Pharmacology π Flashcards
(288 cards)
1
Q
Where should the medicine be introduced to have quick effect?
A
intravenous route.
2
Q
What is pharmacodynamics?
A
It is what the drug does to the body.
3
Q
What is pharmacokinetics?
A
It is what the body does to the drug.
4
Q
What does pharmacokinetics include?
A
Absorbtion
Distribution
Metabolism
Execration
5
Q
What is elimination?
A
Metabolism + excretion
6
Q
Why is there some lag in the start of the curve of the time course of drug action (oral)?
A
Due to Absorption but in intravenous, there is no lag.
7
Q
Where should the drug concentration be kept?
A
In the therapeutic window.
8
Q
What is absorption?
A
Absorption is defined as the passage of a drug from the site of administration to plasma.
9
Q
What are the main routes of administration of drugs?
A
- Sublingual.
- Oral
- Rectal.
- Local.
- Inhalation.
- Injections.
10
Q
Does the sublingual route have any Barriers?
A
No
11
Q
What are the internal routes of administration?
A
- Sublingual.
- Oral
- Rectal.
12
Q
What are the external routes of administration of drugs?
A
- Local.
- Inhalation.
- Injections.
13
Q
What are the factors that affect the rate of Absorption?
A
A. Factors related to the drug:
β’ Ionization of the drug (pKa)
B. Factors related to the absorbing surface:
β’ Rate of the circulation at the site of absorption.
14
Q
What is the ionization constant (pKa)?
A
It is the pH at which the ionized and non-ionized forms of the drug are equal.
15
Q
Are ionized forms lipid soluble or no?
A
Unionized forms are more lipid-soluble and rapidly absorbed.
16
Q
Where do acidic drugs become more ionized?
A
In basic media and vice versa
17
Q
Give an example for acidic and basic drugs respectively?
A
Aspirin - amphetamine
18
Q
What is the clinical significance of pKa?
A
-knowing the site of drug absorption on the GIT.
-Treatment of drug toxicity:
β’ Toxicity with acidic drugs (e.g. aspirin) could be treated by alkalinization of urine, which renders this drug more ionized in urine and less reabsorbable.
β’ Toxicity with basic drugs (e.g. amphetamine) could be treated by acidification of urine, which renders this drug more ionized in urine and less reabsorbable.
19
Q
What is the action of local anesthetic?
A
They block voltage-dependent Na+ channels within the nerve fibers ββ nerve conduction.
20
Q
What is the clinical value of pKa in local anesthetics?
A
β’ All local anesthetics are weak bases. So, the addition of bicarbonate to the anesthetic solution maintains the anesthetic in the non-ionized state and this increases lipid solubility and enhances penetration of the anesthetic into the nerve sheath.
21
Q
What is the bioavailability of drugs?
A
it is the fraction of the drug that becomes available for systemic effect after administration. The bioavailability of drugs given i.v. is 100%.
22
Q
What are the factors that affect drug bioavailability(oral)?
A
Factors affecting oral availability:
- The same factors of drug absorption.
- Hepatic first-pass metabolism for oral route
23
Q
What is the definition of volume of distribution?
A
The apparent volume of water into which the drug is distributed in the body after distribution equilibrium
24
Q
How is Vd calculated?
A
The total amount of the drug in the body
Vd = ββββββββββββββββββββββββββ = L Plasma concentration of the drug after distribution equilibrium
25
What is the clinical significance of Vd?
```
Knowing Sites of distribution of drugs:
1. Plasma (3 liters)
2. Extracellular (9 liters)
3. Intracellular water (29 liters)
β’ So, Vd more than 41 liters means drug moves to tissues.
```
Calculation of the loading dose: LD = Vd target Cp
26
Binding of drugs to plasma proteins
* Most drugs are found in the vascular compartment associated with plasma proteins
* The pharmacological effect of the drug is related only to its free part.
* Binding of drugs to plasma proteins prolongs their effects.
27
What is the major site of drug metabolism?
The liver is the major site of drug metabolism but other organs can also metabolize drugs e.g. kidneys, lungs, and adrenal glands.
28
What must happen to lipids to be excreted?
Many lipid-soluble drugs must be converted into a water-soluble form (polar) to be excreted. However, Some drugs are not metabolized at all and excreted unchanged (hard drugs).
29
What does the metabolism of drugs lead to?
Metabolism of drugs may lead to:
1) Conversion of the active drug into inactive metabolites β termination of drug effect.
2) Conversion of the active drug into active metabolites β prolongation of drug effect e.g. codeine (active drug) is metabolized to morphine (active product).
3) Conversion of the inactive drug into active metabolites (prodrugs) e.g. enalapril (inactive drug) is metabolized to enalaprilat (active metabolite).
4) Conversion of non-toxic drugs into toxic metabolites (e.g. paracetamol is converted into the toxic product N-acetylbenzoquinone).
30
What are the reactions that the drug may undergo to be metabolized?
Phase I reactions
| Phase II reactions
31
What happens if the drug is not liable to conversion into water-soluble by phase I?
it must enter phase Il to increase solubility and enhance elimination.
32
What are the processes included in phase I reactions?
oxidation, reduction, and hydrolysis.
33
What are the enzymes catalyzing phase I reactions?
cytochrome P450, aldehyde and alcohol dehydrogenase, deaminases, esterases, amidases, and epoxide hydratases.
34
What is the set of enzymes that is responsible for the majority of phase I reactions? And where is it present?
cytochrome P450 (CYP450) enzyme system located primarily inside membranous vesicles (microsomes) on the surface of the smooth endoplasmic reticulum of parenchymal liver cells.
35
What are other sites of CYP450 activity?
kidney, testis, ovaries, and GIT.
36
What is a source of variability of drug metabolism in humans?
Genetic polymorphism of medically important CYP450 enzymes.
37
Are drugs metabolized by one CYP450 Enzyme or many CYP450 enzymes?
Drugs may be metabolized by only one CYP450 enzyme (e.g. metoprolol by
CYP2D6) or by multiple enzymes (e.g. warfarin).
38
Is microsomal oxidation induced by certain drugs and environmental substances?
Yes, Some drugs and environmental substances can induce (increase activity) or inhibit certain CYP450 enzymes leading to significant drug interactions.
39
Is non-microsomal oxidation induced by certain drugs and environmental substances?
No, only microsomal oxidation is affected
40
What are examples of non-microsomal oxidation?
xanthine oxidase (converts xanthine to uric acid)
monoamine oxidase (MAO) (oxidizes catecholamines and serotonin).
41
Microsomal enzyme induction
- Microsomal inducers increase the rate of metabolism of some drugs leading to a decrease in their serum levels and therapeutic failure.
- Induction usually requires prolonged exposure to the inducing drug
42
What are examples of inducing agents?
phenytoin, rifampicin, phenobarbitone, carbamazepine,
| smoking, chronic alcohol intake, St John's Wort,
43
What are clinical examples of microsomal enzyme induction?
