Pharmacokinetic Flashcards
(159 cards)
1
Q
What is pharmacokinetics?
A
Is the effect of the body on the drug. Include: ADEM
Absorption
Distribution
Metabolism
Excretion
2
Q
Elimination through liver is called
A
Metabolism
3
Q
Elimination of lipophilic drug occur in
A
Hepatic liver
4
Q
Elimination of hydrophilic drug occur in
A
Kidney
5
Q
Absorption of the drug Occurs mainly by ______ which depends on degree of _______ of the drug
A
Lipid passive diffusion
Ionization
6
Q
What is pka
A
• PKa (Dissociation constant): is the pH of medium at which 50% of drug molecules are ionized & 50 % unionized.
7
Q
pH of medium = pKa of the drug—>
A
50% unionized (lipid soluble) and 50 % is ionized ( water soluble)
8
Q
pH of medium < pKa of drug →
Weak acid :
Weak base :
A
ionization decrease (More unionized)
e.g aspirin [pka =3.5] exist mainly in non ionized (lipid soluble) form at gastric pH 1.5 -2.5
ionization ↑ (less unionized)
9
Q
lonization of weak bases
decreases at
A
Ph>pka
9
Q
E.g for lonization of weak bases
A
e.g. Theophylline (pka = 8.8) is mostly non-ionized (lipid soluble) at alkaline pH of the intestine.
10
Q
lonization of weak bases
decreases at pH > pka
A
e.g. Theophylline (pka = 8.8) is mostly non-ionized (lipid soluble) at alkaline pH of the intestine.
10
Q
lonization of weak bases
decreases at pH > pka
A
e.g. Theophylline (pka = 8.8) is mostly non-ionized (lipid soluble) at alkaline pH of the intestine.
11
Q
lonization of weak bases
decreases at pH > pka
A
e.g. Theophylline (pka = 8.8) is mostly non-ionized (lipid soluble) at alkaline pH of the intestine.
12
Q
lonization of weak bases
decreases at pH > pka
A
e.g. Theophylline (pka = 8.8) is mostly non-ionized (lipid soluble) at alkaline pH of the intestine.
12
Q
lonization of weak bases
decreases at pH > pka
A
e.g. Theophylline (pka = 8.8) is mostly non-ionized (lipid soluble) at alkaline pH of the intestine.
13
Q
lonization of weak bases
decreases at pH > pka
A
e.g. Theophylline (pka = 8.8) is mostly non-ionized (lipid soluble) at alkaline pH of the intestine.
13
Q
lonization of weak bases
decreases at pH > pka
Give e.g for that
A
e.g. Theophylline (pka = 8.8) is mostly non-ionized (lipid soluble) at alkaline pH of the intestine.
14
Q
How peptic ulceration ouccr in GIT due taking aspirin orally ?
A
• Aspirin is acid → mostly unionized (non-polar) = Lipid soluble in the empty stomach → cross the cell membrane of gastric mucosa to be trapped inside these cell(mucosa cells) (acid trap) > death of the cells (peptic ulcer).
• Aspirin → Peptic ulcer (PU) due to acid trap + inhibition of Cyclooxygenase (cox) enzyme → decrease PGs(prostaglandin) which is protective against PU in the stomach دا هو السبب الأهم
15
Q
Aspirin is part of
A
NSAIDs
non-steroidal anti-inflammatory drugs
هي انزيمات وحشه تضرب prostaglandin
16
Q
How to inhibit tubular reabsorption during drug poisoning in kidney?
A
In drug poisoning, Renal drug elimination can be increased by changing urinary pH
↑ drug ionization→ decrease tubular reabsorption of the drug →↑ its renal excretion
17
Q
How to inhibit tubular reabsorption during drug poisoning in kidney?
A
In drug poisoning, Renal drug elimination can be increased by changing urinary pH
↑ drug ionization→ decrease tubular reabsorption of the drug →↑ its renal excretion
17
Q
How to inhibit tubular reabsorption during drug poisoning in kidney?
A
In drug poisoning, Renal drug elimination can be increased by changing urinary pH
↑ drug ionization→ decrease tubular reabsorption of the drug →↑ its renal excretion
18
Q
How to inhibit tubular reabsorption during drug poisoning in kidney?
A
In drug poisoning, Renal drug elimination can be increased by changing urinary pH
↑ drug ionization→ decrease tubular reabsorption of the drug →↑ its renal excretion
19
Q
How to inhibit tubular reabsorption during drug poisoning in kidney?
A
In drug poisoning, Renal drug elimination can be increased by changing urinary pH
↑ drug ionization→ decrease tubular reabsorption of the drug →↑ its renal excretion
19
How to inhibit tubular reabsorption during drug poisoning in kidney?
