Arquivo
Aspectos farmacocinéticos aplicados a
farmacocinética
Dúvidas
denucci@gilbertodenucci.com
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www.gilbertodenucci.com
Evolution of drug dissolution profiles from oral drug delivery systems:
(a) immediate release; (b) sustained release; (c) pulsatile or sustained release
following a lag period
Chronopharmaceutical drug delivery
%
Pulsatile
Sustained
Technical complexity
Lag time
(c)
t
Sustained
%
(b)
t
%
Immediate
(a)
t
1950
1960
1970
1980
1990
2000
Chronology
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.1
Osmotic delivery system for providing modulated drug
delivery of salbutamol
Coated tablet
Tablet core
Laser-drilled hole
Semipermeable
membrane
Salbutamol sulfate
+
Sodium chloride
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.2
Modulated release of salbutamol as a function of diminishing sodium
chloride content in Oros tablet
Chronopharmaceutical drug delivery
Salbutamol release rate (mg/h)
2.0
1.0
0
1
6
Time (h)
12
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.3
Oros tablet with barrier layer to provide delayed release of drug
Coated tablet
Laser-drilled hole
Semipermeable membrane
(allows fluid IN, but not drug Out)
Tablet core
Drug-free layer
(hydrophilic polymer provides barrier to water
reaching the interior)
Drug formulation + hydrogel carrier
(absorbs fluid and carries drug out through orifice)
Osmagent
(absorbs fluid, swell, creates osmotic pressure,
pushes out drug formulation)
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.4
Time-delayed drug release from tablets coated with a swellable
barrier layer
Drug release by diffusion
through gel-barrier layer
Hydrophilic polymer
layer around core tablet
% Release
Hydration of
barrier layer
Uncoated
core tablet
Coated
Time
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.5
Biphasic release from a partially coated tablet
Immediate-release
drug layer
Barrier layer exposed
to fluids
Barrier layer removed;
release of second drug dose
Impermeable coat
(partial)
% Release
Lag
2nd dose
1st dose
Time
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.6
Time-delayed drug release from a tablet coated with an erodible
barrier layer
Chronopharmaceutical drug delivery
Erodible layer
around core tablet
Drug release as core
tablet disintegrates
% Release
Erosion of
barrier layer
Time
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.7
Coated pellet delivery system affording a sigmoidal
dissolution profile
% Release
Chronopharmaceutical drug delivery
Sigmoidal
release
Time
Coating
Eudragit RS+
ethylcellulose
Core
Diltiazem
Microcrystalline cellulose
Sodium carboxymethylcellulose
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.9
Pulsatile dissolution profiles from the TES pellet delivery
system showing influence of coating thickness on burst time
Core
Sugar bead
Drug
Low-substituted
hydroxypropylcellulose
Coat thickness
% Release
Coating
Ethycellulose
Lag-time
Time
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.10
Paracetamol in saliva (μg/ml)
Absorption of paracetamol from the hydrophilic sandwich capsule
7
6
5
(Profile from
one subject)
4
3
PK Parameter
tmax
Cmax
AUC
Time of first
detection in saliva
Value
7.9 h
5.36 μg/mL
565 μg/min/mL
5.7 h
(SD)
(±0.96)
(±2.56)
(±353)
(±0.69)
2
(n = 13)
1
0
0 100 200 300 400 500 600 700 800 900
Time (min)
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.22
Both normal subjects and asthmatic patients have circadian alterations in lung function,
with nadirs occurring at approximately 04.00. Circadian variation in lung function is
increased in asthmatics compared to normal subjects. PEFR, peak expiratory flow rate;
FEV1, Forced expiratory volume in one second.
PEFR or FEV1
Normal
16.00
04.00
Asthmatic
16.00
04.00
Time of day
Chronotherapeutics – Peter Redfern – capitulo 7 – fig. 7.1
This figure illustrates the marked frequency of nocturnal asthma
symptoms independent of medication in 3129 mainly asthmatic
patients.