- Rifampicin accelerates the metabolism of contraceptive pills leading to the failure of contraception.
- Phenytoin accelerates the metabolism of cyclosporine-A leading to graft rejection.
44
What are examples of inhibiting agents?
macrolide antibiotics (e.g. erythromycin), ciprofloxacin, cimetidine, ketoconazole, ritonavir, grapefruit juice.
45
What are clinical examples of microsomal enzyme inhibition?
- Ciprofloxacin inhibits the metabolism of warfarin (anticoagulant) leading to the accumulation of warfarin and bleeding.
- Erythromycin inhibits the metabolism of theophylline leading to toxicity of theophylline (cardiac arrhythmia).
46
What is the concept of Phase II reactions?
It involves the coupling of a drug or its metabolite to a water-soluble substrate (usually glucuronic acid) to form a water-soluble conjugate.
47
What is the set of enzymes that is responsible for the majority of phase II reactions?
Glucuronyl transferase
48
Where is the set of glucoronyl transferase enzymes present?
This set of enzymes is also located inside liver microsomes and is the only phase Il reaction that is inducible by drugs and is a possible site of drug interactions e.g: ο² phenobarbital induces glucuronidation of thyroid hormone and reduces their
plasma levels.
49
What is the role of intestinal bacteria in the prolongation of the duration of some drugs?
Some glucuronide conjugates secreted in bile can be hydrolyzed by intestinal bacteria and the free drug can be reabsorbed again (enterohepatic circulation), this can extend the action of some drugs.
50
What are other examples of non-glucuronide conjugation reactions?
```
sulphate conjugation (steroids),
glycine conjugation (salicylic acid),
glutathione conjugation (ethacrynic acid).
```
51
How are contraceptive pills metabolized? And what is the role of intestinal bacteria in this?
Contraceptive pills contain estrogen, which is metabolized by glucuronide conjugation and excreted in bile as a conjugate, Intestinal bacteria hydrolyze this conjugate to form free estrogen again which is reabsorbed and attain a long duration of action (so contraceptive pills are given once daily).
52
What happens if a woman took contraceptive pills with broad-spectrum antibiotics (kills the intestinal bacteria)?
estrogen will lose its long duration of action and pregnancy can occur.
53
What is the definition of first-pass metabolism?
metabolism of drugs at the site of administration before reaching systemic circulation e.g. the liver after oral administration, the lung after inhalation, the skin after topical administration, etc.
54
Examples of hepatic first-pass metabolism for different drugs.
ο Complete: lidocaine.
ο Partial: propranolol, morphine, nitroglycerine
ο None: atenolol and mononitrates
55
How to avoid hepatic first-pass metabolism?
- By increasing the dose of the drug.
| - By giving the drug through other routes e.g. sublingual, inhalation, or i.v.
56
What is the definition of bioavailability?
ο it is the fraction of the drug that becomes available for systemic effect after administration, The bioavailability of drugs given i.v. is 100%
57
What are the factors that affect bioavailability?
ο Factors affecting absorption.
ο Factors affecting metabolism.
ο First-pass metabolism.
58
What are the mechanisms of drug action (main targets for drug action)?
1. Receptors
2. Ion channels
3. Enzymes
4. Carrier molecules
59
What are receptors?
Receptors are protein macromolecules on the surface or within the cell that combines chemically with small molecules (ligands) and produce physiological regulatory functions.
60
What are the types of bonds between drugs and receptors?
1- The ionic bonds
2- The hydrogen bonds
3- The covalent bonds
61
What are the biological responses to drug-receptor binding?
1) Agonist effect
2) Antagonist effect
3) Partial agonist effect
62
What is an agonist?
The drug has both affinity and efficacy
63
What is the affinity of drugs?
it is the empathy of the receptor to the ligand.
64
What does affinity determine?
It determines the number of receptors occupied by the drug.
65
What is the efficacy of the drug?
It is the ability of a drug to produce a response (effect) after binding to the receptor.
66
What is efficacy measured by?
It is measured by the Emax(the maximal response that a drug can elicit at full concentration)
67
What is an antagonist?
the drug has affinity but no efficacy
68
What is a partial agonist effect?
Agonist gives submaximal response even at full concentration i.e never gives Emax.
69
What is a Graded response?
The response is increased proportionally to the dose of the agonist
ο e.g. the response of the heart to adrenaline.
70
What is a quantal response?
The response does not increase proportionally to the agonist but it is an all-or-none response
ο e.g. prevention of convulsions by antiepileptic drugs.
71
What is the importance of drug-response curves?
- Determination of potency
- Determination of efficacy
- determination of therapeutic index ( a measure of safety)
72
What is ED50 (effective dose)?
-the dose of the drug that gives 50% of the Emax, or it is the dose that gives the desired effect in 50% of a test population of subjects. A drug that gives ED50 in smaller doses is described as a βpotentβ drug.
73
What does TI equal?
LD50/ED50
-Drugs with high TI are safer for clinical use, and vice versa.
74
What does LD50 mean?
means the dose which is lethal to 50% of experimental animals
75
What does ED50 mean?
means the dose which is effective in 50 percent of animals
76
How do drugs affect ion channels?
ο Drugs could modulate ion channels e.g. Ion channels could be physically blocked by the drug molecule e.g. local anesthetics
77
How do drugs affect enzymes?
- The drug may act on the enzyme itself by competition with its normal substrate for the active binding sites on the enzyme.
- The drug molecule may inhibit the enzyme by covalent binding with the structure of the enzyme (irreversible binding).
78
What does it mean if there is a large difference between the dose of a drug that produces the desired effect and the dose that produces a toxic effect?
it is said that the drug has a large TI.
79
What are parasympathomimetics classified according to tp?
According to MOA:
Direct-acting cholinomimetics
Indirect-acting cholinomimetics
80
What is the definition of Direct-acting cholinomimetics?
Act by direct stimulation of cholinergic receptors.
81
What are examples of Direct-acting cholinomimetics?
A-choline esters:
acetylcholine, (M+N)
Bethanechol (M)
Carbachol (M+N)
B-alkaloids :
Natural :Pilocarpine(M)
Synthetic: Cevimeline (M)
C-drugs that augment A.ch.action:
sildenafil
82
What is the definition of Indirect-acting cholinomimetics?
Act by inhibition of choline esterase (AChE) enzyme leading to accumulation of acetylcholine (A.Ch).
83
What are examples of Indirect-acting cholinomimetics?
Reversible Ch.E inhibitors.:
> Physostigmine (M+N +CNS; used topically in glaucoma),
> neostigmine,
> pyridostigmine, donepezil
Irreversible Ch.E inhibitors;
a) Echothiopate: eye drops to treat
b) Organophosphate compounds (M+N +CNS effects)
84
What are the adverse effects of muscarinic agonists?
