Alkaloids: API (active) contain cyclic nitrogen, like morphine, caffeine nicotine... Glycoside: organic structure (aglycone component) with sugar (glycone component), like digitalis (used for heart failure) Gums: Exceipient, used in syrup... Tannins: exciepient, constricts body tissues

What are the animal origin of medicine?

Insulin, thyroxine...

What are the human origins of medicine?

Igs, GH, CG...

What are the microorganism origins of drugs?

Mainly Abx

What are the molecular targets of drugs?

Receptors, enzymes (esterase), ion channels, carrier molecules, nucleic acids

What are pharmacodynamics?

It is what the drug does to the body, the relationship between the concentration of the drug and the response to it.

What are pharmacokinetics?

It is what the body does to the drug ADME Administration, Distribution, Metabolism and Excretion

What are the main routes of administration?

Oral (PO), Sublingual (under the tongue), and rectal (these are the digestive routes) IM, SC, IV (these are the parenteral routes) Inhalation (respiratory diseases), Topical (applied to skin/ mucus membrane for local or systematic effects), Transdermal (applied to skin for systemic effects and stay for hours (should be lipophilic in order to get behind the border of epidermis)

What is meant by first pass effect?

It is the effect of the entery of the drug to the digestive system, passing through the gut and liver before going into the circulation, thus having a lost quantity of the applied medicine. It occurs for PO, Rectal (But not sublingual where drug goes directly to the jugular vien)

How is the distribution of durgs?

After the drugs enter the blood, they may become bound or circulate freely, they take time to exert action or get distributed according to blood flow (rapid for brain/ liver and slow for skin) Solubility (like BBB) Binding (to certain macromolecules) Ability to cross barriers

How are drugs eliminated?

First by metabolism then by excretion, it is related to the termination of dynamic effects. Metabolism is converting lipophilic molecules into hydrophilic ones in order to be excreted, this is done by oxidation and conjugation. Excretion may be through kidneys (most common route), lungs, feces...

What is regulatory oversight of drugs?

ِAny drug to be marketed should be listed in regulatory authorities (FDA, MOPH...) They should have quality-safety and efficacy.

How is the drug approval process?

It takes at least 10 years, and is very costly. We have 2 stages, preclinical testing: In vitro to approve candidates (molecular testing) and then experimental testing on animal subjects in order to study reaction. Then the second stage is the clinical testing, which is divided into 3-4 phases

What are the phases of clinical testing?

First 2 phases are done on healthy individuals in order to study toxicity of the substance, then we have phase 3 which is the premarketing phase, we compare the drug with gloden standard of the drug family. And finally we have phase 4 which is post-marketing surveillence AKA Pharmacovigilence which is done throught the years to monitor drug safety

What happens after we are done with drug approval?

After the drug is approved, it gets patency, which is the exclusivity for the company to market a product, this lasts for however much the drug took time to get approved. During this period no other company can compete with this product (However some make copycats)

What is the bioequivalence test?

Companies may make generic products of the original product, this generic is made of the same API but different excipients To approve those generics no need for testing, only a bioequivalence test is done to see whether this generic has the same effects as the original or not.

How is the nomenclature of drugs?

Each drug has 3 names, chemical , generic (Easier to study than the chemical , put by the WHO) and proprietary/ trade name Chemical and generic are put in lower case but trade name is in upper case

What is pharmacokinetics?

ADME Any successful drug should be able to cross barriers (as they are considered by the body as xenobiotic foreigners) And to be eliminated they should be metabolized by liver and then excreted When distributed they are found in the blood either free or bound (these proportions are in equivalence) The bound molecules serve as reservoir and free ones are what get diffused

What are the main mechanisms of transport?

Filtration (paracellular diffusion through aqueous pores where small molecules and water only go) Passive diffusion (most drugs by gradient and Fick's law, transcellular diffusion) Active diffusion

What is the Fick's law governing passive diffusion rate?

Rate= Diffusion constant * Surface area * Partition constatnt * gradient (Concent high - low) / thickness

What is the partiton constant?