400
Frequency of symptoms
350
250
150
110
70
30
10
10°°
04°°
13°°
07°°
16°°
19°°
22°°
01°°
Time of day
Chronotherapeutics – Peter Redfern – capitulo 7 – fig. 7.2
Pharmacokinetics of salbutamol when given at 22.00 as tablet and 4 h
delayed Pulsincap
Plasma Salbutamol (ng/ml)
6
5
4h
Pulsincap
4
3
2
Tablet
1
0
22°°
08°°
00°°
10°°
02°°
04°°
06°°
Time of day
Pulsincap and immediate-release
tablet administered at 22.00
Chronotherapeutics – Peter Redfern – capitulo 11 – fig. 11.15
The effect of hyoscine and pH on its flux across a membrane; increasing
the pH increases the flux as ionisation is decreasesd
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.28
Influence of molecular size on clearance from intramuscular sites
Substance
Manitol
Molecular weight
Fraction cleared
(5 min)
182
0.7
Insulin
3 500
0.2
Dextran
70 000
0.07
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – tab.9.7
Buccal absorption of some basic drugs
Chlorphenamine (pKa= 8.99)
Methadone (pKa= 8.25)
x Amfetamine (pK = 9.94)
a
Pethidine (pKa= 8.72)
Nicotine (pKa= 8.02)
The drugs were dissolved in buffered solutions of different pH and placed in the mouth of human subjects; absorption rates
were determined from the decrease of drug concentration in expelled solutions
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.16
The influence of vehicle pH on the aqueous humor concentration of
pilocarpine and glycerol
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.34
The solid state in pharmaceutical science: pontential causes ans
effects of structural change
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.6
Photomicrographs showing the solution phase polymorphic conversion of orthorhombic
paracetamol (needles) to monoclinic paracetamol (prisms and plates)
a
b
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – fig. 1.12
Ideal lipophilic character of drug (log Po) in different regions of
the body
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – tab.9.1
Commercially available drug-delivery systems for systemic delivery by the
oral mucosal routea
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – tab.9.5
Relationship between the log P of solute and the percentage absorption
through the buccal mucosa of human subjects for bases and acids
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.15
Widely used drugs that may be incompletely absorbed
after intramuscular injection
Ampicillin
Cefaloride
Cefradine
Chlordiazepoxide
Diazepam
Dicloxacillin
Digoxin
Insulin
Phenylbutazone
Phenytoin
Quinidine
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – tab.9.6
Routes of parenteral medication, showing the tissues penetrated by
intramuscular, intravenous, subcutaneous and intradermal injections.
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.17
Plasma diazepam levels 90 min after intramuscular injection by one doctor and several
nurses, showing the importance of technique and site of injection, which was variable in the
latter group
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.18
Pharmaceutical injections of insulin BP
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – tab. 9.8
‘Bricks and mortar’ model of the stratum corneum, illustraing possible pathways of
drug permeation through intact stratum corneum and the lamellar structure of
intercellular lipids
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.21
Permeability constants of steroids
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – tab. 9.9
Percutaneous absorption of a range of drugs in humans
Drug
Aspirin
Chloramphenicol
Hexachlorophene
Salicyclic acid
Urea
Caffeine
Percentage
dose absorbed
(120h)
22
2
3
23
6
48
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – tab. 9.10
The major components of an iontophoretic drug-delivery system
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.28
(a) The influence of donor pH and ionic strength of the donor medium on buserelin
permeation. (b) Continuous iontophoresis and release of buserelin through the stratum
corneum, showing the effect of increasing the current
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.30
Log P values of beta-blockers
(in increasing order of
lipophilicity)
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.36
• Beta-blocker eye drops (brand names in
parenthesis) approved for glaucoma
treatment include timolol (Timoptic,
Betimol, Istalol), levobunolol (Betagan),
carteolol
(Ocupress),
metopranolol
(OptiPranolol) and betaxolol (Betoptic).
Influence of drug lipophilicity (log P)on the permeability coefficients (Papp) of betablockers across (a) the conjunctiva and (b) the cornea of the pigmented rabbit. Plot (c)
shows the influence of log P on the ratio of the corneal (C) and conjunctival (J)
permeability coefficients
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.37
Deposition of particles in various anatomical regions of the respiratory
tract from bronchus to alveoli according to particle size
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.43
Anatomical structures and pathways of drug movement important in
intrathecal drug administration; the lower part (sacral, lumbar) of the spinal
cord is shown in this diagram
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.56
Cross-section of the penis,
showing differences in the
corpora cavernosa between
erection and flaccidity.
Diffusion path lengths
following direct injection
are short
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 9 – fig. 9.57
Worldwide Pharmaceutical Market by Sectors, through 2008
($ Billions)
RB-191 World Pharmaceutical Markets - Published: March 2004
Data and analysis extracted from this press release must be accompanied by a statement identifying
BUSI(ESSCOMMU(ICATIO(S COMPANY, INC.