DUMBELS
```
D
> Diarrhea &colic
U
> Urination
M
> Miosis
B
> Bradycardia & Bronchospasm
E
> Emesis(Vomiting) & Excretion of CNS
L
> Lacrimation
S
> Salivation, Sweating & Skeletal ms twitches
```
-All of which can be blocked by atropine.
85
What are the contradictions of muscarinic agonists?
Peptic ulcer.
Bronchial asthma.
Heart Block.
86
What is the nature of physostigmine?
Natural plant alkaloid (tertiary amine).
Well-absorbed from the GIT
Can pass to CNS.
87
What is the MOA of physostigmine?
(Reversibly) inhibit cholinesterase enzyme for 3-4 hours,
leading to :
1. Muscarinic effects:
> Hypotension, Bradycardia.
> Salivation, lacrimation.
> +1 GIT peristalsis (diarrhea and colic).
> Miosis.
2. Nicotinic effects:
> Skeletal muscle contraction.
3. Central effects:
> Headache, insomnia, excitation, and convulsions.
88
What are the uses of physostigmine?
- Eye drops to produce miosis and treat chronic glaucoma.
| - The antidote in case of atropine poisoning.
89
What is the nature of neostigmine?
```
Synthetic drug (quaternary amine)
Poorly absorbed from GIT.
Cannot pass to CNS.
```
90
What is the MOA of Neostigmine?
Similar to physostigmine in MOA & effects but it has no CNS actions.
91
What are the uses of neostigmine?
- Reverse postoperative urine retention and paralytic ileus.
- Contraindicated if it is mechanical obstruction (to avoid rupture of the bladder or intestine)
92
What is the MOA of edrophonium?
Similar to pyridostigmine & neostigmine but has a very short duration of action (5-15 minutes).
93
What are the uses of edrophonium?
It is used in the diagnosis of myathenia gravis, Used to differentiate between muscle weakness due to insufficient treatment of myasthenia, or due to excessive treatment with cholinesterase (Tensilon test).
94
Drugs for a Patient with glaucoma
Ecothiophate (Parasympathomimetic)
95
Drugs for the Diagnosis of myasthenia
Edrophonium
96
Drugs for the Treatment of myasthenia
Neo and pyridostigmine
97
What are organophosphate compounds?
-Drugs:
Echothiophate eye drops.
-Insecticides:
Parathion.
Malathion.
Nerve (war) gases:
Sarin
Soman
98
What are the manifestations of organophosphate compounds toxicity?
(The DUMBELS syndrome) (Excretion, Bradycardia, Bronchospasm)
```
D
> Diarrhea &colic
U
> Urination
M
> Miosis
B
> Bradycardia & Bronchospasm
E
> Emesis(Vomiting) & Excretion of CNS
L
> Lacrimation
S
> Salivation, Sweating & Skeletal ms twitches
```
99
What is the management of organophosphate toxicity?
- Ensure patent airway and artificial respiration.
- Gastric lavage and skin wash to remove the toxin.
- Intravenous normal saline to raise blood pressure.
Atropine - Pralidoxime - diazepam
100
What are the drugs used for Postoperative urine retention and paralytic ileus and their receptors?
- Bethanechol, M3
| - Neostigmine, M&N
101
What are the drugs used for glaucoma?
* Pilocarpine, M3
| * Carbachol, physostigmine, M&N
102
What are the drugs used for xerostomia?
Cevimeline, M3
103
What are the drugs used for Alzheimer's disease?
Donepezil, rivastigmine, M&N
104
What are the drugs used for the diagnosis of myasthenia?
Edrophonium
105
What are the drugs used for the Treatment of Myasthenia?
Edrophonium,
106
What are the drugs used for the treatment of Atropine toxicity?
Physostigmine, M&N
107
Bethanechol clinical application and action
- Postoperative urine retention and paralytic ileum
| - Activates bowel and bladder smooth ms.
108
Pilocarpine clinical application and action
- Glaucoma
| - Activates ciliary muscle of eye
109
Neostigmine clinical application and action
- Postoperative urine retention, Myasthenia gravis, and paralytic ileus
- Amplifies endogenous acetylcholine
110
Physostigmine clinical application and action
- Glaucoma, counteract the mydriatic cycloplegic of atropine
| - Amplifies endogenous acetylcholine
111
What are examples of parasympatholytics?
1- Nicotinic blockers:
-NMBs (block Nm)
> e.g: D- tubocurarine.
-Ganglionic blockers (block Nn):
> e.g: Trimethaphan.
2- Muscarinic antagonists:
```
-Ipratropium
Hyoscine butylbromide
-Pirenzepine (M1)
-Oxybutynin, tolterodine
-hamatropine, tropicamide
-Benztropine
```
112
What is the nature of muscarinic antagonists?
They are either tertiary amine alkaloids or quaternary amines :
> Plant alkaloids: atropine & scopolamine (hyoscine) is found in Hyoscyamus
Niger. They are tertiary amines (i.e. well absorbed and can pass to CNS).
> Synthetic derivatives: either tertiary or quaternary amines (limited CNS penetration).
113
What is the action of different muscarinic antagonists?
Ipratropium: Used mainly as bronchodilators.
Hyoscine butyl bromide: Used mainly as antispasmodics.
Pirenzepine (M1): Used mainly to decrease HCL secretion.
Oxybutynin, tolterodine: Used mainly for the genitourinary system.
Homatropine, tropicamide: Used mainly as mydriatics.
Benztropine: Used mainly to treat parkinsonism.
114
What are the therapeutic uses of muscarinic antagonists?
* Bradycardia (atropine, mainly M2).
* Bronchial asthma: (ipratropium is given by inhalation to dilate the bronchi and reduce secretions in asthma and chronic obstructive pulmonary disease (COPD).
β’ Pre-anesthetic medication (atropine GIT disorders) :
> Peptic ulcer: pirenzepine. (M 1- antagonist).
> Diarrhea.
> Abdominal colic: eg , hyoscine butylbromide (Buscoban)
β’ Urinary disorder :
> Acute cystitis: oxybutynin
> Urine incontinence in adults: tolterodine
* Eye: Funds examination &lridocyclitis
* CNS: Parkinson's disease: benztropine
* Motion sickness: scopolamine.
* Organophosphate toxicity: atropine.
115
What is the nature of atropine?
An alkaloid derived from the plant Atropa belladonna.
116
What is the MOA of atropine?
Competes reversibly with Ach at the muscarinic receptors both peripherally and centrally.
117
What are the pharmacological effects of atropine? Ml DDT
β’ Mydriasis, cycloplegia & loss of accommodation to near
vision
β’ Tachycardia (increased heart rate).
β’ Decreases the tone and motility of GIT & UB
β’ Decrease the secretions (salivary, lacrimal).
β’ large doses - skin flushing, hallucinations & coma.
118
What are the therapeutic uses of atropine?
