Pharmacology for

physioterapists -

bachelor study

Faculty of Physical Education and Sport

Academic year 2015-2016

Lecturers:

Dalibor Černý, Pharm.D. Ph.D.,

Nikolina Kutinová Canová M.D., Ph.D.

Lectures for physiotherapists

Lecture 1 – 13th October 2015 (DČ*)

Lecture 2 – 3rd November 2015 (NKC*)

Lecture 3 – ???10th November 2015 (DČ*) – needs to change

Lecture 4 – 24th November 2015 (NKC*)

Final test – ???1st December 2015(DČ*) - needs to change

Topics:

• Introduction to Pharmacology ; Conditions for course credit; General Pharmacology- pharmacokinetics, pharmacodynamics, adverse drug effects etc.

• Drugs affecting autonomic nervous system; Peripherial myorelaxants; Cardiovascular drugs.

• Local antibiotics; Respiratory drugs; Obesity and metabolic syndrom treatment.

• Drugs affecting CNS; Central myorelaxants.

• Non-steroidal antiinflammatory drugs; Pain killers.

• Sex Hormones and hormonal contraception; Anabolic steroids; Antidiabetics; Glucocorticoids; Agents affecting bone mineral turnover.

General conditions

• Start/End: 14:00 / 17:00

• Location: FTVS, José Martího (DČ) or Institute of Pharmacology

1. LF UK, Albertov 4, Praha 2, classroom on the 2nd floor (NKC)

• Two lecturers: Dalibor Černý, Nikolina Kutinová Canová

• Conditions for getting classified credit

– full presence at four seminars (one absence is possible when

having a confirmation from physician)

– to pass the multiple choice test at the end – 50 questions

• Useful literature: Ramesh K, Ashok SK., Pharmacology For

Physiotherapist (Jaypee Brothers Medical 2005)

What is pharmacology?

• science dealing with drug destiny and effects, which are

observed in living organisms

• science studying drug interactions with organism on different

levels (molecular, cellular, tissue, organs)

• Basic pharmacology – general pharmacology – observing the

drug absorption, distribution and elimination in/from human

organims (pharmacokinetics) and molecular aspects of drug-

organism interaction (pharmacodynamics)

• Applied pharmacology – special pharmacology – dealing with

drug treatment of specific diseases

Place

for

pharmaco-

logy

in

medical

sciences

MEDICINE

diagnosis therapy

physiotherapy

pharmacotherapy actinotherapy

psychotherapy

subtitutional/symtomatological causal

FARMACOLOGY TOXICOLOGY

A) Farmacodynamics

B) Farmacokinetics

Experimental pharmacology Clinical pharmacology and pharmacy

PHARMACY

Terms in pharmacology

• Drug – substance or product, used or considered for use in order to modify or affect the physiological systems or patological stages for the benefit of the organism that is receiving this substance

• Medicament = remedy – formulated drugs - effective drug with adjuvants in some form (injection, tablets, suppository) which is applicable for patients

• Adjuvants - inert substances without any significant effects used to prepare or manufacture the formulated drugs (lactose, sucrose, mineral oils)

Pharmaceutical

phase

desintegration

desagragation

disolution

Pharmacokinetic

phase

absorption

distribution

metabolism

excretion

Pharmacodynamic

phase

drug-receptor

interaction

drug form

availability

biological

availability

biological

effect

Usual ways how to administer drugs

• oral – by mouth

• peroral – to GIT

• intravenous – to the vein system

• intramuscular – to muscles

• transdermal – via skin

• rectal – to anus

• intrathecal – to cerebrospinal liquid

• by inhalation – to lungs

absorption

distribution

metabolism

excretion

pharmacokinetics

enzymes

transport systems

location of drug effect

pathophysiology

disease

pharmacodynamics

receptors

enzymes

ion channels

drug effect +

Factors affecting drug effect

Molecular mechanisms of drug effect

• NON-receptor mechanisms

(non-specific)

using the physical-chemical properties

low selectivity

• Receptor mechanisms

(specific)

direct interaction with the natural macromolecule

(drug targets – mainly receptors)

high selectivity

Non-receptor mechanisms

• General anaesthetics: liposolubility affecting of neurone membrane fluidity

• Drugs with osmotic activity : osmotic diuretics (mannitol), infuse solutions, plasma expanders - dextrane, osmotic laxatives (magnesium sulphate)