In drug poisoning, Renal drug elimination can be increased by changing urinary pH
↑ drug ionization→ decrease tubular reabsorption of the drug →↑ its renal excretion
20
During Acidic drugs poisoning in renal , the urine should be ____ for treatment
Alkalized
21
E.g for Acidic drug
Aspirin, phenobarbital
22
During basic drugs poisoning in kidney, urine should be ____ to avoid reabsorption of it in blood
Acid
تذكر قصة دكتور خليفة مع الود إلي شرب صاحبه عصير برتقال عشان ينقذه من جرة amphetamine
23
E.g for basic drug
Amphetamine
اي مركب آخره mine هو قاعدي
24
What is bioavailabilty?
Definition: It is the percentage of drug that reaches the systemic circulation and becomes available for biological effect.
25
Bioavailability of IV
100%
26
↑ Absorption --> increase bioavailability
True
27
Increase of First pass metabolism--> Increase of bioavailability
False
28
How to calculate bioavailability?
(AUC oral/AUC IV) × 100
29
Factors affecting bioavailability (F)
Amount of drug absorbed = Factors affecting GIT absorption
2 First Pass Metabolism (FPM) = Pre-systemic elimination
30
E.g for parental
IV
IM
subcutaneous
31
What is bioequivalence?
2 dosage forms have the same (bioavailability & time to reach the peak)
32
What is Therapeutic equivalence?
2 drugs form have same bioequivalent drug + have similar efficacy & toxicity.
33
Name factors affecting absorption from GIT
. Factors related Dosage form: (affect disintegrationتفكك)
Factors related to Drug: (affect dissolutionنحلل)
Factors affecting drug Stability in GIT content
GIT pH & drug's pKa
Factors related to Absorptive system
34
E.g for factors related to Dosage form
Synthesis techniques طرق التصنيع
& excipients added during preparation إضافات لتحسين الدواء
35
E.g for factor related to Drug
Molecular weight (MW)
lipid solubility
36
Factors affecting drug Stability in GIT content
GIT secretions (HCL) --> with e.g
Food-->
HCL can destruct some drugs : e.g. erythromycin
Dairy food منتجات الالبان decreases absorption of tetracyclines (ca++)
37
GIT pH& drug's pKa example
Affect degree of drug ionization → affect lipophilicity
38
Factors related to Absorptive system
•GIT motility:
Surface area:
• GIT disease:
Prokinetics (↑) & anticholinergics (decrease) motility of GIT
Intestine >>> stomach معظم كمية الدواء تمتص في الأمعاء
e.g. Mal absorption syndrome
39
What is pre systematic elimination or FPM?
It is the metabolism of the drug through the liver, GIT wall or lung before reaching systemic circulation
40
E.g for FPM drug in
Hepatic:
Pulmonary:
Intestine:
Nitroglycerine يؤخذ sublingualافضل & propranolol
اي دواء آخره lol هو beta bloker يعمل VC فيوقلل Hepatic blood flow
Nicotine
Estrogen
41
Portal hypertension cause ____ by a drug called ____
Decrease Hepatic blood flow (الجسم يفتح قنوات اسمها porto-systimic shunt تقلل ضغط الدم)
Propranolol ,it's a beta blocker -->VC
42
Liver failure cause _____ by drug called enzymes inhibitor or ___
Decrease Hepatic enzymes
Erythromycin
43
How to avoid (bypassing) FPM ?
Change the route into Sublingual or Parenteral (injection) / Rectal
44
Drugs with variable Bioavailability (F) in their different dosage forms:
Digoxin(treatment of heart failure) & Phenytoi(treatment of epilepsy)
45
What distribution?
The drug passes through body compartments (plasma, interstitial & intracellular fluids) = 42L/70kg
46
What is volume of distribution (Vd) ?
Apparent volume of fluids that would تستوعبaccommodate total dose of the drug if(الحرف دا مشكلة🤣) its concentration in body equal to that in plasma
47
Importance of Vd
It is an estimate of the extent of tissue uptake of drugs
In cases of treatment of drug toxicity by hemodialysis
1.
2.
Vd can be used to calculate the loading dose (LD):
48
If Volume of distribution is smal , then tissue uptake is___
Low
49
High tissue up take means high Vd
True
50
E.g for small Vd in tissue
Frusemide
51
E.g for high large Vd in tissue uptake
Digoxin
52
Why dialysis is not useful for high Vd?
most of drug is in the tissues)
53
Why is dialysis useful for low Volume of distribution?
most of drug is in blood and ECF(plasma and ISF)
54
How is loading dose calculated?