1. Antispasmodic
2. Bradycardia
3. Pre-anesthetic agent
4. Funds examination.
5. Treatment of poisoning by anticholinesterase agents
because it antagonizes the actions of Ach (OCP
poisoning)
119
What are the side effects of atropine?
1. Rapid pulse.
2. Dilated pupils, resulting in photophobia &blurred vision.
3. Dry mouth.
4. Flushed skin.
5. Rise in body temperature, especially in children.
6. Restlessness, confusion, and disorientation.
120
What happens if two or more drugs combine together?
Drug combination is very common in clinical practice. When two or more drugs are combined together, one of the following may occur:
a) Summation or addition
b) Synergism and potentiation
c) Antagonis
121
summation or addition (1+1=2)
- Summation means that the combined effect of two drugs is equal to the sum of their individual effects
- It usually occurs between drugs having the same mechanism
- Example: the use of two simple analgesics together.
122
Synergism (1+1=3)
- It means that the combined effect of both drugs is greater than the sum of their individual effects.
- The two drugs usually have different mechanisms of action.
- Example: The use of penicillin with aminoglycosides to exert a bactericidal effect.
123
Potentiation (1+0=2)
- is similar to synergism but, in potentiation, the effect of one drug itself is greatly increased by the intake of another drug without notable effect
- For example, Phenobarbitone has no analgesic action but it can potentiate the analgesic action of aspirin.
124
What are the types of antagonists?
1. Pharmacological antagonism: Pharmacodynamics antagonism and Pharmacokinetic antagonism.
2. Physiological antagonism
3. Physical antagonism
4. Chemical antagonism
125
What is pharmacodynamics antagonism?
Competitive antagonism
126
What is pharmacokinetics antagonism?
Antagonism occurs at the level of absorption, distribution, metabolism and excretion.
127
What is the definition of competitive antagonism?
The drug competes with the agonist for the same site on the receptor and it has two forms either reversible or irreversible. (With description)
128
What is irreversible antagonism?
makes with the receptor so that you cannot overcome the inhibition by increasing the dose of the agonist (shifts the curve downwards)
129
What is Physiological antagonism? And what is an example of it?
-antagonism between two drugs producing opposite effects by acting on different receptors.
- Example: adrenaline is the physiological antagonist of histamine because while:
β’ histamine causes hypotension and bronchoconstriction through activation of histamine H1 receptors.
β’ adrenaline causes hypertension and bronchodilatation through activation of adrenergic Ξ± & Ξ² receptors.
130
What is physical antagonism and what is an example of it?
-Antagonism between two drugs carrying opposite charges
-Example:
β protamine is used for the treatment of heparin overdose because protamine carries +ve charge while heparin carries βve charge
131
What is chemical antagonism and what is an example for it?
- one acidic drug when added to a basic drug can cause precipitation of each otherβs
- Example: the addition of gentamycin (basic drug) to carbenicillin (acidic drug) in the same syringe causes a chemical complex.
132
What does a competitive antagonist do to ED50?
A competitive antagonist increases the ED50
133
What are the factors modifying the dose-response relationship?
Factors related to the drug
1. Drug shape (stereoisomerism)
2. Drug size(MW)
3. Time of drug administration (Chronopharmacology)
4. Drug cumulation
5. Drug combination
```
Factors related to the patient
1. AGE:
2. WEIGHT:
3. SEX:
4. Pathological status:
β Liver diseases or kidney diseases could alter significantly the response of the patient to the therapeutic doses of drugs.
5. Hyper-reactivity to drugs.
6. Hypo-reactivity to drugs.
```
134
What are forms of hypo-activity to drugs?
Tolerance:
β decreased response to the same dose of the drug after repeated administration.
β It occurs over a long period
Tachyphylaxis :
β it is a type of tolerance, which occurs very rapidly
135
What are the probable mechanisms of hypo-reactivity to drugs?οΏΌ
1. Receptor down-regulation:
β Prolonged exposure to the agonist leads to a decrease in the number of receptors due to endocytosis by the cells β e.g. B2 agonists.
2. Increased metabolic degradation:
β Barbiturates can activate hepatic enzymes and accelerate their own metabolism and metabolism of other drugs.
136
What are other terms for hyper-reactivity to drugs?
ο Hyper susceptibility
ο Super sensitivity
ο Intolerance
137
What is intolerance and it shouldnβt be confused with?
β It is an exaggerated response that occurs to a pharmacologic dose of a drug.
β It is not to be confused with drug allergy
138
What is the definition of the rebound effect and what is an example for it?
- it is the re-emergence of symptoms that were controlled while taking a medication
- E.g. sudden stop of beta-blockers causes severe tachycardia due to up-regulation of beta receptors
- Drug withdrawal is the group of symptoms that occur upon the abrupt discontinuation e.g. morphine.
139
What is Pharmacogenetics?
It is the study of variation in response to a single drug due to genetic variation of SINGLE for a few gene(s).
140
What is pharmacogenomics?
It is a broader term, which studies how ALL of the genes (the genome) can influence the responses to drugs
Currently, variations in around 20 genes provide useful predictions of reactions to 80 - 100 drugs
141
What are succinylcholine and mivacurium? And what are they used for?
They are neuromuscular blockers, often used during general anesthesia to relax skeletal muscles.
142
What are succinylcholine and mivacurium metabolized by?
These drugs are metabolized by the pseudocholinesterase (PChE) enzyme in plasma.
143
What is the rate of occurrence of PCHE deficiency?
1:3000
144
What are the adverse effects of PCHE Deficiency?
when they receive these drugs during general anesthesia, they develop prolonged paralysis of respiratory muscles (succinylcholine apnea)
145
How are the side effects of PCHE Deficiency managed?
include fresh plasma transfusion and mechanical ventilation until the drugs are cleaned from the body.
146
What is the most common human enzyme defect?
G6PD deficiency is the most common human enzyme defect (X-linked recessive most often affects males).
147
What is the function of G6DP?
- G6PD enzyme catalyzes the reduction of NADP+ into NADPH which maintains glutathione in the RBCs in its reduced form.
- Reduced glutathione keeps hemoglobin in the reduced (ferrous) form and prevents its oxidation into methemoglobin (by oxidizing drugs) which leads to cell membrane injury and hemolysis (ideosacritic reaction)
- Individuals with a deficiency of G6PD may suffer acute hemolysis with jaundice if they are exposed to many oxidizing drugs (e.g. nitrates and antimalarial drugs), and fava beans.
148
What are the oxidizing Agents that affect RBCs?
aspirin, nitrates, antimalarial drugs, sulfonamides, and fava beans
149
What is the function of Thiopurine methyltransferase (TPMT)?
It is an enzyme that methylates thiopurine anticancer drugs (e.g. 6-mercaptopurine and 6-thioguanine) into less toxic compounds.
150
What are the adverse effects that happen due to Thiopurine methyltransferase (TPMT) Deficiency? And how to avoid it?