• Drugs using their redox potential: cyanides and nitrits intoxication therapy

• Drugs affecting pH: in urine: NaHCO3, NH4Cl; in stomach: Mg(OH)2 nebo Al(OH)3 + HCl H2O + MgCl2 nebo AlCl3,;

• Adsorbents: activated carbon (carbo medicinalis); diosmectid

• Drugs making chelate complexes: ion bounding - deferoxamine, penicilamine, CaEDTA, dimercaprol

• X-ray contrast substances: high density of X-ray absorption (iodine substances)

• Radionuclides: 88Sr – bone cancer diagnostics, 131I thyroid gland cancer treatment

Receptor mechanisms

• Direct signal transduction from receptor to efector

• RECEPTORS = selective molecular parts of the

biological system, interacting with drug

• EFFECTORS = molecular components joined to

receptors and inducing functional changes of cells by

chemical intra- or intercellular signaling

Receptor types

• Dividing according to cellular localization:

– transmembrane proteins/enzymes

– transmembrane proteins connected to G-protein (metabotropic)

– ion channels on membrane (ionotropic)

– intracelullar receptors

Dividing according to the function (drug targets):

– key regulatory proteins (targets for neuromediators/hormones)

– transport proteins (ion pumps, reuptake systems)

– structural proteins

– enzymes

Dividing according to cellular localization

• Ionotropic receptors – located directly on ion

channels, affecting the permeability of channel →

depolarization or hyperpolarization of membrane,

response very quick (ms)

• Metabotropic receptors – located on membrane,

affecting the second messengers (cAMP, cGMP, Ca

signal…), changes in the cell, response quick (s)

• Receptors joined with proteinkinase activity –

changes in cell mediated via phosphorylation of

specific (key) protein, response quite slow (min)

• Intracellular receptors – located on the membrane

covering the cellular nucleus, reponse slow (h,d)

1. RECEPTORS

2. ION

CHANNELS

3. TRANSPORT

MOLECULES

4. ENZYMES

r. on ion channels

r.joined with G proteins

membr.

regulated by

membrane potential

- calcium

- natrium

„pumps“ - natrium

- proton

transporters

cardioglycosides

PP inhibitors

local anaest.

amlodipine

perhaps 45% of

drugs, f.e. beta-

antagonists

antidepressants

ACE, MAO inhibitors

perif. myorelaxants

drug examples:

r. on enzymes intracelul.

.

regulated ligands, f.e. by G-

prot., etc..

ACE, MAO, COX, HMG-CoA reduktase etc.

Dividing according to the function

Affinity and efficacy

Affinity (A) • drug molecule ability to bind itself to receptor

• is related with the concentration, which causes 50% of maximum

effect

• see figure

Intrinsic activity (α) - efficacy • drug molecule ability to make signal, induce changes and cause

effect

Affinity (A)

Black drug has lower affinity than blue

one!

Intrinsic activity (α) - efficacy

full agonist

partial agonist

antagonist – kompetitive, irreversible

(inverse agonist)

Drug-receptor interaction aspects

R = receptor

A = drug

RA = drug-receptor complex

k+1 = constant of association

k-1 = constant of dissociation

T = transducer

effectors = molecules implementing the drug-receptor

interaction to the cell activity changes

Receptor theories (RT)

• Occupation RT – total effect is directly depende on

amount of occupied receptors

– Linear variation – the highest efffect is concerned with

the occupation of all the receptors

– Non-linear variation - the highest efffect is not

concerned with the occupation of all the receptors,

the rest is receptor reserve [R] see the next slide…

• Frequential RT – achieved effect is directly

concerned with the frequency of establishment and

extinguishment of drug-receptor complexes –

agonists (quick), antagonists (slow)

Other related terms concerned with receptors

• Receptor heterogenity – means existence of more

receptor subtypes frome one type; they can have

different structure, function, regulatory mechanism

and tissue occurence

• Receptor function regulation – desenzitisation,

hypersensitivity

= lower/higher sensitivity on drug with different clinical

affects

• Receptor „diseases“ – mutation in the gene for

receptor, autoantibodies against receptors..