Worldwide Pharmaceutical Market by Sectors, 2000-2003 and 2008
($ Billions)
RB-191 World Pharmaceutical Markets - Published: March 2004
Data and analysis extracted from this press release must be accompanied by a statement identifying
BUSI(ESSCOMMU(ICATIO(S COMPANY, INC.
Absorption rate hydrocortisone tertiary butyl acetate
and prednisolone tertiary butyl acetate (mg h-1 cm-2)
Physicochemical Principles of Pharmacy – Fourth edition – capitulo 1 – tab 1.5
Nasal Surface Area and Nasal Dose Volume Comparison Between Species
Proteins and Peptides Phamacokinetic, Pharmacodynamic and Metabolic Outcomes – Pag. 181 – Tab. 1
(A) Insulin pharmacokinetics in humans for intranasal formulation (solid line) and
NovoLog (filled circles). (B) Comparison of bioavailability of various IN insulin
formulations dosed in rabbits and humans
Proteins and Peptides Phamacokinetic, Pharmacodynamic and Metabolic Outcomes – Pag. 183 – Fig. 2
Insulin phamacodynamics in humans for IN formulation (black line), insulin aspart (gray line), and usual therapy
(dash line). With respect to postmeal glucose at the 60- and 90-minute postmeal time points, the study demostrated
that both insulin aspart and IN insulin were significantly better than placebo at lowering postmeal glucose and that
IN insulin was non-inferior to insulin aspart. IN insulin results in statistically significant postmeal glucose reduction
compared with usual therapy at 60 and 90 minutes. The glucose reduction following IN insulin is noninferior to
thatfollowing insulin aspart at 60 minutes and 90 minutes.
Proteins and Peptides Phamacokinetic, Pharmacodynamic and Metabolic Outcomes – Pag. 184 – Fig. 3
Oral Protein and Peptide Therapeutics in Clinical Development
Proteins and Peptides Phamacokinetic, Pharmacodynamic and Metabolic Outcomes – Pag. 193 – Tab. 1
Brief description of Alza’s two OROS® osmotic therapeutic systems: (a)
basic osmotic pump; (b) push-pull OROS®
Oral Controlled Release Formulation Design and Drug Delivery – Pag. 7 – Fig. 1.4
Medical errors are an important factor that influences the quality of patient care. According to Barach et al., nearly
100,000 individuals per year in the US die of preventable medical errors. (J Am Med Inform Assoc. 2008;15:585– 600.
DOI 10.1197/jamia.M2667)
Objective: Evaluation of a computerized physician order entry in an Internal Medicine Department, with a unit-dose
distribution system.
Setting: Pharmacy Department, Internal Medicine Department.
S. Francisco Xavier Hospital, Lisbon, Portugal.
Method: This study was carried out in December 2001 and January 2002. After two years experience of the CPOE system,
medication errors were evaluated prospectively, in an internal medical department of a 360-bed academic hospital. Data were
collected once a week. Pharmacists reviewed all medical prescriptions as part of their routine work. Medication errors detected
were recorded on a data collection form with a design based on the types of errors as defined by the American Society of
Hospital Pharmacists (ASHP). Completed forms were reviewed and medication errors were classed according to ASHP
guidelines.
Results: A total of 2268 orders were monitored (162 patients). In these orders, 73 medication errors (22.4% of the patients)
were detected and documented (59 prescribing errors and 14 monitoring errors). The most common prescribing errors were
deficiencies related to the right class but wrong drug (28.3%): omeprazole vs. ranitidine/sucralfate in stress ulcer prophylaxis;
incorrect dose (30%) and unclear orders (13.3%). Errors related to incorrect frequency of administration (5%); maintenance of
IV route (5%); duplicated drug therapy (11.7%); drug interactions (1.7%) and length of therapy (3.3%) were also detected. The
14 monitoring errors detected were failures to review a prescribed regimen for appropriateness and detection of problems.