It describes how lipophilis is the molecule being studied whether it diffuses or not. logP (could be negative)

Why should we know ionization state of drugs?

Since ionized drugs cannot pass by passive diffusion, so we should study the pH of the drug and thus knowing where will it be absorbed and where not. To compensate we may alkalinize the drug if it where acidic either by swallowing or by urine or by rectum. We may also use an antedote to stop toxin and inhibit it

How to get ionized/ non ionized forms of a product?

Using Henderson's

Talk about aspirin absorption

Most aspirin is non-ionized so it gets easier to blood As a defense of excess aspirin, we administer bicarbonate to alkalinize stomach and not absorb aspirin by becoming ionized

What is carrier-mediated membrane transport?

For non-lipid soluble molecules, rapid, active transport (if against gradient) or facilitated (if with gradient) Active (needs energy, has saturation, selectivity and competitiveness/ occurs at specific places like BBB neurons and renal tubules and liver) Facilitated (No energy needed, just a carrier, usually for endogenous products but can be used by drugs (glucose by RBC/ Choline by neurons to make Ach)

How is filtration transport?

Through pores like urinary excretion

How are endo and exocytosis?

Endo (phago or pino) and Exo (NTs)

What factors modify GI absorption (gastric factors)?

Factors accelerating gastric emptying increase absorption (hunger, exercise, diluted solutions) Factors delaying gastric emptying (anticholinergics, antihistamines) Gastric secretions (insulin is destroyed) Some drugs are coated in order to not cause gastric irritations (NSAIDs and aspirin)

What are the stages of pharmacokinetics?

Absorption (entry to plasma) Distribution (Leaving bloodstream into interstitial and intercellular) Metabolism (Biotransformation in liver or other tissues) Elimination (through urine/feces)

What is bioavailability?

It is the percentage of administered drugs that reach bloodstream. It is the quantity reaching circulation/ quantity administered

Why is their a lost quantity of the disease?

Since it will pass through liver where some administered drugs is metabolized. So if the liver has a great metabolic activity on the drug, its bioavailability will be reduced largely Note that IV drugs have 100% bioavailability

What do we mean by first-pass liver metabolism?

Entry of drugs through portal veins into the liver before being distributed to the desired target (this usually occurs for toxins as a protective measure detox) So a fraction of the administered drugs is inactivated (Non-enteral routes are not subjected to first pass)

What is the are under the curve (AUC)?

It is a quantification of the amount of drugs getting administered to the bloodstream (Curve is of amount of drug in bloodstream versus time)

What are the factors influencing drug bioavailability?

First pass liver metabolism (nitroglycerin has 10% bioavailability due to first pass) Solubility of drug (Hydrophilic products are poorly absorbed, extremely lipophillic are also poorly absorbed since they cannot circulate in the blood - this is why drugs are either weak acids or bases) Chemical Instability (Degrarded by enzymes (insulin) and acidity (penicillin)) Nature of drug Formulation (size, shape, crystrallization, coating)

What kinds of effects can a drug have?

Local (if drug acts near site of admin) Systemic (If it need to go to circulation)

What routes of entry possess systemic effects?

Enteral routes (Oral, sublingual and rectal) PRL Skin (nitroglycerin patches avoiding first pass effect) Nose (like cocaine and desmopressin) Vagina/rectum Lung (like general anesthesia)

What routes of entry posses local effects?

Skin (corticosteroids like hydrocortisone to decrease inflammation) Nose (decongestants like otrivin nasal spray) Rectum (hemmorrhoids preparation H and procto synalar vasoconstrictors) Lung (salbutamol beta agonist bronchodilator) Eye (atropine to dilate pupil)

What factors affect the oral administration of drugs?

Site characteristics (blood flow to site of absorption and surface area of absorption) Drug characteristics (physical state of drug, water or lipid solubility, and concentration administered)

What are the premium conditions for drug absorption?

