolerance to

opiates, lactation, use caution with unknown abdominal &

intracranial dx.

• Side effects: Same as other narcotics. Resp. depression,

hypotension, bradycardia or reflex tachycardia, N&V, vertigo,

sedation & drowsiness.

• Dosage: – Adult: moderate to severe pain 1-4 mg IVP, q 4-6 hrs PRN.

– Pediatric: 0.015mg/kg every 4-6 hrs.

– Supplied as 1mg/ml, 2mg/ml, 4mg/ml & 10mg/ml

Fentanyl Citrate

• Class: narcotic opiate

• Action: narcotic analgesic approx 10 times more potent

than morphine, and more prompt in onset with less

prolonged duration

• Indications: for analgesic purposes similar to morphine,

particularly useful as adjunct for endotracheal intubation

during RSI

Fentanyl Citrate

• Contraindications: Similar to morphine. Also avoid use

in pts receiving monoamine oxidase inhibitor drugs (MOIs)

within previous 14 days, myasthenia gravis & during active

labor with delivery. Also known sensitivity.

• Side effects: Similar to morphine with euphoria, vertigo,

delirium, bradycardia, hypotension, NV, and muscle rigidity

(especially in peds)

• Dosage: – Adult: 25-200mcg slow IVP over 1-2 min.

– Pediatrics: 1-2 mcg/kg IVP over 1-2 min.

– Supplied: 100 mcg ampules

Nalbuphine Hydrochloride

(Nubain)• Class: Narcotic Opiate agonist-antagonist

• Action: synthetic opioid agonist-antagonist analgesic with

actions on the opiate receptor sites similar to morphine. This

drugs analgesic action will relieve moderate to severe pain

with low potential for dependence

• Indications: moderate to severe pain, may also be used to

slow labor. In hospital it is used for both pre op analgesia, and

operative analgesia

• Contraindications: allergy to nalbuphine, prolonged use in

pregnancy may result in neonate withdrawl

Nubain

• Side effects: similar to morphine in its CNS,

cardiovascular & respiratory depression

• Dosage:

– Adult: 5-10mg IVP q 3-6 hrs PRN

– Pediatric: 0.1-0.15mg/kg q 3-6 hr

– Supplied: 10mg or 20mg ampules / vials

Narcotic Antagonists

• Naloxone hydrochloride (Narcan)

• Class: Narcotic Opiate antagonist

• Actions: Blocks opiate receptor sites & reverse effects of

narcotic administration or overdose. Produces no significant

analgesia or respiratory depression when given in the

absence of narcotics.

• Indications: complete or partial reversal of narcotic

drugs. Known or suspected overdose of opiate narcotic

Narcotic Antagonists

• Contraindications: other than known allergy, None

• Side effects: HTN, tachycardia, ventricular dysrhythmias,

risks of abrupt withdrawal symptoms in long term narcotic

users/abusers

• Dosage:– Adult: initial dose ranges from 0.4mg to 2.0mg IVP, IM, SQ q 2-3 min

up to 10mg.

– Pediatrics: 0.01mg/kg IV,IM,SQ q 2-3 min as needed.

– Supplied: 0.4 mg/ml and 2mg/ml vial or syringes

Anesthetics

• These types of drugs are CNS depressants.

They have a reversible action on nervous

tissues.

• There are 3 types of anesthetics

– General

– Regional

– Local

Anesthetics

• Anti-anxiety, Sedative-Hypnotic agents &

Alcohol

– Sedative: small dose of medication to create a

calming sensation

– Hypnotic: larger dose of same medication to

induce sleep.

Anesthetics

• Alcohol

– Actions that of both sedative & hypnotic

– Self prescribed anti-anxiety agent

• Reticular formation

– Group of nuclei formed together make up neural pathways

called the reticular activating system

– Regulates the bodies sensations from the senses, and level

of awareness to environment.

