adverse drug rxns

med effects

1. therapeutic

2. secondary effects: – different terminology; may not be beneficial or even expected.

adverse drug rxn

Any unintended or undesirable consequence of drug therapy.

predictable variables that influence drug action and ADRs

1. sex

2. age

3. geriatric

4. child

5. body mass

6. environment

7. genetics

8. pathologic

9. psychological factors

10. chronobiology

11. pregnancy & lactatio

12. drug admin factors

sex influencimg drug action and adrs

higher number of ADR in females

age influencing adrs

young and elderly more likely

geriatric influence on adrs

Decreased GI absorption

Blood flow increased to brain and heart; decreased to kidney and liver

Change in plasma protein; increased fat %; decreased metabolism.

Decreased kidney function. Sometimes decreased liver function.

Many diseases common to elderly are treated with drugs

child infleuncing adr

1.     Has numerous peculiar ADR, as well as predicted

a.     -Liver and kidney not yet mature

                                               i.     -Decreased protein

                                             ii.     -Weight and fat distribution varies

body mass affecting adr

Is more appropriate than just weight; especially important with those not “average” sized – obese, thin, muscular.

     i.     -Nutritional state will affect also.

     ii.     -Dosages are suggested based on “average”.

     iii.     -Body surface area is most accurate way to decide dosage for child.

environemtn affecting adrs

1.     Factors influence blood flow and hepatic, renal and gastric function.

               i.     -Physical – altitude, light, temperature, stress

               ii.     -Chemical – oxygen tension, pollution, climate, diet

genetics affecting adrs

Probable susceptibility to ADR is partially genetically induced

pathologic state affecting adr

1.     Disease states can alter pharmacokinetics and responses

psychological factors affectign adr

Symbolic meaning important; placebo

chronobiology affecting adrs

Study of rhythms in biologic phenomena.  Look at body rhythms and correlate with drug and kinetics.  Body may be more responsive to different drugs at different times of day (e.g. steroids have natural increase during pre-dawn time due to stimulation by liver).

pregnancy and lactation affecting adrs

1.     Physical changes induce altered response to some drugs.

2.     Infant exposed to wide variety of food and meds.  Immune system not developed so probably not allergic response.  Dependence can occur in fetus.

drug admin factors affecting adr

1.     Need to look at various administration factors.

         i.     Amount of drug – Adequate amount must be present, not too much

          ii.     Route: Topical has high sensitization; parenteral – more severe reactions seen, less than 30% of medications have “first pass”

        iii.     Bioavailability – Drugs vary in ingredients and from process of drug manufacture

           iv.     Degree of exposure:  More likely with higher drug dose and prolonged administration. Multiple drug therapy:  Incidence of ADR increases with number of drugs given.

            v.     Drug interactions:  With lab tests, foods, diseases, drugs.

summation

(additive) two or more drugs added together

synergism

two, but adds to greater effect than that expected from the two

drugs.

potentiative

intensify effects of drug (positive or negative).

antagonism

effect is decreased or blocked when two given

cumulation

body cannot metabolize one dose of drug before another

dose is administered.  Drugs are excreted slower than

absorbed.

tolerance

decreased physical response to repeated administration of

drug.

dependence

reliance on drug to maintain state of well-being.  WHO

recommends this term, rather than addiction and

habituation.

Terms of ADRs

-side effects often predictable.  May be due to an extension of pharmacologic effects of drug.

 -toxic effects are seen as more severe.

Boxed warnings” or “Black Box Warnings”

strongest safety warning a drug can carry.

Adverse drug reactions –

one way to characterize drug responses that have not been optimally, clearly, or distinctly defined.

adrs predictability

70-80% of ADRs are predictable; 20-30% are not predictable; allergy and idiosyncrasy

predictable

– often extension of action of drug.  Documented in testing of drug.

one specific predictable ADR

Iatrogenic disease

latrogenic disease

Generally, refers to groups of adverse effects produced unintentionally.  Seen as diseases or disease processes in many instances. Can be same as disease of natural causes.