Solid forms are governed by the rate of dissolution and water solubility (if low water solubility and dissolution very limited) absorption is favored by non-ionized lipophilic forms Weak acids are better absorbed in stomach while basic substance are absorbed in intestines (pH=7)

What is the difference between abosption in stomach and intestine?

Stomach (thick epithelium and small surface area and acidic) Intestine (thin mucosa, large area, and basic

What factors modify GI absorption (gastric factors)?

What factors modify GI absorption (intestinal factors)?

Time of preservation in intestine (larger favors absorption like antidiarrhea drugs decreasing peristalsis) Increasing peristalsis decreases absorption (laxatives)

What are the advantages and disadvantages of oral administration?

Advantages (easy, safe, cheap, convenient) Dis (limit absorption, emesis, destruction of drugs, irregular absorption due to food, metabolized by first pass)

What is meant by therapeutic window?

When the dosage of effectiveness of a drug is very close to the toxic dose (like digoxine)

Describe sublingual route of administration.

It is absorption through oral mucosa, limited area, but goes into superior vena cava directly without first pass Like nitroglycerin (very effective in sublingual and potent)

Describe rectal route of administration.

When pt is unconscious or vomiting, more than 50% bypasses liver (superior rectal vein goes to inf mesenteric), others go to inferior vena cava (middle and inferior rectal veins go to inferior pudental vein to vena cava)

What is parenteral route of administration?

IV, IM and SC. Introduced directly into systemic circulation or tissues. 100% Bioavailability, used for hardly absorbed drugs (like insulin and heparin), unconscious pts, and in case we need to yield rapid onset of drugs. Not subject to first pass they are irreversible, cause damage fear infection...

How is the IV route of entry?

In aqueous solution form, since complete and rapid bioavailability. Could be given as a bolus (all in one go, but should take some time in order to dilution in blood to occur and not be toxic) or as continuous infusions Can cause infections

How is the IM route of entry?

Could be aqueous solution or depot preparation (oily/ supension which can be absorbed slowly, such as polyethylene glycol) Used for sustained release drugs (for longer time usage) like haloperidol and medroxyprogesterone Can be modulated by heating, massage or exercise which increases blood flow. Drugs that are too irritating to SC are given IM.

How is the SC route of entry?

Used for not too irritating drugs (that may cause necrosis or damage) Constant and slow to provide sustained effect. Administring vasoconstrictors may be used to delay the absorption and increase the sustained effect (like lidocaine local anesthetics incorporate epinephrine in its dosage) Some drugs may be as devices implanted under the skin after an incision. Heparin and Insulin are introduced SC

What are the advantages of PRL administration?

Delivery in active form (like infliximab or remicade Ab) Rapid, predictable delivery Accurate Used for unconscious pt who cant swallow

What are the disadvantages of PRL administration?

Asepsis, pain and difficulty self medication

What is the intrathecal route of administration?

Injection into the spinal canal and further into subarachnod space and CSF, useful in spinal anesthesia, chemo and radiotherapy

What is the pulmonary route of absorption?

Gases and volatile drugs are given for systemic effect and are easily absorbed Some drugs are as particles aerosols local effect and maybe systemic (like Salbutamol for bronchial asthma) No first pass Important for drugs of abuse and toxins (nicotine, opium)

What is the topical route of administration?

Either through mucus membrane or through the skin Through mucus membrane, used for local effects, drugs enter circulation rapidly, may be systemic effect (ADH nasal), or local anesthetics (xylocaine gel) Through the skin, should penetrate through the epidermis primarily (either through the appandanges or through it itself)

What types of particles enter through topical?

Very small and polar molecules. passive diffusion (anelgesics like NSAIDs and Ibuprofen) Facilitated diffusion (fentanyl opoid anelgesic for pain management) Inflammation can increase absorption by increasing the blood flow to the dermis Hydrated skin is more permeable.

Give examples of topical patches.

Nicotine for tobacco-smoking withdrawal, scopolamine for motion sickness, nitroglycerin for angina pectoris, testosterone and estrogen for replacement therapy.