• This group of drugs works to depress this system

Anesthetics

• Benzodiazepines & Barbiturates

– Typical drugs used to treat anxiety or induce sleep

– Benzodiazepines were introduced in the 1960’s as anti-

anxiety drugs

• Today some of the most widespread prescribed drugs

• Very high therapeutic index, overdoses of 1000x’s therapeutic

dose have not resulted in death

– Barbiturates are an older class of drug used for sedation to

anesthesia

• 4 class of barbiturates

– Ultra short, short, intermediate, long acting

Anesthetics

• Benzodiazepines

– Alprazolam (Xanax)

– Clonazepam (Klonopin)

– Diazepam (Valium)

– Flurazepam (Dalmane)

– Midazolam (Versed)

– Lorazepam (Ativan)

– Temazepam (Restoril)

Benzodiazepines

• Midazolam hydrochloride (Versed)

• Class: Benzodiazepinesanti convulsant, sedative-hypnotic

• Actions: short acting benzodiazepine with hypnotic, sedative

and amnestic properties. Drug acts on GABA receptor sites in

CNS where it increases GABA activity to induce calming,

skeletal muscle relaxation, & sleep with higher doses

• Indications: sedation due to general anxiety, adjunct to

endotracheal intubation, sedation in ventilated patient &

suppress acute seizure activity

• Contraindications: hypotension, decreased LOC,

hypoperfusion, alcohol intox., narrow-angle glaucoma

Benzodiazepines

• Side effects: hypotension (could be profound), tachycardia or

bradycardia, respiratory depression, altered LOC

• Dosage:

– Adult: 1.0-2.5mg slow IVP over 1-2 min

– Pediatrics: 0.05mg-0.2mg/kg slow IVP over 2-3 min.

– Supplied: 2mg, 5mg, 10mg vials

Benzodiazepines

• Diazepam (Valium)

• Action: benzodiazepine derivative, similar to Versed in action

• Indications: same as Versed, drug of choice in status

epilepticus

• Contraindications: hypersensitivity, severe depression to

either pulmonary or cardiovascular systems

• Side effects: same as Versed but longer half life, side effects

may be more profound and longer

• Dosage:

– Adult: 2-10mg slow IVP

– Pediatrics: 0.5-2.0mg slow IVP

– Supplied in 5mg or 10mg vials or syringes

Benzodiazepines

• Lorazepam (Ativan)

• Actions: Same as Versed, but is most potent of the available

benzodiazepine agents. Sedation & skeletal muscles

relaxation may be more profound.

• Indications: same as Versed

• Contraindications: hypersensitivity and same as Valium or

Versed

• Side Effects: Same as other agents

• Dosage:

– Adult: 0.5-2.0mg slow IVP (may need up to 2-4mg)

– Pediatrics: 0.03-0.05mg/kg slow IVP up to 4mg max

– Supplied in 2mg vials

FLUMAZENIL (ROMAZICON)

• Class: Benzodiazepine antagonist

• Actions: antagonist used to block GABA receptor sites in the brain, used

to reverse effects of benzodiazepine administration or overdose

• Indications: reverse the effects of benzodiazepine on the CNS including

sedation, impairment of recall, & psychomotor impairment

• Contraindications: allergy to medication, long term use of

benzodiazepines (sz pt)

• Side effects: hot flashes, pain at site, agitation, seizures anxiety

• Dose:

– Adult: 0.2 mg IVP as needed to 1.0mg

– Pediatrics: 0.01mg/kg up to 0.05mg/kg or 1mg

– Used with caution in patients with dependence

Hypnotics

• Propofol (diprivan)

• Class: general anestheia, sedative-hypnotic

• Action: sedative-hypnotic in fat emulsion, action is unknown but is

thought to slow impulses in the limbic system

• Indications: sedative used for induction in conscious sedation procedures,

used as adjunct in endotracheal intubation, and sedation for mechanical

ventilation

• Contraindications: allergy to medication or additives, allergy to eggs

• Side effects: hypotension, altered LOC, respiratory depression,

bradycardia, tachycardia, pain at site

• Dosage:

– For induction: 2.0-2.5mg/kg slow IVP over 1 min

– Maintenance dosage: 6-12mg/kg/hr continuously

– Pediatric dosage: ( 3yrs old) 2.5-3.5 mg/kg IVP over 1 minute

– Pediatric maintenance: 7.5-18mg/kg/hr continuously

– Supplied: 10mg/ml

Non-Barbiturate Hypnotic

• Etomidate (amidate)

• Class: General Anesthesia

• Action: hypnotic that causes few changes to hemodynamics

after administration. Is both rapid acting and short lived drug

(100 second period of hypnosis per 0.1mg/kg dose). Again

mechanism of action is unknown, but is thought to work at

the limbic system

• Indications: induction agent for endotracheal intubation or

anesthesia

• Contraindications: known allergy, pregnancy, adrenocortical

function suppression

Etomidate (amidate)

• Side effects: respiratory depression, bronchospasm, bruzism,

vein irritation, muscle tightening

• Dosage:

– Adult: 0.1-0.3 mg/kg IVP over 1 min

– Pediatric: ( 10 yrs old) 0.1-0.3mg/kg over 1 min


Neuromuscular Blockers

• Also known as paralytics

• Use of this type of medication is very helpful

in airway management.

• There are 2 types of neuromuscular blocks

– Depolarizing

– Non-Depolarizing

Depolarizing

Neuromuscular Blockers

• Have a rapid onset with a short half life.

• Works very good for intubation

– Metabolized quickly if intubation unsuccessful

• Succinylcholine Chloride

– (anectine, quelicin, sucostrin)

Succinylcholine Chloride

• Class: Autonomic Nervous system agent (sympathomimetic),

skeletal muscle relaxant, depolarizing

• Action: Neuromuscular blockade that combines with

cholinergic receptors of the motor end-plate to produce

depolarization, observed as fasciculations. Onset of flaccid

paralysis is rapid <1min and lasts 4-6min

• Indications: adjunct to facilitate intubation when employing

an RSI procedure

Succinylcholine Chloride

• Contraindications: personal or family hx of malignant

hyperthermia, skeletal muscle myopathies. Use cautiously in

pediatrics, burn pts., and trauma pts. Due to hyperkalemia

that may develop

• Side effects: respiratory paralysis, hyperthermia, muscular

fasciculations, increased ICP, increased intragastric pressure

• Dosage:

– Adult: 1.0-1.5mg/kg IVP

– Pediatric: 1.0-2.0mg/kg IVP

– Supplied: 2mg/ml vials

Non-Depolarizing Neuromuscular

Agents• Commonly used after intubation.

– This group of drugs has a longer onset, not being a good option for

intubation

– Longer half life which makes it good option post intubation

• Vecuronium (norcuron)

• Pancuronium Bromide (Pavulon)

• Rocuronium Bromide (Zemuron)

Vecuronium (norcuron)

• Action: Nondepolarizing agent that acts by competing for

cholinergic receptor sites at motor end-plates resulting in

paralysis. This drug is about 1/3 more potent than pavulon

and has a shorter half life

• Indications: airway maintence & enhance ventilatory

management of the intubated patient

• Contraindications: none other than known sensitivity

• Side effects: similar to succinylcholine but without

fasciculatations

• Dosage:

– Adult: paralyzing dose, 0.08-0.10mg/kg IVP, may repeat in 1-2 hrs

– Pediatrics: 0.1mg/kg IVP, repeated in 1-2 hrs

– Supplied: 10mg vials

Pancuronium Bromide (Pavulon)

• Action: similar to vecuronium, but produces little hisamine

release or ganglionic blockade & does not precipitate

bronchospasm or hypotension

• Indications: facilitate intubation & to provide long-term

paralysis to patients receiving ventilations

• Contraindications: known sensitivity, extreme tachycardia

• Side effects: same as vecuronium but cardiovascular effects

may be more pronounced including tachycardia & ectopy

• Dosage:

– Adult: 0.04-0.10mg/kg IVP

– Pediatric: Same

– Supplied: 2mg/ml vials

Rocuronium Bromide (Zemuron)

• Actions: Same as Vecuronium, but limited cardiovascular side

effects

• Indications: adjunct to general anesthesia to facilitate RSI.

