Arquivo

1

• Arquivo
• Aspectos farmacocinéticos aplicados a
  farmacocinética
• Dúvidas
• denucci_at_gilbertodenucci.com
• Site
• www.gilbertodenucci.com

2
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

Lag time
(c)
t
Sustained

Technical complexity
(b)
t

Immediate
(a)
t
1950 1960 1970 1980
1990 2000
Chronology
Chronotherapeutics Peter Redfern capitulo 11
fig. 11.1
3
Osmotic delivery system for providing modulated
drug delivery of salbutamol
Coated tablet
Tablet core
Laser-drilled hole
Salbutamol sulfate Sodium chloride
Semipermeable membrane
Chronotherapeutics Peter Redfern capitulo 11
fig. 11.2
4
Modulated release of salbutamol as a function of
diminishing sodium chloride content in Oros tablet
Chronopharmaceutical drug delivery
2.0 1.0 0
Salbutamol release rate (mg/h)
1 6 12
Time (h)
Chronotherapeutics Peter Redfern capitulo 11
fig. 11.3
5
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
6
Time-delayed drug release from tablets coated
with a swellable barrier layer
Hydrophilic polymer layer around core tablet
Drug release by diffusion through gel-barrier
layer
Hydration of barrier layer
Uncoated core tablet
Coated
Release
Time
Chronotherapeutics Peter Redfern capitulo 11
fig. 11.5
7
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)
Lag
2nd dose
Release
1st dose
Time
Chronotherapeutics Peter Redfern capitulo 11
fig. 11.6
8
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
Erosion of barrier layer
Release
Time
Chronotherapeutics Peter Redfern capitulo 11
fig. 11.7
9
Coated pellet delivery system affording a
sigmoidal dissolution profile
Chronopharmaceutical drug delivery
Coating Eudragit RS ethylcellulose
Sigmoidal release
Release
Core Diltiazem Microcrystalline cellulose Sodium
carboxymethylcellulose
Time
Chronotherapeutics Peter Redfern capitulo 11
fig. 11.9
10
Pulsatile dissolution profiles from the TES
pellet delivery system showing influence of
coating thickness on burst time
Coating Ethycellulose
Coat thickness
Core Sugar bead Drug Low-substituted hydroxypropyl
cellulose
Release
Lag-time
Time
Chronotherapeutics Peter Redfern capitulo 11
fig. 11.10
11
Absorption of paracetamol from the hydrophilic
sandwich capsule
7 6 5 4 3 2 1 0
PK Parameter tmax Cmax AUC Time of first
detection in saliva
Value (SD) 7.9 h (0.96) 5.36 µg/mL (2.56) 565
µg/min/mL (353) 5.7 h (0.69)
(Profile from one subject)
Paracetamol in saliva (µg/ml)
(n 13)
0 100 200 300 400 500 600 700 800
900
Time (min)
Chronotherapeutics Peter Redfern capitulo 11
fig. 11.22
12
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.
Normal
16.00
04.00
PEFR or FEV1
Asthmatic
04.00
16.00
Time of day
Chronotherapeutics Peter Redfern capitulo 7
fig. 7.1
13
This figure illustrates the marked frequency of
nocturnal asthma symptoms independent of
medication in 3129 mainly asthmatic patients.
400
350 250 150
Frequency of symptoms
110
70 30 10
10 13 16 19 22
01 04 07
Time of day
Chronotherapeutics Peter Redfern capitulo 7
fig. 7.2
14
Pharmacokinetics of salbutamol when given at
22.00 as tablet and 4 h delayed Pulsincap
6 5 4 3 2 1 0
4 h Pulsincap
Plasma Salbutamol (ng/ml)
Tablet
22 00 02 04
06 08 10
Time of day
Pulsincap and immediate-release tablet
administered at 22.00
Chronotherapeutics Peter Redfern capitulo 11
fig. 11.15
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
16
Influence of molecular size on clearance from
intramuscular sites
Substance Molecular weight Fraction
cleared (5 min) Manitol
182 0.7 Insulin 3 500 0.2 Dextran 70
000 0.07
Physicochemical Principles of Pharmacy Fourth
edition capitulo 9 tab.9.7
17
Buccal absorption of some basic drugs
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
18
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
19
The solid state in pharmaceutical science
pontential causes ans effects of structural change
Physicochemical Principles of Pharmacy Fourth
edition capitulo 1 fig. 1.6
20
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
21
Ideal lipophilic character of drug (log Po) in
different regions of the body
Physicochemical Principles of Pharmacy Fourth
edition capitulo 9 tab.9.1
22
Commercially available drug-delivery systems for
systemic delivery by the oral mucosal routea
Physicochemical Principles of Pharmacy Fourth
edition capitulo 9 tab.9.5
23
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
24
Widely used drugs that may be incompletely
absorbed after intramuscular injection
Ampicillin Digoxin Cefaloride Insulin Cefradin
e Phenylbutazone Chlordiazepoxide Phenytoin Dia
zepam Quinidine Dicloxacillin
Physicochemical Principles of Pharmacy Fourth
edition capitulo 9 tab.9.6
25
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
26
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
27
Pharmaceutical injections of insulin BP
Physicochemical Principles of Pharmacy Fourth
edition capitulo 9 tab. 9.8
28
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
29
Permeability constants of steroids
Physicochemical Principles of Pharmacy Fourth
edition capitulo 9 tab. 9.9
30
Percutaneous absorption of a range of drugs in
humans
Drug Percentage dose absorbed
(120h) Aspirin 22 Chloramphenicol 2 Hex
achlorophene 3 Salicyclic acid 23 Urea 6
Caffeine 48
Physicochemical Principles of Pharmacy Fourth
edition capitulo 9 tab. 9.10
31
The major components of an iontophoretic
drug-delivery system
Physicochemical Principles of Pharmacy Fourth
edition capitulo 9 fig. 9.28
32
(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
33
Log P values of beta-blockers (in increasing
order of lipophilicity)
Physicochemical Principles of Pharmacy Fourth
edition capitulo 9 fig. 9.36
34