LD = Vd x Steady state plasma concentration (Css)
55
Vd is affected by:
Vd is affected by:
Perfusion
Lipophilicity (diffusion)
Binding to plasma protein
Binding to tissues
Degree of tissue uptake
Loading dose
56
What is perfusion ?
↑ blood flow → ↑ Distribution
57
What is diffusion ?
↑ lipophilicity → ↑ Distribution
58
Perfusion and diffusion have a relationship, name it
Direct relationship
59
Name Drugs and there Binding to cell and tissue constituents
Chloroquine: Liver
Tetracyclineيحب Ca++: Bone & Teeth
lodides: Thyroid & salivary glands
60
Significance of HIGH lipophilicity:
Or
Q. Mention pharmacokinetic characters of lipophilic drugs
↑ Absorption
↑ Vd
↑ Hepatic elimination (lipophilic drugs can enter hepatocytes)
Dec. Renal elimina tion (due to ↑ renal reabsorption)
61
Binding to Plasma protein (pp): → Drug Mainly binds to ____
Albumin
62
Drug in blood exists in 2 forms in equilibrium:
Free form
Bounded form
63
Bound form is
is inactive, non-diffusible, cannot be metabolized or excreted. Acts as reservoir
64
Free Form is:
is active, diffusible and can be metabolized and excreted.
65
Significance of binding to plasma protein: Highly bound drugs ->
Affect pharmacokinetics:
↑ absorption (by Decrease free concentration of the drug in plasma)
Decreases Distribution ( Vd tissue uptake and penetration)
Decreases elimination (Prolong ti/2). The bound drug can not be elimina releases the free part.
65
Significance of binding to plasma protein: Highly bound drugs ->
Affect pharmacokinetics:
↑ absorption (by Decrease free concentration of the drug in plasma)
Decreases Distribution (Decreases Vd tissue uptake and penetrationالإختراق او التغلغل)
Decreases elimination (incerse Prolong t1/2). The bound drug can not be eliminated and acts as reservoir which continuously releases the free part.
66
Significance of binding to plasma protein: Highly bound drugs ->
Affect pharmacokinetics:
↑ absorption (by Decrease free concentration of the drug in plasma)
Decreases Distribution ( Vd tissue uptake and penetration)
Decreases elimination (Prolong ti/2). The bound drug can not be elimina releases the free part.
66
Significance of binding to plasma protein: Highly bound drugs ->
Affect pharmacokinetics:
↑ absorption (by Decrease free concentration of the drug in plasma)
Decreases Distribution ( Vd tissue uptake and penetration)
Decreases elimination (Prolong ti/2). The bound drug can not be elimina releases the free part.
67
Plasma protein Not effective against ___
dangerous infections
لأنها اغلبها تمسك (albumin ) ومش رح تكون free form
68
E.g Site of drug interaction (خناقة الادوية) on acidic binding sites of albumin:
NSAIDS displace Warfarin from binding sites → ↑Free form of warfarin>↑warfarin effect (bleeding من الانف ): see drug interaction
69
Why NSAID drugs could take the place of wafrine?
Drugs with high Affinity to bind to pp → DISPLACEMENT of drugs with low affinity
70
toxicity from low affinity drug if it is _____ to plasma protein
Higley bound
71
Aim of Biotransformation (metabolism)
Aim: Change the drug into more H20 soluble (polar= ionized) metabolites ---> easily excreted in urine
72
Consequences of biotransformation(metabolism)
Inactive drug (prodrug)--->converte to active drug which take two pathway
1.active metabolism
2. Toxic "
Or it may take another pathway, to be inactive metabolites) most of drug ) with no adverse effects
73
E.g for pro drugs
Enalapril (ACED) -->active form enalaprilat
Prednisone (Cortisone)--> active form prednisolone
74
E.g for active metabolism
Codeine(دواء الكحة) changes to morphine
الناس المدمنة تشربوا كامل عشان الجسم رح يحوله ليمورفين
75
E.g for toxic metabolism
- Paracetamol metabolized to toxic epoxide which then conjugated with SH (Glutathione) to non- toxic metabolites.
76
Types of biotransformation reaction
Phase I (Non synthetic)
Phase ll (synthetic)
77
Phase 1 (Non synthetic)
Include: Oxidation (by cytochrome P450), reduction & hydrolysis
اي يزيل جزء من الدواء
Unmasking of a polar group (-0H,-SH, - NH2)
Converting the drug to an H20 soluble the can be excreted
78
What is phase 2 (synthetic)
Include: Conjugation with: glucuronic acid, Glutathione,
Glycine, Sulfate,..