• Contraindications: known hypersensitivity

• Side effects: same as vecuronium, but limited cardiovascular

effects

• Dosage:

– Adult:

• RSI; 0.6mg/kg IVP

• Maintenance; 0.1-0.2mg/kg IVP q 1-2hrs

• Continuous infusion; 0.01-0.012 mg/kg/min

– Pediatric: >2yrs, 0.6mg/kg IVP


Antiepileptics

• Drugs given to suppress seizure activity with

new onset seizures, breakthrough seizure or

status epilepticus

Antiepileptics

• Phenytoin Sodium (dilantin)

• Phenobarbital Sodium (luminal, barbital,

solfoton)

• This type of medication is not normally given

in the prehospital environment.

Other Nervous System Medicaions

• During events of TBI either medical or trauma

ICP must be reduced in order to maintain

cerebral perfusion

• As ICP goes up, cerebral perfusion goes down,

resulting fromedema

• CPP=MAP-ICP

Mannitol (Osmitrol)

• Class: electrolytic balance & water balance, diuretic, osmotic

• Action: hyperosmolar agent that draws fluid into the vascular

space. This fluid is then filtered at the kidneys to reduce Na+

reuptake and promotes water loss. Onset of action 15min to

decrease ICP

• Indications: acute trauma, medical brain injury with evidence

of ICP

• Contraindications: hypotension in trauma pt, severe

dehydration, acute pulmonary edema, anuria

Mannitol (Osmitrol)

• Side effects: hypotension, dehydration, acidosis, electrolyte

imbalances. If pt has poor renal function, edema, HTN, HA,

NV

• Dosage:

– Adult: for ICP 1.5-2.0g/kg IV over 30-60min

– Pediatrics: Not given for ICP

– Supplied: 20% vials containing 200g

Methylprednisolone

(Solu-Medrol, Medrol)• Class: hormone & synthetic substitiutes, Corticosteroid,

glucocorticoid, anti-inflammatory

• Actions: intermediate-acting synthetic glucocorticoid used for

anti-inflammatory & immunosuppressive properties. Alters

the bodies immune response to a variety of stimuli

• Indications: decrease inflammation & swelling, treatment of

acute bronchospasm, anti-inflammatory agent for chronic

inflammatory diseases

• Contraindications: suspected fungal infections, known

sensensitivity

Methylprednisolone

(Solu-Medrol, Medrol)• Side effects: edema, hypokalemia, hypotension,

hypertension, hyperglycemia, CHF

• Dosage: Once recommended for spinal cord injury. More

recent evidence shows it to be ineffective, and has multiple

complications.

– Now it is only a treatment option for acute spinal cord injury

– Adult dose: 30mg/kg IV over 10-20 min. Followed by 5.4mg/kg/hr for

23 hrs

– For acute bronchospasm:

• Adult: 40-125mg IVP over 2 min

• Pediatrics: 1-2mg/kg IVP over 2 min

– Supplied: 40mg, 125mg, and 1g vials

Dexamethasone (decadron)

• Class: hormone & synthetic substitutes, corticosteroid,

glucocorticoid

• Action: used for anti-inflammatory properties, it is able to

cross the blood brain barrier for use with acute increased ICP

(less common)

• Indications: adrenal insufficiency with a mineralocorticoid

inflammatory condition, allergic states, collagen diseases,

hematologic disorders.