How are drugs distributed in the body?

After drugs reach the blood (and minorly lymph), they should go to target organ/ tissues. They circulate in a specific form (bound -usually to albumin or glycoproteins, or free) They should get to the targets in a therapeutic concentration (enough to exert action)

What factors influence drug distribution?

Blood flow to tissue, capillary permeability, lipophilicity of the drug, degree of binding to the proteins Usually muscles, viscera and fat get delivered drugs slowly while other organs have a higher rate of distribution like liver, brain, spleen... There also should be equilibrium between drug in blood and target organ (bound drugs in blood compensate the drugs that go to interstitium)

How does blood flow influence drug distribution?

Blood flow varies among organs and tissues. An example is propofol (anesthetic which is very lipophilic goes directly to the brain and crosses BBB easily, exerts action for 15 min since after it crosses barrier easily blood should equilibrate it so the drugs entering brain will go back to the blood and after this much time exert action on other tissues Blood flow is also related to the organ mass so we should look at normalized blood flow (ml/kg/min

How does capillary permeability affect drug distribution?

Diff structural characteristics of capillary and drug nature determine drug distribution. Brain: continuous capillaries, liver: fenestrated (drug enters passively or actively by transporters) ex: levodopa has specific transporters in BBB Cardiac muscles drugs entry is through endocytosis

How does lipophilicity affect drug distribution?

Lipophilic drugs cross membranes easily whereas hydrophilic ones cannot. Ex: antiHTN hydrophilic (Atenolol) lipophilic (Propanolol)

How does binding of drugs to plasma proteins affect drug distribution?

When drugs bind proteins they arenot able to cross membranes, so more binding means less transfer Albumin binds drugs and serves as a reservoir maintaining constant fraction of free drug in plasma Ex: >99% of ketorolac (NSAIDs) is protein bound

How does binding to tissue proteins affect drug distribution?

As drugs can accumulate in tissues, they may be bound to lipids, proteins or nucleic acids or may be actively transported to the tissue. So tissue binding can prolong drug action or cause local toxicity Ex: Digoxin accumulates at muscles acts as a reserve to make a balance into blood when drug is reduced prolonging the effect. Ex: Acrolein (cyclophophamide) can cause hemorrhagic cystitis as it accumulates in bladder

What is volume of distribution?

It is a way if estimating the volume in which the administered drug is present in inside the body Since we can get drug concentration in blood and the mass administered we can get the volume where this drug is present in (the volume of distribution Vd) = Dose/Concentration in blood

What are indications given by volume of distribution?

Vd greater than body fluids means drug is gone to tissues highly. So drugs with higher lipophilicity, less charge and less weight will have a higher volume of distribution than drugs with high ionization and weight...

What are the compartments of distribution of drugs?

Water compartments (4 L plasma, 10 L interstitial fluids, 28 L intracellular) So total water in body is 42 L . Drugs could also get into tissues (not water) acc to type of drug and tissue

Talk about plasma drug distriubution compartment.

Heparin has this type of distribution, high molecular weight and extremely protein bound, trapped in plasma so low Vd almost equal plasma concentration (4L)

Talk about interstitial fluid drug distriubution compartment.

Aminoglycosides, low molecular weight but hydrophilic so stays extracellular but out of capillary Vd=14 L (of interstitial and plasma fluid)

Talk about drugs of total body water distribution?

Low molecular weight and lipophilic, Vd=42L Like ethanol

How are drugs bound to plasma proteins?

Drugs bind reversibly to plasma proteins. Mostly albumin, acts as a reservoir, amount of free drugs increase if it is displaced by another drug on albumin, or albumin levels are decreased Thus if free drug is increased we have a higher rate of going into tissues and elimination

Give examples on plasma proteins binding drugs.

Albumin for acidic drugs, a1 acid glycoproteins for basic drugs. Sex-hormone binding globulin for estrogen or testosterone. Thyroxine-binding globulin (TBG) Non-specific binding (lesser extent) usually 2 bond types electrostatic and hydrophobic.