- Some people (1:300) have a genetic deficiency in WWI when they take thiopurine drugs for cancer treatment, they develop severe myelotoxicity and bone marrow suppression due to the conversion of these drugs into more toxic compounds
- Screening for TPMT deficiency is necessary for patients planning to be treated with thiopurine anticancer drugs.
151
What are examples of drugs that are metabolized by acetylation and where?
Many drugs are metabolized in the liver by acetylation (e.g. isoniazid)
152
What is acetylation controlled by?
genetic control and people can be classified according to their rate of acetylation into rapid and slow acetylators
153
What are the adverse effects that happen in rapid acetylators?
excess toxic metabolites of isoniazid accumulate in the liver causing hepatotoxicity
154
What are the adverse effects that happen in slow acetaylators?
```
Accumulation of Isoniazid
β
Inhibition of pyridoxine "vit B6"
β
Inhibition of synthesis of the myelin sheath
β
Neurotoxicity.
```
Accumulation of hydralazine
β
SLE like syndrome
155
What is warfarin and what is its function?
Warfarin is an anticoagulant drug used to prevent thrombosis in high-Risk patients
156
What is the mechanism of action of warfarin?
* Inhibition of VKOR enzyme by warfarin leads to inhibition of vitamin K-dependent clotting factors (II, IIV, IX, X).
* Some people (rare) have a genetic abnormality of VKOR enzyme that makes it less able to bind to warfarin, thus less able to inhibit.
* People carrying the mutant enzyme either need high doses of warfarin to get the usual anticoagulant effect or do not respond to the drug at all.
157
What is clopidogrel and what is its function?
Clopidogrel is an antiplatelet drug used to prevent thrombosis in high-risk patients.
158
What are the side effects of resistance to clopidogrel?
ο The drug itself is inactive and must be catalyzed by the hepatic enzyme CYP2C19 to exert its antiplatelet effect.
ο Some people (14%) have a genetic deficiency of this enzyme (called CYP2C19 poor metabolizers),
ο thus their livers can not activate clopidogrel and so they are at risk of therapeutic failure.
159
What is the metabolizer of clopidogrel?
hepatic enzyme CYP2C19
160
What are adrenergic agonists?
These drugs act either directly or indirectly (by the release of norepinephrine stored), to activate adrenergic receptors and mimic the effects of endogenous catecholamines (sympathetic stimulation)
161
Do all Sympathomimetics activate adrenergic receptors by the Same degree?
- Not all sympathomimetic drugs activate the adrenergic receptors to the same degree.
- some drugs have a higher affinity towards certain receptor classes (selectivity) depending on the ultrastructure of these receptors; however, in large doses, this selectivity is lost.
162
What is the classification of adrenergic receptors?
β According to the chemical structure
β According to the mechanism of action
β According to selectivity
163
What are adrenergic agonists classified into according to chemical structure?
I. Catecholamines (contain catechol nucleus)
ο Natural: adrenaline, noradrenaline, dopamine
ο Synthetic e.g Isoprenaline
II. Non-Catecholamines
ο phenylephrine ο amphetamine
164
What are adrenergic agonists classified into according to MOA?
A. Direct acting: e.g. E, NE, and dopamine
B. Indirect acting: e.g. amphetamine
C. Both direct and indirect: e.g. ephedrine
165
What are adrenergic agonists classified into according to selectivity?οΏΌ
A. Drugs acting mainly on Ξ±1 receptors: e.g. NE, phenylephrine
B. Drugs acting mainly on Ξ² receptors:
ο On Ξ²1 mainly: e.g. dobutamine
ο On Ξ²2 mainly: e.g. salbutamol and terbutaline
ο On both Ξ²1 and Ξ²2: e.g. isoprenaline
C. Drugs acting on Ξ± and Ξ² receptors: e.g. adrenaline, ephedrine
D. Drugs acting on Ξ±, Ξ², and dopamine receptors: dopamine
166
What is the nature of epinephrine?
Natural alkaloid synthesized by the adrenal medulla.
167
What is the pharmacokinetics of adrenaline?
ο It is ineffective when given orally. It should be given IM or SC.
ο IV injection is highly dangerous and is likely to precipitate ventricular fibrillation (tachyarrhythmia)
ο It does not cross BBB(highly polar)
ο Because of the extensive metabolism (MAO, COMT) of the drug, little is excreted unchanged in the urine.
168
What is the pharmacodynamics of adrenaline?
Mechanism of action:
ο Epinephrine Stimulates all Ξ±1,Ξ±2,Ξ²1,Ξ²2,Ξ²3 receptors.
ο Ξ±1-adrenoceptors activation leads to an increase in intracellular IP3& DAG(Gq).
ο Ξ²-adrenoceptors activation leads to an increase in intracellular cAMP (Gs).
ο Ξ±2-adrenoceptors activation leads to decrease intracellular cAMP (Gi).
169
what are the pharmacological effects of epinephrine on the eyes?
ο Local adrenaline: no effects (destroyed by the alkalinity of the tears).
ο Local dibivalyl adrenaline (pro-drug):β IOP (due to VC of ciliary BV β β aqueous humor secretion) by a different mechanism from physostigmine
170
what are the pharmacological effects of epinephrine at CVS?
ο Heart: Increase rate (chronotropic effect) and force (inotropic effect) of the cardiac muscle (Ξ²1)
ο BP: (small dose = VD)
ο Increases systolic pressure due to positive inotropic and chronotropic effects (Ξ²1),
ο decreases diastolic pressure (because VD of skeletal muscle blood vessels (Ξ²2) overcomes the VC produced by Ξ±1 receptors in the skin and splanchnic vascular beds).
ο Blood vessels : (Large (therapeutic) dose = VC)
ο At high doses, VC (Ξ±1) of all vascular beds predominates leading to an increase in both systolic and diastolic BP.
ο Increase coronary blood flow due to increased cardiac work (accumulation of metabolites), and Ξ²2 stimulation (VD).
171
what are the pharmacological effects of epinephrine on the respiratory system?
ο Relaxation of bronchial smooth muscle (Ξ²2). = Bronchodilation
ο Decrease bronchial secretions (due to VC)(Ξ±1). =bronchial decongestion.
172
What are the pharmacological effects of epinephrine on the GIT and urinary system?
ο Wall: relaxation (Ξ²2).
| ο Sphincters: contraction (Ξ±1).
173
What are the pharmacological effects of epinephrine on the exocrine glands?
Sweat glands: sympathetic sweating (forehead and palms) (Ξ±1).
174
What is the metabolic action of epinephrine?
ο Liver β β glycogenolysis (Ξ²2). (Even though insulin secretion is increased by beta two but the net effect is in favor of glycogenesis)
ο Kidney β β renin secretion (Ξ²1)
ο Fat cells β β lipolysis ( Ξ²3)
175
What are the local effects of epinephrine?