a.     blood dyscrasias (agranulocytosis, thrombocytopenia)

b.    hepatic toxicity (biliary obstruction, hepatitis-like)

c.    renal damage (especially glomerular damage)

d.    teratogenic effects (malformation in fetus)

e.    dermatologic effects (acne, psoriasis, eczema)

f.     ocular

g.    sexual dysfunction – affect libido, erection, etc.

h.    other:

                                               i.  ASA and steroids – ulcer

                                             ii.  oral contraceptives – thrombi/emboli

                                            iii.  carcinogenic effects

non predictable ADR

1. drug allergy

2. idiosyncrasy

drug allergy

altered response of body, result of body’s immune response to prior exposure to drug (or similar drug).  Variety of symptoms – minor (rash) to life-threatening (anaphylactic shock).

idiosyncrasy

any abnormal or peculiar response to drug.  Generally thought to result from genetic enzymatic deficiencies that lead to abnormal mech. of metabolized drugs.

 

ANS

Closely connected with CNS but considered as separate system.  *Controls heart, secretory glands (saliva, sweat, gastric, and bronchial), and smooth muscle (blood vessels, bronchi, GI, and GU)

ANS activated by?

Activated often by autonomic reflexes (sensory signals from peripheral nerve receptors send signals to centers in spinal cord, brain stem, and hypothalamus).  Then, appropriate reflex responses are transmitted

ans has 2 parts:

1. oarasympathetic

2. sympathetic

parasympathetic

principal functions:  slow heart rate, increased gastric secretion empty bladder, empty bowel, focus eye for near vision, constriction of pupil, contract bronchial smooth muscle.  “Rest & digest” response.

Parasympathetic fibers leave CNS through?

several cranial nerves.  75% of these fibers are in the 10^th cranial nerve VAGUS – passing to entire thoracic and abdominal regions. 

sympathetic

principal functions:  regulate CV system (increase HR and BP), dilate bronchi, dilate pupils, mobilize stored energy, shunt blood to skeletal muscles, regulate body temperature. “Fight or flight” reaction.

skeletal muscle innervation

Skeletal nerve endings secrete also.  These synapse axons directly with skeletal muscle-neuromuscular junction.  No ganglion (as only one neuron).

secretion: neurotransmitter is – synthesized in neuron, then

stored

released

inactivated

3 major neurotransmitters in ANS:

Acetylcholine (Ach), Norepinephrine (NE), and Epinephrine)

One other that is not clear:

Dopamine (? Not distinctly clarified in ANS)

May have modulating role at ganglion: is precursor for norepinephrine we know.  Is prominent in CNS.  Also has effects on renal, mesentery, heart.

acetylcholine skeletal:

neuromuscular junction

ANS acetylcholine

1.       preganglionic fibers of both PNS and SNS

2.       postganglionic fibers of PNS

3.       a few postganglionic fibers of SNS – (sweat glands, pilomotor) is called Cholinergic neurotransmitter

noepinephrine

is major one in SNS

Epinephrine and dopamine also found here

Is post-ganglionic in SNS

Neurotransmitters are called Adrenergic (also called catecholamines)

 

inactivation

Neurotransmitters have been made, stored, and then used.  Now must get rid of them.

acetylcholine inactivation

by cholinesterase (also called acetylcholinesterase)

norepinephrine inactivated 2 ways:

a.            reuptake by neuron – 50—80% then reused or broken down f broken down is by MAO (monoamine oxidase)

b.        diffusion to surrounding body fluids & destroyed by enzymes

1.              outside neuron – one enzyme is COMT

            (catechol-O-methyltransferase)

2.          or in distance, especially in liver and GI tract

receptor substances

found in effector cells, usually in cell membrane

              1.          changes cell membrane permeability

              2.          activate enzymes in cell membrane to promote chemical reaction  within cell

Called same as secreted neurotransmitter

ach receptor type:

cholinergic

not all receptors are the same.  Two major types:

1. nicotinic

2. muscarinic

nicotinic

nicotinic₁ (nicotinic_n)-stimulates effects on ganglia, adrenal medulla nicotinic₂ (nicotinic_m)-skeletal muscle

muscarinic

named for effect of some mushrooms.  Affect receptors at

effectors in post ganglionic area (especially cardiac muscle, smooth muscle, and glands)

norepinephrine receptor type:

Adrenergic

Two different types of receptors for this

1. alpha

2. beta

alpha types

alpha 1

generally – contract mediates vasoconstrictor effects; also affects sex organs and the eye

alpha 2

controls amount of norepinephrine released, does not have much effect on pharmacology in ANS

 

beta types

B₁ cardiac

B₂ smooth muscle of bronchioles, arterioles, and other viscera

Dilate bronchi, relax uterus, dilate vessels in heart, lung, and muscles, promotes glycogenolysis (breakdown of glycogen to glucose)

 

*Different drugs affect the two types of receptors.  Some are specific to B₁ and some to B₂.

dominant organ control

Basal control

Most organs are dominantly controlled by one or other of PAS or SNS yet are innervated

by both.  (Usually) In same organ, produce opposite and mutually antagonistic effects.

Example: Heart SNS – increased heart rate (SA node):  PAS – decreased heart rate (vagus); sometimes complementary effects (PAS – erection; SNS – ejaculation)

discrete discharge vs mass discharge

PAS is discrete, very specific (“rest & digest”)

SNS is mass “fight or flight” entire body response

tone

Basically, is a balance.  Does not have to be all or nothing.

Example: SNS – vasoconstriction.  Keeps middle ground.  Vessels are usually kept at ½ blood vessel max. diameter.  Therefore, can constrict more or relax.

autonomic drugs

They mimic (imitate) or intensify effects of SNS and PNS OR block (inhibit) SNS or PNS.

4 groups:

1. cholinergic

2. cholinergic blocking

3. adrenergic

4. adrenergic blocking

cholinergic

act like mediators of PNS (parasympathomimetic)

cholinergic blocking

block PNS (parasympatholytic)

sdrenergic

act like SNS (sympathomimetic)

adrenergic blocking

block SNS (sympatholytic)

cholinergic (parasympathomimetic)

Cholinergic fibers are widespread – heart, spleen, uterus, vas deferens, colon, vessels of skin

and muscles; and likely others.  GI tract – PNS innervation predominates.  Stimulates motor and

secretory action.

cholinergic (parasympathomimetic) uses

Cholinergic drugs are used to: 

lower intraocular pressure of glaucoma, terminate

curarization (adjunct to anesthesia), treat myasthenia gravis, promote salivation and sweating, dilate peripheral blood vessels in conditions of vasospasm, stimulate intestines and bladder postop.

cholinergic (parasympathomimetic) SE

Result of PNS (cholinergic) stimulation (bradycardia, decreased BP, salivation, vomiting, diarrhea, cramps, heartburn, bronchoconstriction, tearing [eye], and visual disturbance).

2 types of cholinergic (parasympathomimetic)

1. direct acting

2. indirect acting

direct acting

muscarinic agonists -combine with receptors just like Ach would - thus    mimic effect. 

Ach itself rarely used:  broken down quickly and has many sites of action.

Other drugs are longer acting than Ach.

examples of direct acting

a.         urecholine (Bethanechol) has rather selective effects on smooth muscle of GI and GU tracts, promoting motility of intestines and contraction of bladder.

b.         pilocarpine -constricts pupil

indirect acting

- anticholinesterases -inhibit cholinesterase, therefore accumulate Ach and prolong effects.  Affects ganglionic and post-ganglionic (nicotinic and muscarinic

indirect acting examples

a. reversible -short acting, highly specific for cholinesterase; neostigmine family (prostigmine, tensilon, mestinon)

b. irreversible - mainly organophosphate compounds (often insecticides) highly toxic.  Those used in chemical warfare are in this category, “nerve gas”.        

 

cholinergic blocking agents

May be called cholinergic blocking agents, parasympatholytic, or anticholinergics, or antimuscarinics.

cholinergic blocking agents action

Combination of the drug and Ach receptor.  Does not stop release of Ach; just takes spot on receptor and Ach cannot connect and stimulate action.

cholinergeic blockign agents uses

Relax smooth muscle - especially bronchioles; inhibit secretion of duct glands (including sweat - SNS and salivary; pre-op - decrease secretion; dilate pupils (is local action) for diagnostic purposes;  GI - decrease motility and secretion; GU - relax motility and secretion but constrict bladder sphincter - treat enuresis; cardiac - stop or prevent bradycardia if due to vagus nerve (large doses).