What factors affect drug binding to plasma proteins?

Drug concentration, affinity to binding sites and number of binding sites. Also some disease affect it (hypoalbuminemia (2ary to liver disease), Acute phase response conditions (MI, Crohns, cancer...) elevate a1 acidic glycoprotein enhancing the binding Competition may occur between drugs (unconjugated bilirubin replaced by sulfonamide on albumin binding sites causing bilirubin encephalopathy for newborns

What affects tissue binding of the drug?

Some drugs accumulate at tissues more than blood, like antimalarial drug quinacrine (at liver) resulting in more active transport into cells. It occurs on proteins, lipids or nucleic proteins Reversible binding and may be used as reservoir causing prolonged action or maybe toxicity (aminoglycoside gentamycin in kidney and vestibular system )

How is fat as reservoir?

Could be a reservoir for lipid soluble drugs as it is stable and has low blood flow. Ex: thiopental presents in fat 3 hours after admin Ex: insectiscide DDT Ex: Antianxiety drug clorazepate

How is bone as a drug reservoir?

Tetracyclins and heavy metals accumulate and crystallizes in bone tissue Could be toxic (lead Pb2+ poisoning) Could be therapeutic (osteoporosis bisphosphonate make hydroxyapatite crystals reducing osteoclastic function)

What is drug redistribution?

Redistribution of drugs is a way of terminating the action of a drug Drugs go to another tissue than the action mediated one. Terminates effect of liposoluble drugs in heart and CNS like anesthetic thiopental which acts within seconds on brain, but then diffuses with time into muscles giving a rapid onset and termination of the anesthesia

How is the placenta drug distribution?

Critical for anomalies in children, drugs transferred through placenta are liposoluble, plasma bound, and anionized (as fetal plasma is more acidic than mothers pH=7 There are efflux proteins Pgp proteins limiting fetal exposure to toxic substances, also there are influx transporters

How is CNS drug distribution?

Needs liposoluble drugs transport is primarily transcellular (not paracellular cause of increased tight junctions) Imp for side effects Ex: Loratidine antihistamine is non sedating as it is hydrophilic whereas diphenhydramine could cause sedation with antihistamine effect Drugs may enter CNS by specific uptake transporters into brain and CSF Also output is possible by efflux carriers (like Pgp, or OATP (also seen in GI))

How does the body metabolize drugs?

It involves the same pathways and transport systems that are utilized for normal metabolism of dietary constituents. They are considered as xenobiotics, which has made it difficult to produce them because of interindividual variations, drug-drug interactions and species differences (in trials)

What is the form of drugs that we are able to eliminate?

Hydrophobic drugs are hard to eliminate as they accumulate in fat, so xenobiotic-metabolizing enzymes convert them into hydrophilic ones to be eliminated via urine (decreasing biological activity of the drug)

What are the toxic effects of drug-metabolizing enzymes?

They may metabolize drugs into toxic or teratogenic metabolites, when this unstable metabolite reacts with cells, may be electrophilic or nucleophilic E.g: Epoxidation microsomal reaction are carcinogens inducing cellular and tissue necrosis

What is drug biotransformation?

They are reactions done to enhance the hydrophilicity of drugs to make them susceptible to be excreted renal. two rxn: oxidation-reduction/ hydrolysis (phase I), and Conjugation (phase II) They can either convert drug into inactive form, or convert it into a toxic form, or convert prodrug into active form

Where are the sites of drug metabolism?

Kidneys, GI (oral drugs), lungs, skin. However liver is the most important undergoing the first-pass effect So we give higher dose oral than IV

What is the phase I drug reaction?

Polar reactive group added to the drug to make it suitable for phase II, microsomal microoxidation, cytosolic or mitochondrial oxidation, reduction and hydrolyses

What is the phase II drug reaction?

Products of phase I undergo conjugation with another functional group (hydroxyl, halogen, methyl, carboxyl) Modify compounds by attaching hydrophilic groups to create more polar conjugate, less toxicity and more readily excreted.