• Contraindications: allergy to drug, systemic fungal infection,

acute infections, TB

Dexamethasone (decadron)

• Side effects: edema, hypokalemia,

hypotension, HTN, hyperglycemia, CHF

• Dosage:

– Adult: 1-2mg/kg as a single dose then 1.0-

1.5mg/kg tapered dose over 4-6hrs

– Pediatrics: 0.5-1.0mg/kg as loading dose

– Supplied: 4mg/ml vial

Sympathomimetic Aerosols

• Albuterol (proventil, ventiolin)

• Ipratropium Bromide (atrovent)

• Levalbuterol hydrochloride (xopenex)

Albuterol (proventil, ventiolin)

• Class: sympathomimietic

• Action: beta 2-specific agent, promotes relaxation of

bronchiole smooth muscle. Does have small beta 1 and alpha

properties.

• Indications: acute bronchospasm in COPD & asthma

• Contraindications: excessive tachycardia, cardiac

dysrhythmia, preexisting HTN

• Side effects: tachycardia, HTN, cardiac dysrhythmia, anxiety,

palpitations, NV, dilated pupils

• Dosage:

– Adult: 2.5mg mixed in 3-5ml of NS & neubulized

– Pediatric: 1.25-2.5mg mixed in 3-5ml of NS & neubulized

– Supplied: 2.5mg /0.5ml vial

Ipratropium Bromide (atrovent)

• Class: sympathomimetic & parasympatholytic bronchodialator

• Actions: cholinergic blocking agent, chemically related to atropine, that

antagonizes the action of acetylcholine, causing smooth muscle relaxation

• Indications: bronchoconstriction in COPD & bronchospasm not resolved

by albuterol. May also be long term use by COPD pts.

• Contraindications: hypersensitivity, not first line drug in acute situations

• Side effects: tachycardia, palpitations, nervousness, HA, dry mouth

• Dosage:

– Adult: 500mcg q 4-6hrs, if using MDI 2 inhalations q 4hrs

– Pediatric: (3-12yrs) 125-250mcg nebulized or 1-2 inhalations from an MDI

Levalbuterol hydrochloride

(xopenex)• class: sympathomimetic, beta adrenergic agonist, bronchodilator

• Action: chemically related to albuterol, but has higher specificity for beta

2 receptor sites with a longer duration of action. Decreases airway

resistance, facilitates mucous drainage, and increases vital capacity

• Indications: same as albuterol also prevention of reversible

bronchoconstriction in susceptible patients

• Contraindications: hypersensitivity, children under 6yrs, pregnancy

• Side effects: nervousness, HA, tachycardia, palpitations

• Dosage:

– Adult: 0.63-1.25mg q 6-8 hrs by nebulizer

– Pediatrics: >6yrs 0.31-0.63mg q 6-8hrs by nebulizer

– Supplied: 0.31mg/3ml; 0.63mg/3ml; 1.25mg/3ml

Sympathomimetic Injection

• Terbutaline (brethaire, brethine)

• Class: autonomic nervous system sympathomimetic; beta-adrenergic

agonist sympathomimetic; bronchodilator

• Action: specific beta 2 receptor stimulant, resulting in bronchodilation &

relaxation of peripheral vasculature, also produces uterine muscle

relaxation

• Indications: acute bronchospasm unresponsive to nebulizer therapy or in

patients when nebulizer is to feasible due to severe bronchoconstriction

• Contraindications: sensitivity, severe HTN, CAD, lactating mothers, &

concurrent digitalis toxicity

• Side effects: tachycardia, HTN, nervousness, NV, palpitations

• Dosage:

– >12 yrs old, 0.25mg SQ initially q 15-30 min up to 0.5 mg in 4hrs

– <12 yrs old, 0.005-0.001 mg/kg (max 0.4mg) q 15-20 min for 2 doses

– Supplied: 1mg/ml ampules

nervous system pharmacology -...

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