 

Large doses can cause excitement of CNS - main use is due to peripheral action.

adrs cholinergic blocking agents

wide margin of safety.  Toxic effect could be paralysis.

example of cholinergic blocking agents

Atropine, another is scopolamine.  Is a competitive inhibitor or antagonist.  An aerosol one is Atrovent.  Other similar drugs are quite specific to particular organs in body (or try to be). e.g. GI -- probanthine, bentyl.

ADRENERGIC--(SYMPATHOMIMETIC) direct acting

direct acting -- catecholamines (natural occurring)

act directly on adrenergic receptors (agonists)

are chemically related drugs, norepinephrine, epinephrine, dopamine

Catecholamines are broken down in the body by..

MAO and COMT - in nerve endings and throughout the body, including the GI tract. That means  brief action, cannot be given orally.

Are also very polar - so cannot cross blood/brain barrier.

indirect acting ADRENERGIC--(SYMPATHOMIMETIC)

(can be dual-acting combination of direct and indirect acting)

A. produce effects by releasing stored catecholamines

B. block norepinephrine reuptake

C. inhibit norepinephrine inactivation

ADV

Are less polar than catecholamines - do cross blood/brain barrier; longer acting; can be given orally since only broken down slowly or very little by enzymes in GI tract.

in general, alpha action:

produces excitatory effects except GI and eye

in general, beta action:

inhibitory except heart (beta excitatory and alpha not much effect)

alpha 1

*1.  vasoconstriction of arterioles of skin & splanchnic area

2.    pupil dilation

3.    relaxation of GI

 

does contract pylorus, constrict bladder trigone and sphincter, contract uterus, blocks insulin’s release, and stimulates ejaculation.

alpha 2 action

Not used much at this time for therapeutics

beta 1 actions

1. cardiac acceleration and increased contractility

2. Chronotropic = cardiac rate.  Positive is increased pulse rate.

3.  Dromotropic = conduction.  Positive is increased conduction.

4.  Inotropic = contractility.  Positive is increased contraction.

In stimulating these receptors, you will increase cardiac need for oxygen consumption.  So, may eventually diminish heart efficiency.

beta 2 actions

1. bronchial relaxation – increased breathing capacity.

2. vasodilatation of arterioles supplying skeletal muscle for fight or flight.

3.  uterine relaxation.

4.  metabolism – glycogenolysis (liver breaks down glycogen to glucose).

Also decreases stomach motility and tone, relaxes bladder detrusor, and increases free fatty acid release.

direct acting sympathomimetic drugs

actually, catecholamines-closely resemble each other.

Three catecholamines - natural occurring

1. adrenalin (epinephrine)

2. norepinphrine

3. dopamine

4. synthetic catecholamine

Adrenalin (epinephrine)

adrenal medulla; emergency

norepinephrine

highest proportion in body, important transmitter of nerve impulses

dopamine

does have definite role in CNS, not sure here; is precursor of norepinephrine; affects blood flow to mesentery and renal; stimulates cardiac.

synthetic catecholamine

Isuprel - not found naturally

sympathomimetic emeergency conditions:

B1, B2, alpha

b1 sympathomimetic

stimulates heart, increases rate, force and conduction

In cardiac arrest, makes heart more responsive to defibrillation.

b2 sympathomimetic

dilate bronchi (increase tidal volume and vital capacity); dilate arterioles to vital organs and muscles

alpha sympathomimetic

constricts arterioles of bronchioles and inhibits histamine release (although anaphylaxis has release of other chemicals); prevents edema and congestion; decrease nasal congestion also; used as nasal spray.

CNS sympathomimetic

stimulates; yet don’t know how since does not cross blood/brain barrier directly

ADR sympathomimetic CNS

nervousness, dizziness, restlessness, headache

ADR sympathomimetic CV

palpitation, tachycardia, angina, increased BP, arrhythmia

ADR skin sympathomimetic

pallor

ADR resp sympathomimetic

bronchial irritation, pulmonary edema, rebound bronchospasm