Decongestant (hemostatic), Delay absorption of drugs given SC (Toprolongs the action of anesthetics and it is due to vasoconstriction)
176
Which one causes higher VC?
| Adrenaline or noradrenaline
Noradrenaline does, because it only affects alpha receptors and has no effect on beta receptors
177
What are the therapeutic uses of adrenaline?
Anaphylactic shock
Acute bronchial asthma
Cardiac arrest
Local uses
178
What are anaphylactic shocks?
It is a life-threatening condition (acute hypersensitivity reaction) resulting from the massive release of histamine from inflammatory cells in response to exposure to an allergic substance (e.g. penicillin). Histamine causes severe hypotension and bronchoconstriction by its effect on histamine (H1) receptors.
179
How are anaphylactic shocks treated?
Injection of epinephrine immediately dilates the bronchi (Ξ²2), decreases bronchial secretions (Ξ±1), and elevates BP (VC); so, epinephrine is considered the βphysiological antidoteβ of histamine as it can reverse all its effects by actions on different receptors.
180
Use of adrenaline for acute bronchial asthma
within minutes after s.c. administration, epinephrine:
ο induces bronchodilation (Ξ²2)
ο decrease airway edema (Ξ±1 )
181
Use of adrenaline for cardiac arrest
early i.v. epinephrine administration, during cardiopulmonary resuscitation (CPR), can restore cardiac activity (Ξ²1) and improve vascular tone collapse (Ξ±1).
182
Local uses of adrenaline
- In acute epistaxis (nasal bleeding) to produce VC of nasal BV.
- Injected locally with local anesthetics: To prolong the duration of local anesthetics due to local VC...
183
What are the adverse effects of adrenaline?
1. Severe hypertension and cerebral hemorrhage.
2. Tachycardia, palpitations, and ventricular fibrillation.
3. Acute heart failure.
4. Gangrene of fingers when used with local anesthetics in high concentrations (due to VC).
184
What are the contradictions of adrenaline?
1. Heart diseases & Hypertension.
2. Hyperthyroidism
3. During general anesthesia with halothane or cyclopropane because they increase the sensitivity of the sympathetic receptors.
4. With local anesthesia in fingers and toes
185
What are the receptors for NE?
It activates Ξ± (mainly) and Ξ²1-receptors, It has little activity on Ξ²2-receptors
186
What is the effect of NE?
increase both systolic and diastolic BP with reflex bradycardia.
187
What is NE used for?
It is used as VC (by slow i.v. infusion) in acute hypotensive states.
188
What is the nature of dopamine?
It is a natural catecholamine
189
How is dopamine given?
Continous I.V
190
What is the effect of dopamine in low (therapeutic) doses?
stimulates dopamine D1 receptors in renal and mesenteric vascular beds leading to VD and increase renal and hepatic blood flow
191
What s the effect of dopamine in intermediate doses?
stimulates cardiac Ξ²1 receptors leading to increase contractility and COP.
192
What is the effect of dopamine in large doses?
stimulates vascular Ξ±1 (stronger than D1) receptors leading to VC and ββ BP
193
What are the therapeutic uses of dopamine?
β Shock states: restores adequate tissue perfusion by increasing COP (Ξ²1) and increasing renal blood flow (RBF) and glomerular filtration rate (GFR; D1).
194
What is the nature of dobutamine?
synthetic catecholamine
195
What is the method of administration of dobutamine?
I.V infusion because of its short duration (2 min).
196
What are the receptors that are affected by dobutamine?
It activates mainly cardiac Ξ²1-receptors with no effect on dopamine receptors leading to increase COP with little or no vascular effects.
197
What are the therapeutic uses of dobutamine?
ο cardiogenic shock(a complication of left ventricular infarction)
ο It is given by continuous i.v. infusion in
ο to reverse myocardial depression and increase COP (Ξ²1).
198
What is the nature (chemistry) of salbutamol, terbutaline?
synthetic non-catecholamines
199
What are the pharmacodynamics of salbutamol, terbutaline?
greater selectivity at Ξ²2 receptors
200
What are the effects of using salbutamol, terbutaline?
leading to relaxation of bronchial smooth muscles, Bronchodilatationin bronchial asthma
201
What are the side effects of salbutamol, terbutaline?
TTT
ο In high doses, selectivity on Ξ²2 receptors is lost, leading to tachycardia and even arrhythmia (Ξ²1).
ο Tremors
ο Tolerance
202
What are the nature and receptors targeted by isoprenaline (isoproterenol)?
Synthetic catecholamine predominantly stimulates both Ξ²1 and Ξ²2 receptors.
203
What are the effects of isoprenaline?
It increases HR and contractility, and relax bronchial smooth muscles.
204
What are the uses of isoprenaline?
used as a bronchodilator (rarely used)
205
What is the nature of Phenylephrine, methoxamine, and midodrine? And what is their duration?
non-catecholamines have a long duration of action.
206
What are Ξ±-adrenoceptor agonists?
Phenylephrine, methoxamine, midodrine, clonidine, and tizanidine.
207
What is the effect of Phenylephrine, methoxamine, and midodrine?
They selectively stimulate Ξ±1-receptors leading to VC and increase both systolic and diastolic pressures with reflex bradycardia. (Like NE)
208
What causes reflex bradycardia?
NE, Phenylephrine, methoxamine, and midodrine
209
What are Phenylephrine, methoxamine, and medodrine Used for?
1. used as vasopressors to correct hypotension.
| 2. could be used locally as eye or nose drops to produce VC and relieve congestion (i.e. nasal decongestants).
210
What is used o relieve hypotension?
- Phenylephrine, methoxamine, and midodrine
| - NE (acute)
211
What is the effect of clonidine?
It is a centrally acting Ξ±2 (inhibition of CNS)agonist leading to decrease central sympathetic outflow and blood pressure.
212
What is the effect of tizanidine?
ο It is another centrally acting Ξ±2 agonist (congener of clonidine)
ο with a greater effect on presynaptic Ξ±2 in the spinal cord
ο it inhibits neurotransmission
ο reduces muscle spasms with minimal effect on blood pressure.
213
What are the side effects of clonidine?
Dry mouth
214
What are the uses of clonidine?
Antihypertensive
215
What are the side effects of tizanidine?
Minimal SE
216
What are the indirect-acting Sympathomimetics?
I. Releasers: Amphetamine
| II. Reuptake inhibitors: Cocaine, Tricyclic antidepressants
217
What are the mixed acting Sympathomimetics?
Ephedrine
218
What is the method of administration of ephedrine?
Effective orally
219
What are the pharmacodynamics of ephidrine?
Mixed effect:
1. Indirect: release of NE from nerve endings.
2. Direct stimulation of Ξ± and Ξ² receptors
3. CNS stimulation.
220
What are the uses of mixed-acting sympathomimetics?
1. Ephedrine: nocturnal enuresis
| 2. Pseudoephedrine is one of the isomers of ephedrine. It is present in many nasal decongestants
221
What are the side effects of ephedrine?
Tolerance
222
What is the classification of Sympatholytics?