What is drug-drug interaction?

Effect of phase I or II reaction also depends on presence of other drugs, barbiturates for example are powerful enzyme inducers while others (like cimetidine) are able to inhibit these enzymes thus less metabolization.

What are prodrugs?

Drugs administered in inactive form that need metabolization to be active, used to facilitate the elimination half-life of a drug E.g: Perfalgan (paracetamol injectable) proparacetamol formed by esterification of paracetamol and carboxylic acid diethylglycine making it more water-soluble, fast hydrolysis by plasmatic esterase.

Give some examples of prodrugs?

Irinotecan (prodrug of SN-38 chemotherapy) Prednisone (prodrug of corticosteroid, anti-inflammatory)

What are phase I oxidation reactions?

They involve enzymes on SER of hepatocytes or other cells, oxidases catalyze these reactions (typically cytochrome p450 heme monooxygenases, AKA CYP), which are microsomal oxidases involved in metabolism of 75% of drugs

How is the CYP reaction?

CYP uses O2 on drugs + NADPH + H+ to oxidize the drug by adding OH to it Most of the CYPs in liver exhibit broad substrate specificity (superfamily) , which is divided into subfamilies and enzyme families and gene number (so they are called CYP4A3 for example)

What are the CYPs found in humans?

12 CYPs (CYP1A1,1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5) are the ones involved in oxidation of xenobiotics, seen in the liver, some in GI, lungs, kidneys, and CNS. Most active ones are CYP2C, 2D and 3A CYP3A4 is most abundant and used in metabolism of 50% of used drugs. other subfamilies are not involved in drug metabolism but in activation of protoxins and procarcinogens (CYP1A, CYP1B, CYP2A, CYP2B, and CYP2E ).

What are some of the CYP-dependent oxidation reactions?

Alipathic Hydroxylation (barbiturates, digotoxin, cyclosporin) Aromatic hydroxylation (propranolol, phenytoin) N-Dealkylation (lidocaine) O-Dealkylation (Codeine) S-oxidation (Cimetidine) N-Oxidation (Quinidine) Desulfuration (thiopental) Epoxide formation (carbamezipine)

Describe the metabolism of paracetamol.

It is absorbed into blood as acetaminophen, where 85 % of it are directly conjugated and excreted. The remaining 15% is oxidized by CYP and natural product solvents into NAPQI (N-acetyl parahydroquinoneimine), which may either bind to proteins and have a toxic effect, or be conjugated by GSH and be excreted.

How is the drug-drug interaction on CYPs?

More than 95% of drug biotransformations are done by CYP, so when 2 drugs coadmin and metabolized by same CYP they will compete, which can result in the inhibition of metabolism of one or both drugs leading to elevated plasma levels. So if there is a narrow therapeutic index for the drugs they will exhibit toxicity.

Give some inducers and inhibitors of CYP.

Inducers (Tabac, cortisol, Rifampicine) Inhibitors (griffon juice)

What is the effect of cyclosporins A on CYP?

Cyclosporin is an immunosupressant used widely in drug transplantation. as they inhibit CYP3A4, in addition to the inhibition of T cells.

What are other pathways used to oxidize lipophilic molecules other than CYP?

Alcohol dehydrogenase (ADH) is an enzyme found in microsomes that oxidize alcohols in aldehydes, which is the basis of intoxication due to ethanol consuption. RK: Ethanol has a higher affinity on ADH than methanol so it can be used as a treatment of methanol toxicity. Ethanol is converted into acetaldehyde by MEOS (microsomal ethanol oxidizing system), which is then further oxidized by ALDH (aldehyde dehydrogenase) into acetate in mitochondria which is eliminated in the circulation.

What is the mechanism of alcohol flush reaction?

It is due to inherited deficiency in ALDH, causing increased acetaldehyde and thus flushing syndrome (characteristic of Asian population where we see erythema of face, neck, shoulders and maybe the entire body)