• 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).

35
Influence of drug lipophilicity (log P)on the
permeability coefficients (Papp) of beta-blockers
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
36
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
37
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
38
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
39
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.
40
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.
41
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
42
Nasal Surface Area and Nasal Dose Volume
Comparison Between Species
Proteins and Peptides Phamacokinetic,
Pharmacodynamic and Metabolic Outcomes Pag. 181
Tab. 1
43
(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
44
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
45
Oral Protein and Peptide Therapeutics in Clinical
Development
Proteins and Peptides Phamacokinetic,
Pharmacodynamic and Metabolic Outcomes Pag. 193
Tab. 1
46
Brief description of Alzas 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
47
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. 200815585 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
48
120 100 80 60 40 20 0
Loperamide
Clup (mL.100 g-1.min-1)
250 200 150 100 50 0
Verapamil
C. Dagenais et al. / Biochemical Pharmacology 67
(2004) 269276 fig 2
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 lt
0001 vs. control using Bonferroni t-tests.
CTL
4 µM
20 µM
100 µM
Quinidine
49
Interações Medicamentosas

• Antes ou depois da administração
• Interações farmacocinéticas TGI, plasma, fígado,
  rim, cérebro
• Interações farmacodinâmicas

50
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

51
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

52
Alterações que podem influenciar o metabolismo de
medicamentos

• Redução do clearance hepático
• Interação com outros medicamentos

53
Alterações que podem influenciar a eliminação de
medicamentos

• Redução da taxa de filtração glomerular
• Redução da secreção ativa tubular

54
Características comum dos idosos com problemas de
medicação

• Idade gt 85 anos
• Clearance creatinina estimado lt 50mL/min
• IMC lt22kg/m2
• Mais de 6 doenças crônicas
• Reação adversa anterior
• gt 12 doses de medicação por dia
• gt de 9 medicamentos

55
Relação entre a frequência de pacientes que
apresetam reações adversas e o número de drogas
prescritas (r 0.77 P lt 0.001).
60 50 40 30 20 10 0
Risco de DRAPE ()
1 2
3 4
5 6
7 8
9 10
11 12
13 14
15 16
Número de Drogas
OLD DRUGS OLD PEOPLE NEW INSIGHTS - Can J
Clin Pharmacol Vol 12 (1) Winter 2005 e28-e32
January 10, 2005
56
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

57
Interações Medicamentosas

• Antes ou depois da administração
• Interações farmacocinéticas TGI, plasma, fígado,
  rim, cérebro
• Interações farmacodinâmicas

58
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

59
Interações Medicamentosas devido à Eliminação de
Medicamentos

• Inibidores/indutores do sistema da glicoproteína P

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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?

61
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