(addition: ---ation ?)
يضيف جزء للدواء
79
Types of metabolizing enzymes
Microsomal enzyme
Non-Microsomal enzyme
80
Microsomal enzyme Bound to ____
endoplasmic reticulum
81
E.g for Microsomal enzyme
Cytochrome P450(phase1)
Glucuronyl transferase(phase 2)
82
Non Microsomal enzyme : found in ___or ____
Plasma
Cytoplasm
83
E.g for non microsomal enzyme in plasma and cytoplasm
Plasma: Choline esterase
Cytoplasm: Xanthine oxidase
84
Not liable
Non-microsomal enzyme
85
Factors affecting drug metabolism
1) Physiological: Age, Sex
2) Pathological
3) Pharmacogenetic variation
4) Enzyme induction & enzyme inhibition
86
Factors affecting drug metabolism
E.g for physiological
Age:
Sex:
extreme of age (newborn, very old) →decrease metabolism
testosterone ↑ metabolism while
Estrogen decreases "
87
E.g for pathogenesis factor effecting metabolism
2) Pathological: Liver diseases > decraes metabolism
88
E.g for 3) Pharmacogenetic variation
3) Pharmacogenetic variation: Slow acetylators > decrease metabolism of isoniazid
تذكر acetylation polymorphism
89
What are enzyme induction
•Enzyme inducer →↑ metabolism → dec. effect
Increase dose
90
Enzyme inhibitor function
•Enzyme inhibitor → decrease metabolism-> ^ effect
91
Importance of enzyme induction, with e.g for each
1. Increase its own metabolism > tolerance e.g. phenobarbitoneدواء غبي
2. ↑ metabolism of other drugs → drug interactions e.g. Rifampicin →↑ Oral contraceptive pills (0CP) metabolism > dec
effect of OCP → pregnancy. Also rifampicin > ↑ Warfarin metabolism >dec. its effect
3. ↑ metabolism of Endogenous substrates → (e.g. phenobarbitone enzyme inducer >ink. metabolism of bilirubin(on plasma protein) in case of drug therapy of neonatal jaundice or kernicterus) ) يستخدم في علاج الصفرة عند حديثي الولادة
92
*Enzyme inducers→ ↑ activity of___
Cytochrome P450
93
Enzyme induction is reversible/irreversible. occurs over a few/many days & disappears over 2-3/6-8 weeks after withdrawal of the indu
Reversible
Few
2-3
94
Importance of Enzyme Inhibition
Enzyme inhibitors >dec. activity of Cytochrome P450 and other microsomal enzymes --> dec. metabolism of drugs.
This can lead to significant drug interactions.
* It occurs faster than enzyme induction.
95
E.g for enzyme inducer
Carbamazepine treat epilepsy
Phenytoin(T.B)
Phenobarbitone , same
Rifampicin , same in CNS
Nicotine
96
E.g for enzyme inhibitors
• Chloramphenicol
•Erythromycin
•Ciprofloxacinسيبروفلوكساسين
Ketoconazole
97
Kidney is the main site of drug excretion by:
1. Filtration
2. Active tubular secretion
(e.g. Penicillin, Amphetamine)
98
Factors affecting Renal elimination (Excretion) or _____
Glomercular filtration : Glomerular filtration rate (GFR) علاقة طريقة بالنسبة للإخراج
• Plasma protein binding (PPB)→ prevent filtration علاقة عكسية
• Drug Lipophilicity (affected by Pka of the drug & pH of the urine) → enhances reabsorption of the drug after being filtrated غلاقة عكسية
99
Elimination half life (t1/2) is
is the time needed to dec. Drug con. In plasma to half the initial concentration
100
Calculation of t1/2
t1/2=0.693 X Vd/CLs
101
0.693 =
Vd =
CLS =
0.693 = Constant
Vd = Volume of distribution
CLS = Systemic clearance
102
Values (significance) of elimination t1/2 are
1. Determination of dosage intervals (t)المسافة بين الجرعات
2. Determination of Tss (time needed to reach Css) = 4-5 t1/2
103
If t= tı/2 then
Body stores twice the dose. Accepted choice for most of drugs
104
Ift < tı/2 then
Drug accumulation occurs -->
adverse effects هنا يعمل مشكلة
105
If t> t1/2 then
Dec. drug concentration between the doses مش حيشتغل كويس
106
if the t1/2 is very short the drug is taken
IV infusion الحقن بالتقطير
Oral slow release (SR) preparation
107
Steady state concentration (Css) is
Definition:
It is the concentration of the drug at which rate of drugs administration = rate of drug elimination
108
Time needed to reach Css (Tss) is
4 to 5 t1/2 if fixed dose is taken every t1/2
109
Calculate LD
Loading Dose = Vd X Css