Quantal relationship dose-effect

• Quantal curves describes interindividual variability

in population; it means we can achieve at different

people the same effect by different doses

– Quantal reaction – we administer some acurate dose

to the group of people and then we observe, if the

effect occurs or not: YES/NO system

– Medium effective dose (ED50) – dose, which causes

expected effect at 50% of treated people (in group)

– Medium toxic dose (TD50) - dose, which causes

adverse effects at 50% of treated people (in group)

• Derived parameters:

• Therapeutical index – IT=TD50/ED50=TD5/ED95

• Therapeutical range – difference mezi TD50 a ED50

Repeated drug administration…

…can cause:

• amplification of effect - accumulation

• attenuation of effect - adaptation

• drug addiction

Accumulation risks

• failure of elimination organs – liver, kidney

(non-steroidal antiinflammatory drugs, sedatives)

• fuctional failure of other organs or tissues – nerves

(local anaesthetics, aminoglycosides + furosemide)

• chronical damage of tissues by high lipophilic

substance – risk for gravidity (PCB)

Adaptation

– Tolerance – slow and silent attenuation of effect

• Kinetic – due to higher elimination

• Dynamic – due to adaptation in tissues

– Physical addiction - graduated dynamic tolerance

(example. ethanol, opiates, clonidine, laxatives,

antiepileptics)

two symtoms typical at sudden drug layoff:

• Abstinential syndrome – new inconvinient symtoms

• Rebound phenomen – there occurs new worse symtoms

than those, for them you administer the original drug

(up/down receptor amount regulation)

Tachyphylaxis Obr. 33. Tachyfylaxe po opakovaném podávání efedrinu (pokles vlivu na TK)

E = podání efedrinu

EE E

0 5 10 15 20 25 30min

Tachyphylaxis after repeated administration of ephedrine

(decrease of blood pressure involvement) – depletion of NA reserves

E = ephedrine administration

Drug interactions

Drug interactions and statistics

• the more drugs are used, the higher risk of

interactions occurs

– 10 drugs 10% risk, 15 drugs 20% risk, 20 drugs

50% risk!!!

• adverse effects are the 4th most frequent cause of

death in USA (70% of cases are caused by drug

interactions) (Philips et al: JAMA 2001)

Definition and types

DI = drug interacts with another substance in body (endogenous/exogenous)

– with an explained/not-explained mechanism

Different aspect of dividing od DI: • pharmacodynamic (on receptor) / pharmacokinetic (on

the level of ADME) – SPECIAL BRANCHE OF PHARMACOLOGICAL RESEARCH!

• Pharmacodynamic DI:

– positive (synergic) / negative (antagonistic) - detrimental

– clinically significant (reported) / non-significant („silent“)

Positive (synergic) interaction

Summation (1+1=2)

• one-sided : analgetics + narcotics

• both-sided : combination of cytostatics

Potenciation (1+1=3)

• one-sided : Ca2+ + digoxin

• both-sided : digoxin + thiazide diuretics

Negative (antagonistic) interaction

Antagonism can be:

• pharmacological ACH + atropine

• physiological ACH + adrenaline

• chemical (pharmaceutical) heparine + protamine

sulphate

Pharmacodynamic interaction - examples

• Diuretics + digoxin: hypokalaemia - cardio-

glykosid toxicity

• MAOInhibitors + ephedrine, tyramine: hyper-

tension

• Warfarin + ASA (NSAID): bleeding

• NSAID + antihypertension treatment: of

antihypertension effect

• antihistaminics + alcohol: sedation

Pharmacokinetic interactions

…on the level of:

• Absorption

• Distribution

• Biotransformation

• Excretion

…Absorption

• Inhibition/activation of release from drug form

– omeprazole in enterosolvent coat + antacids

• Inhibition of resorption

– cholestyramine, active carbon x warfarin, digoxin

– adrenaline in local anaestetics

• GIT motility affecting, stomach propulsions

– acceleration - metoclopramide, cisapride

– deceleration - atropine, opioids

…Distribution

• Plasma protein binding – short term changes in drug

levels, competition between drugs for the plasma

protein

• warfarin + NSAID, peroral antidiabetics,

sulfonamides, fenytoin

• verapamil, amiodarone + digoxin

• diazepam + fenytoin, tubocurarin, suxamethonium

…Biotransformation (overview)