I- Adrenergic receptor blockers
βͺ Ξ±- Adrenergic blockers βͺ Ξ²- Adrenergic blockers
II- Centrally acting drugs
βͺ Ξ±-methyl dopa βͺ Clonidine
223
What is the action of adrenergic blockers?
These drugs interact with either Ξ±- or Ξ²-adrenoceptors to prevent or reverse the actions of endogenously released catecholamines or exogenously administered sympathomimetics
224
What is the classification of alpha-adrenergic blockers?
1. Non-selective Ξ±-receptor blockers: phenoxybenzamine, phentolamine
2. Selective Ξ±1-receptor blockers: prazosin , terazosin, doxazosin
3. Selective Ξ±2-receptor blockers: yohimbine
225
What are the pharmacological effects of alpha-blockers?
ο Alpha receptor antagonist drugs lower peripheral vascular resistance (PVR) and blood pressure.
ο Hence, postural hypotension and reflex tachycardia are common during the use of these drugs.
ο Other minor effects include miosis, nasal stuffiness, etc
226
What is the mechanism of action of PHENOXYBENZAMINE?οΏΌ
Irreversible non-selective Ξ±1 & Ξ±2 antagonist
227
What are the uses of PHENOXYBENZAMINE?
Pheochromocytoma(with Ξ²-blocker)
228
What are the side effects of PHENOXYBENZAMINE?
ο Hypotension
ο Reflex tachycardia
ο Miosis
229
What are selective alpha 1 blockers?
Prazosin, terazosin, doxazosin and tamsulsin
230
What are the characters of prazosin?
ο Prazosin is the Prototype drug.
ο All of these agents decrease peripheral resistance and lower arterial BP (like most adrenergic blockers) by:
a) Ξ±1- receptor blockade.
b) Direct VD of both arterial and venous smooth muscles.
ο They cause minimal changes in COP, RBF, and the GFR. (Unlike dopamine)
ο They donβt trigger reflex tachycardia by the same degree (as the non-selective blockers.)
ο They improve plasma lipid profile and decrease LDL and TGs
231
What are the therapeutic uses of prazosin?
1) Mild to moderate hypertension
2) Benign prostatic hyperplesia (BPH):
βͺ reduces the tone of the internal sphincter of the urinary bladder.
3) Raynaudβs syndrome
232
What are the characters of tamsulosin (more selective)?
ο is the most commonly used for the treatment of BPH because:
- It has a high affinity for Ξ±1A & Ξ±1D, the 2 receptor subtypes responsible for mediating smooth muscle contraction in prostatic tissue.
- It has little effect on standing BP compared with other Ξ±1-blockers. (Like prazosin)
233
What are the adverse effects of prazosin?
βͺ First dose hypotension (syncope)
βͺ Fluid retention (salt and water retention)
βͺ False-positive test for the antinuclear factor of rheumatoid arthritis
βͺ Ξ±- blockers can worsen incontinence in women with pelvic floor pathology
234
What are the characters of yohimbine?
βͺ Selective presynaptic Ξ±2-blocker that leads to increased norepinephrine release. (As it prevents negative feedback)
235
What is yohimbine used for?
βͺ It is sometimes used as an aphrodisiac (enhance sexual desire) without clinical evidence.
236
Is pheochromocytoma rare?
It is an uncommon cause of hypertension, estimated to occur in approximately 0.1 to 1 % of hypertensive patients.
237
How is pheochromocytoma treated?
βͺ Clinical awareness of this tumor should be stressed because:
i. Surgical removal is curative in more than 90 % of patients
ii. Tumor excision has a significant effect on hypertension, the most important cause of pheochromocytoma related mortality and morbidity.
238
What is the selectivity of beta-blockers related to?
The Ξ²-receptorβblocking drugs differ in their relative affinities for Ξ²1 and Ξ²2 receptors; however, the selectivity is dose-related and tends to diminish at higher doses.
239
What are non-selective beta-blockers?
βPropran - pindo - timo - sota - Nadoβ
propranolol, pindolol, timolol, sotalol, nadolol
240
What are cardio-selective beta 1 blockers?
βNebi - biso - meto - ateβ βVPPNβ
nebiVolol, bisoProlol, metoProlol, ateNolol,
241
What are beta-blockers with additional VD action?
βDileva - Carvediβ
dilevalol, carvedilol
242
How do some beta-blockers cause VD?
the VD action comes from either: blocking the vascular Ξ±1 receptors; increasing PGE2 and PGI2 synthesis; or by the release of endothelial NO.
243
Pharmacodynamics and chemistry of beta-blockers?
ο Propranolol is the prototype Ξ²-adrenoreceptor antagonist.
ο Ξ²-blockers are absorbed well after oral administration, many have low bioavailability because of extensive first-pass metabolism.
ο Lipophilic Ξ²-blockers (e.g. propranolol) can pass readily to the CNS and are cleared by hepatic metabolism. Hydrophilic Ξ²-blockers (e.g. atenolol) have limited penetration to the CNS and are excreted primarily by the kidney with little hepatic metabolism.
ο Ξ²-blockers that undergo hepatic metabolism usually require multiple daily dosing.
ο Drugs eliminated via the kidney are suitable for once-daily administration
244
What are the organs affected by beta-blockers?
- CNS
- Eye
- CVS
- Respiratory
- Sk. Ms.
- Metabolic effects
- Specefic properties
245
What are the effects of beta-blockers on CVS?
ο They block cardiac Ξ²1 receptors and decrease all cardiac properties (β contractility and COP, β A-V conduction "bradycardia", β excitability, and automaticity).
ο They block the Ξ²2-mediated VD in peripheral vessels leading to β blood flow to most tissues.
ο They decrease blood pressure through:
a. ββ COP by their βve inotropic and chronotropic effects.
b. ββ renin release from the kidney (Ξ²1).
c. ββ norepinephrine release and central sympathetic outflow
(by blocking presynaptic Ξ²2).
246
What are the effects of beta-blockers on the respiratory system?
Bronchospasm even with the Ξ²1-selective blockers (in high doses)
247
What are the effects of beta-blockers on the eye?
Decrease the rate of Aqueous humor production.
248
What are the metabolic effects of beta-blockers?
βaggravation of hypoglycemic effect of insulin
β plasma K+ (hyperkalemia) in patients with renal faI lure (mo uptake of k+)
249
What are the effects of beta-blockers on CNS?
1. Antianxiety effects.
2. Nightmares, vivid dreams, and depression.
3. Sexual dysfunction through combined central and
peripheral mechanisms.
250
What are the effects of beta-blockers on Skeletal muscles
βͺ β essential tremors due to blocking of Ξ²2 in skeletal muscles.
251
What is the specific use of propranolol?
has local anesthetic (membrane-stabilizing) action i.e. it can inhibit excitability of the cardiac muscle.
252
What is the specific use of pindolol?
is a partial agonist i.e. it doesnβt cause excessive bradycardia.