110
Maintenance dose is
And calculate it
is the dose needed to maintain Css
Mantainance dose = Clearance × Css
111
Css is reached only in
first order kinetic drugs
112
Factors affecting elimination t1/2
1. The state of elimination organs: i.e. Liver & Kidney function
2. The delivery of the drug to elimination organ:
a. Plasma protein binding limits renal filtration
b. Drugs with very high Vd may escape in the tissue from elimination
113
1 order kinetics Elimination (EL)
proportional to plasma concentration (El a Cp)
114
Kinetic orders are
1st order kinetics
Zero-order kinetics
Saturation kinetics
115
Zero order kinetics elimination is
Constant , طالب كسلان
116
drug eliminated/unit time in 1st order kinetics
Constant fraction (%) of the doses
117
drug eliminated/unit time in zero unit elimination
Constant amountكمية من الجرعة
118
1st order kinetics
Metabolizing enzymes:
Unlimited
119
Zero-order kinetics
Metabolizing enzymes:
Limited
120
In 1st order kinetics
Modest changes in doses or Bioavailability
Tolerance الجسم ممكن يتحمل التغير
121
Zero-order kinetics
Modest changes in doses or F
Toxicity
122
In 1st order kinetics
T1/2:
Constant
123
In Zero-order kinetics
T1/2
Variable, not constant
124
Css in 1st order kinetics
is reached on repeating the doses
Tss = 4-5 t/2
↑ Dose → ↑Css
125
Css in Zero-order kinetics
No Css.
Repeating the doses →
overshooting of drug Concentration (Cp)
126
Drug metabolized in 1st order kinetics
Fixed
127
Drug metabolism in Zero-order kinetics
May vary with increasing the doses
128
Most drug are
1st order kinetics
129
E.x for Zero-order kinetics drugs
Ethanol
130
What is saturation kinetics ?
Definition: The drugs follow 1* order kinetics in low doses and follow zero order kinetics in higher doses.
Elimination mechanism is saturable in higher doses.
طالب نص نص
131
Significance of saturation kinetics:
• Modest changes in dose or F of the drug → unexpected toxicit
Drug interaction are more common and important clinically
132
E.g for saturation kinetics
Phenytoin , enzyme inducer
Theophylline
133
Extraction ratio (ER) is
It is the fraction of the drug eliminated by the liver.
134
How to calculate ER
ER = (Arterial drug conc.) - (Venous drug conc.) / (Arterial drug conc.) =
Amount extracted/amount entered
Maximum is 1 (100%),0.4[40%]
Least is 0
135
Types of extraction ratio
Low: <0.2
High > 0.7
Moderate: 0.2 - 0.7
136
Low ER clearance in liver
Enzyme dependent
137
High ER clearance in liver
Flow depend enzyme
138
Moderate: 0.2- 0.7 clearance in liver
Both enzyme & flow dependent
139
E.x for low elimination ratio
Wafrine
140
E.g for high ER drug
Phenobarbitone
141
E.g for moderate ER drug
Paracetamol(acetaminophen), chloramphenicol
142
F in low ER drugs
High
143
F in high Elimination ratio is
Low
144
Bioavailability in moderate elimination ratio drug is
Moderate
145
Hepatic clearance:
Hepatic clearance: Volume of the blood cleared by the liver per unit time
146
Calculate Hepatic clearance
CL liver = Extraction ratio × hepatic blood flow (Q)
147
. Systemic clearance (Cls)
Volume of fluid cleared from the drug per unit time.
لو جبتلكم في ام سي كيو دراج ، خطأ
148
Calculate systemic Cls
Renal clearance (Clr) + non-renal clearance (Clr)
Like lung , liver ....
149
* Factors affecting drug clearance
* Factors affecting drug clearance 1. Blood flow to the clearing organ(direct relationship)
2. Activity of processes responsible for drug removal as hepatic enzymes, glomerular filtration rate (direct relationship)
3. Binding of the drug to plasma proteins(inverse relationship)
150
Significance of Drug clearance
1. Calculation of the maintenance dose (MD)
2.The dosing regimen of drugs eliminated by glomerular filtration can be guided by creatinine clearance e.g (دواء هايلي هيدروفيليك ومش مهم حفظ اسم الدواء بس احفظه محمد سان)Gentamicinيساعد في إعادة ضبط جرعة في حالات قصور وظائف الكلى
151
Calculate Mantainance dose
Maintenance Dose= CLs x Steady state plasma concentration (Css)