Phase I

(Functionalization):

Oxidation

Cytochrome P450

Alcohol Dehydrogenase

Monoamine Oxidase

Reduction

Cytochrome P450

Hydrolysis

Esterases (ASA)

Amidases (indometacin)

Phase II

(Conjugation):

Glucuronosyltransferases

Acetyltransferases

Sulfotransferases

Methyltransferases

Glutathione Transferases

Amino Acid Transferases

Cytochrome P 450 (CYPs)

• CYP3A4 (metabolizes 50% of drugs)

– inhibitors: amiodarone, clarithromycine, fluconazole, ethinylestradiol..

– inductors: phenobarbital, phenytoin, rifampicine, troglitazone..

• CYP2D6 (metabolizes 25-30% of drugs) - high polymorphism!

– inhibitors: amiodarone, metoclopramide, moclobemide, paroxetin

– inductors: antidepresants, neuroleptics, metoprolol, tramadol

• CYP2C9 (metabolizes 15% of drugs) – high polymorphism!

– inhibitors: fluvastatine, trimethoprim, barbiturates, paroxetine

– inductors: diclofenac, losartan, ibuprofen, tamoxifen

• CYP1A2 (only in the liver)

– inhibitors: oestrogens, grapefruit sauce, lidocaine

– inductors: grilled meat, coffeine, omeprazole, griseofulvine

…Excretion

• Binding change to plasma proteins - free fraction of

drug - glom. filtration - exkretion by kindey

• Inhibition of tubullar sekretion

– probenecid x penicilin, azithromycine

• Change in urine amount or pH

– diuretics, system antacids

Adverse effects of drugs

Adverse effect definition

• An unwanted, undesirable or harmful effect of drug

to an organism, indicated by some result such as

mortality, altered food consumption, altered body

and organ weights, altered enzyme concentrations

or visible pathological changes.

Serious adverse effect / event

• death

• health hazard

• serious health damage

• permanent results after treatment

• hospitalisation

• congenital abnormality in baby

Unexpected adverse effect

= effect of drug, which is not written in SPC information

or in documentation for examinator in case of

clinical research

Obligation to make report for healt care workers

(by law)

• physician, pharmacist or stomatologist are obligated to

report all the serious or unexpected adverse effect, not

adverse effects already reported or published

System of farmacovigilance

• continual drug safety monitoring in state and drug producing

company position

• analysis of risks

• AIM:

– to minimalize risks concerned with drug usage

Adverse effects occurrence

• 10 - 20 % of all hospitalised pacients

• Pirmohamed BMJ 1998;316:1295-98

Classification od adverse effects

Klasifikace nežádoucích účinků léčiv

Typ (jednoslovná

charakteristika

v angličtině )

Popis Příklad

A (Augmented) Vyplývají z farmakologických účinků léčiva, přičemž

se projeví (zvýrazní) ty, které jsou nežádoucí. Jsou

proto předvídatelné a mohou se vyskytnout u kohokoli

v závislosti na dávce a terapeutické šíři.

zácpa po opioidech nebo

anticholinergních léčivech

B (Bizzare) Nezávisí na typických farmakologických účincích

léčiva ani na dávce. Obvykle nepředvídatelné.

Vyskytují se jen u někoho, jako projev přecitlivělosti,

idiosynkrazie.

exantém po ampicilinu

porfyrie po karbamazepinu

aplast. anemie po

chloramfenikolu

C (Continuous) Spojené s dlouhodobým podáváním léčiva analgetická nefropatie

tardivní dyskinézy po

neuroleptikách

D (Delayed) S opožděným (oddáleným) výskytem (i po delší době

po přerušení podávání léčiva)

teratogeneze

karcinogeneze

E (Ending of Use) Brzy po vysazení léčiva adrenokortikální

nedostatečnost po vysazení

kortikoidů

Types of adverse effects

• Reversible

• bleeding after anticoagulation treatment,

hypoglykemia at insulinoterapia

• Ireversible

• tarditive dyskineses after neuroleptics

• agranulocytosis after clozapine

Thank you for your attention….