Inc heart rate of alone
Decrease rate with beta agonist
253
What is the specefic use of Elmolol?
ο² is ultrashort acting (t1/2 = 10min) because of extensive hydrolysis by plasma esterases;
ο² it is administered by i.v. infusion to control arrhythmia during surgery and emergency situations.
254
What is the specefic use of Labetalol?
blocks Ξ²-receptors and Ξ±1-receptors (VD) (mixed blocker).
255
What are the therapeutic uses of beta-blockers?
```
βͺ CVS:
o Hypertension
o Prophylaxis against angina
o Cardiac arrhythmias (inc rate of atria)
o Myocardial infarction (heart attack)
```
βͺ Thyrotoxicosis
βͺ Anxiety states (suppression of the physical manifestations of situational anxiety)
βͺ Prophylaxis against migraine attacks
βͺ Open angel glaucoma(β aqueous humor secretion)
256
What are the adverse effects of beta-blockers?
CNS - CSV - Respiratory - GIT - all with masks are tired and aggravated
ο CNS: Vivid dreams nightmares and hallucinations
ο CVS: Heart failure (low contractility), Heart block (low conductivity), Hypotension, and severe bradycardia
ο Respiratory: Bronchospasm
ο GIT: nausea, vomiting
ο Allergic reaction
ο Withdrawal symptoms in case of abrupt discontinuation
ο Masking of hypoglycemia in diabetic patients
ο Tiredness & fatigue (no k + uptake)
ο Aggravation of peripheral ischemia (more VD due to alpha 1)
257
What are the contradictions of beta-blockers?
ο Absolute contraindications:
a) Bronchial asthma.
b) Any degree of heart block.
c) Sudden withdrawal after long-term use. d) Acute or severe heart failure
ο Relative contraindications;
a) Peripheral vascular diseases (PVD). b) Diabetes mellitus.
c) In athletes
258
What is the mechanism of action of alpha methyldopa?
ο In the CNS, Ξ±-methyldopa competes with dopa for dopa decarboxylase enzyme, leading to the formation of Ξ±-methylnorepinephrine, (and also Ξ±-methyldopamine),
which is a false transmitter.
259
What is an example of centrally acting symapathoplegic drugs?
Alpha-methyldopa
260
What are the therapeutic uses of alpha methyldopa?
Methyldopa is the drug of choice to treat arterial hypertension in pregnancy
261
What are the adverse effects of alpha methyldopa dopa?
βDue to decrease in central sympathetic outflowβ
a) Sedation.
b) Nightmares, mental depression
c) +ve Coombs test & autoimmune hemolytic anemia
D) Parkinsonism
E) suicidal activities
262
What are the factors affecting drug absorption?
- Factors related to the drug
| - Factors related to the absorbing surface
263
What are the factors related to the drug that affects drug absorption?
ο· Molecular size: Small molecules are absorbed > large molecules.
ο· Drug formulations: Sustained-release (SR) tabletsβ slow absorption.
ο· Drug combination: Vit C ββ iron absorption.
ο· Lipid solubility: The pKa and drug ionization
264
What are the factors related to the absorbing surface that affect drug absorption?
ο· Route: The IV route is the fastest, while the rectal is the slowest.
ο· The integrity of the absorbing surface: may β or β absorption.
ο· Total surface area: absorption across the intestine more
efficient (intestine has a large surface area).
ο· Rate of the circulation: at the site of absorption (blood flow).
265
How is loading dose calculated? And what does it depend on?
Ld = Vd * Cp
Vd (volume of distribution)
266
How to calculate maintanence dose? And what does it depend on?
{MD= CL X Cp}
Cl (clearance rate)
267
What is the definition of clearance?
```
ο· The volume of fluid (usually plasma or blood) from which drug is removed per
unit time (ml usually per minute).
```
268
What is the definition of elimination?
ο· The processes involved in the removal of drugs from the body (and/or plasma)
269
What is elimination half-life? And what is it used for?
- It is the time taken for the concentration of a drug in the blood to fall half its original value.
- Used in determination of inter dosage interval.
270
What are the patterns of elimination?
- First-order elimination
| - Zero-order elimination
271
What is the definition of first-order elimination? And what dugs show this type of elimination?
- A constant fraction (PERCENTAGE) of the drug is eliminated per unit time (t1/2 is constant).
- Most drugs follow first order
272
What is the definition of zero-order elimination?
- A constant AMOUNT of drug is eliminated per unit time (t1/2 is variable), Drug cumulation and interactions are common.
- Aspirin & phenytoin (zero-order in high doses)
273
What is steady-state concentration?
- Steady level of drug in the plasma is achieved when the rate of administration equals the rate of elimination.
- Steady-state plasma concentration abbreviated β Cpss.
274
What is the concept of the role of 5?
The rule of 5 :
1. Cpss is reached after 4-5 t 1/2.
2. If a dose is changed, new Cpss after 4-5 t 1/2
3. Complete drug elimination after 4-5 t 1/2. (if the drug given once or stoped after continuous administration)
275
How to achieve Cpss. After first t 1/2?
To achieve Cpss after first t 1/2 β give double the dose (loading dose) in the first time only then give the usual dose (maintenance dose)
276
Percentage of the drug in body after one-time administration or stopping after continuous administration.
```
50
25
12.5
6.25
3.125
```
277
Percentage of the drug in blood in cases of Continous administration
```
50
75
87.5
93.75
96.875
```
278
What are the types of receptors?
Ligand-gated ion channel:
- Nicotinic & GABAA receptor.
G protein-coupled:
- Muscarinic receptors.
- Adrenergic receptors.
- Histamine 1&2 receptors.
Tyrosine kinase linked:
- Insulin receptor.
Intracellular:
- Glucocorticoid receptors.
279
What are adverse drug reactions?
An ADR is any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, or therapy.
280
What are types of clinical defect of the drug?
- Desirable
| - Undesirable
281
What are type types of adverse drug reactions?
```
Type A - Augmented
Type B - Bizzare
Type C - Continous
Type D - Delayed
Type E - End of use
```
282
Type A - Augmented
Related to the pharmacological action
E.g: bleeding with anticoagulants
283
Type B - Bizzare
Unrelated to the pharmacological action
example: plastic anemia from carbimazole
284
Type C - Continous
Chronic affects - dose and time related
Example: Analgesic nephropathy
285
Type D - Delayed
Unmmon, time-related delay in Onset
Example: Tetratogenesis
286
Type E - End of use
Soon after withdrawal
Example: MI by beta blocker withdrawal
287
What are examples of type A ADRs?
They may result from an exaggerated response (e.g. hypotension from an antihypertensive) or non- specificity (e.g. anticholinergic effects with antihistaminic).
288
What are predisposing factors for ADRs?
βͺ Multiple drug therapy
βͺ Age :
o very old
o very young
βͺ Associated disease:
o impaired renal function.
o impaired hepatic function.