Conclusions: Computerized prescription order entry has demonstrated effectiveness in eliminating medication errors related to
transcribing and patient identification. Nevertheless, medication errors related to prescription and monitoring still occur.
a. Qual seria a(s) sua(s) sugestões? Justifique. (1.0)
Prova Medicina Unicamp 2009 – Turma B
250
200
Loperamide
Verapamil
150
100
50
0
Quinidine
C. Dagenais et al. / Biochemical Pharmacology 67 (2004) 269–276 – fig 2
Clup (mL.100 g-1.min-1)
Initial brain uptake clearances (Clup, mL100
g1min1) of loperamide (2 mM) and verapamil
(0.5 mM) in the absence (control) and
presence of increasing concentrations of
quinidine during in situ perfusion (100 s) in
wild-type mice. P < 0:001 vs. control using
Bonferroni t-tests.
120
100
80
60
40
20
0
Interações Medicamentosas
• Antes ou depois da administração
• Interações farmacocinéticas: TGI, plasma, fígado,
rim, cérebro
• Interações farmacodinâmicas
Alterações que podem influenciar a absorção
de medicamentos
•
•
•
•
•
Redução do fluxo intestinal
Redução do tempo de esvaziamento gástrico
Redução do peristaltismo intestinal
Hipocloridria
Redução da superfície gastrointestinal
Alterações que podem influenciar a distribuição de
medicamentos
•
•
•
•
Redução da concentração de albumina
Redução da alfa-glico proteína
Redução da massa muscular
Aumento da gordura corporal
Alterações que podem influenciar o metabolismo de
medicamentos
• Redução do clearance hepático
• Interação com outros medicamentos
Alterações que podem influenciar a
eliminação de medicamentos
• Redução da taxa de filtração glomerular
• Redução da secreção ativa tubular
Características comum dos idosos com
problemas de medicação
•
•
•
•
•
•
•
Idade > 85 anos
Clearance creatinina estimado < 50mL/min
IMC <22kg/m2
Mais de 6 doenças crônicas
Reação adversa anterior
> 12 doses de medicação por dia
> de 9 medicamentos
Relação entre a frequência de pacientes que apresetam reações
adversas e o número de drogas prescritas
(r = 0.77; P < 0.001).
60
50
40
30
20
10
15 – 16
13 – 14
11 – 12
9 – 10
7–8
5–6
3–4
1–2
0
Número de Drogas
OLD DRUGS – OLD PEOPLE – NEW INSIGHTS - Can J Clin Pharmacol Vol 12 (1) Winter 2005: e28-e32; January
Medicação para efeitos colaterais
• Antagonistas alfa-adrenérgicos – tratamento de retenção urinária devido
a agentes anti-colinérgicos
• Antieméticos – tratamento de náusea induzida por digoxina
• Antitussígenos – tosse causada por inibidores de ECA (captopril)
• Antiácidos, bloqueadores H2, inibidores de bomba de prótons –
dispepsia causada por AINEs
• Laxantes – constipação causada por verapamil
• Agentes sedativos – agitação causada por antidepressivos tipo fluoxetina
Interações Medicamentosas
• Antes ou depois da administração
• Interações farmacocinéticas: TGI, plasma, fígado, rim,
cérebro
• Interações farmacodinâmicas
Interações Medicamentosas devido a metabolismo
hepático
• Quase sempre devido à interação com reações
de fase I, raramente reações de fase II
• Geralmente interação com enzimas do
citocromo P450, que podem estar ausente
Interações Medicamentosas devido à
Eliminação de Medicamentos
Inibidores/indutores do sistema da glicoproteína P
9 perguntas fundamentais
•
1. Cada medicação é necessária?
•
2. Esta medicação está contra-indicada nesta faixa etária?
•
3. Há duplicação de medicamentos?
•
4. O paciente está tomando a menor dose necessária para eficácia?
•
5. A medicação que está sendo associada é para tratar efeito colateral de outra medicação?
•
6. É possível simplificar o esquema terapêutico?
•
7. Há interação medicamentosa no atual esquema terapêutico?
•
8. O paciente é aderente ao tratamento?
•
9. O paciente está tomando OTC, vitaminas ou alguma medicação sugerida/dada por outra
pessoa?
Medicamentos com alto potencial de interação
•
•
•
•
•
•
•
•
•
Amiodarona
Beta-bloqueadores
Sequestrantes de ácido biliares
Carbamazepina
Cimetidina
Digoxina
Diuréticos
Eritromicina
Fluoroquinolonas
•
•
•
•
•
•
•
•
•
Suco de toronja
Cetoconazol
Inibidores da MAO
Nitratos
Fenobarbital
Fenitoína
Simvastatina
Teofilina
Warfarina
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