Molecular size

structural features

degree of ionization

Relative lipid solubility of its ionized and nonionized form

Binding to plasma and tissue proteins (including fat)

Passive diffusion

Facilitated diffusion

active transport

Endocytosis

Phagocytosis

Diffusion occurs down an electrochemical or concentration gradient of the drug

Lipid-soluble drugs penetrate the cell membrane through aqueous channels or pores

Water-soluble drugs move across due to their solubility in the membrane lipid bilayers

Dominates transmembrane movement of most drugs

Need energy

Use transmembrane carrier proteins

allowing the passage of drugs into the cell based on their concentration or electrochemical gradient

require energy

can be saturated

use transmembrane carrier proteins that require input of energy derived from the hydrolysis of ATP

against their electrochemical or concentration gradients

can be saturated

non-selective and may be competitively inhibited by other co-transported substances

An example of active transport mechanism is Na+/K+-ATPase, a target of digoxin for the treatment of heart failure

Transporters are membrane proteins

always require energy

usually focus on transporters from two major superfamilies, ABC (ATP binding cassette) and SLC (solute carrier) transporters.

control the influx of essential nutrients and ions, and the efflux of cellular waste, environmental toxins and drugs

Rely on ATP hydrolysis to pump their substrates across membranes; function as efflux transporters

Cystic fibrosis transmembrane regulator (CFTR): found in the liver, kidney, GIT and blood-brain barrier (BBB); involved in the uptake and efflux of drugs

P-glycoprotein (Pgp, also termed MDR1): involved in the regulation of salt and water on several membranes such as those found on lungs

ABC transporters are expressed on the apical side of intestinal epithelia where they can pump out orally administered drugs

ABC transporters are expressed in polarized tissues: kidney and liver

Involved in the uptake of bigs molecules into cells

Best recognized SLC transporters include the serotonin transporter (SERT) and the dopamine transporter (DAT)

Transporters in the SLC superfamily transport diverse ionic and nonionic endogenous compounds and drugs

mostly active transporters

play physiological roles: intestines and kidney: transport neurostransmitters across plasma membranes

Decreased uptake of drugs is mediated by reduced expression of influx transporters required for entry of drug into cells

Enhanced efflux of hydrophobic drugs can be mediated by increased expression of efflux transporters (e.g., overexpression of P-glycoprotein in tumor cells after exposure to anticancer agents can lead to the pumping out of the drug and development of resistance)

Transporters play critical roles in the development of resistance to anticancer, antiviral and anticonvulsant drugs

Increase in plasma concentrations of a drug based on a decrease in the uptake and/or secretion in clearance organs (e.g., liver and kidney)

Decreased uptake of drugs is mediated by reduced expression of influx transporters required for entry of drug into cells

Increase in plasma concentrations of a drug based on a decrease in the uptake and/or secretion in clearance organs (e.g., liver and kidney)

Increase in plasma concentrations of a drug in toxicological target organs (liver, kidney, brain, etc) due to increased uptake or reduced efflux

Increase in plasma concentrations of an endogenous compound in the target organ due to drug-inhibited efflux of the endogenous compound

TRUE

FALSE

TRUE

FALSE

include oral and sublingually

advantages: Safest, most common, convenient and economical route

disadvantages: patient compliance, food may affect absorption, always undergo first pass metabolism

advantage of the sublingual route: rapid absorption, bypass GI environment and avoid first pass metabolism by liver

include subcutaneous, intramuscular, intravenous and intrathecal.

most common route of administration

Used for drugs that are poorly absorbed from the gastrointestinal (GI) tract and for treatment of the unconscious patient

advantages: rapid, do not undergo first pass hepatic, high bioavailability, control of delivered dose of drug, decrease risk of infection

disadvantages: irreversible, may be painful

True

false

Absorption can be modulated to some extent by local heating, massage or exercise

the rate of absorption from the deltoid muscle is faster than the gluteus maximus

slow, constant absorption from IM sites results if the drug is in an water-based solution

example: haloperidol and medroxyprogesterone

true

false

also referred to as topical administration

membranes site include ocular, pulmornary, nasal, rectal and vagina

avoid first pass metabolism by liver

slow absorption

The skin is a viable route of administration for highly hydrophilic drugs

Absorption of drugs is dependent upon the surface area

Absorption can be enhanced by suspending drug in an oily vehicle and rubbing the preparation into the skin

bypasses first-pass hepatic metabolism

The route is often used for sustained delivery of drugs in patches such as nicotine, scopolamine and estrogen

absorption:The process of transfer of a drug from its site of administration to the blood stream

For solid dosage forms, it requires the dissolution of the tablet or capsule leading to the release of the drug before absorption

Bioavailability = Quantity of drug reaching systemic circulation/Quantity of drug excretion

bioavailability for drugs administered by the IV route is 100%.

the bioavailability of orally administered drugs is also 100%

pH

blood flow to site of absorption

total surface area available for absorption

contact time at the absorption site

temperature of absorption site

cardiac output and regional blood flow

capillary permeability

tissue volume

the degree of binding of drug to plasma and tissue proteins, and fat

the relative hydrophobicity of the drugs

Most drugs and drug metabolites are eliminated from the body through renal and biliary excretion. Some drugs are excreted through the lungs, breast milk and skin

Drugs are eliminated from the body either unchanged or as metabolites

nonpolar compounds are more efficiently eliminated than those with low lipid solubility

Excretion of drugs in breast milk is important because excreted drugs may affect the nursing infant

Excretion from lungs is important mainly for the elimination of anesthetic gases

Renal excretion of unchanged drug constitutes the major route of elimination for 25-30% of drugs administered to humans

Excretion of drugs and metabolites in the urine involves three distinct processes: glomerular filtration, active tubular secretion and passive tubular reabsorption

glomerular filtration: renal blood flow, glomerular filtration rate and drug binding to plasma proteins determines the amount of drug that enter the tubule

urinary drug concentration increases in the proximal tubule because of passive diffusion, facilitated diffusion

Secretion of drugs into the proximal tubule occurs by two active processes, one for anions (deprotonated forms of weak acids) and another for cations (protonated form of weak bases)

Membrane transporters (e.g., SLC and ABC families) located on the distal renal tubule are responsible for the reabsorption of drugs from the tubular lumen back into the systemic circulation

Non-ionized forms of weak acids and bases undergoes active reabsorption

The pH of the urine can be manipulated to increase the ionized form of the drug leading to increased elimination of an undesired drug

Changing the rate of urine flow through the tubules can also affect the rate of drug reabsorption (example in aspirin overdose)

Weak acids can be eliminated by alkalinization of the urine whereas, the elimination of weak bases can be increased by the acidification of the urine (the ion trapping process)

Transporters present in hepatocytes (e.g., ABC,OAT2, OCT1, NTCP) passively secrete some drugs and metabolites into bile

Ultimately, drugs and metabolites present in the bile are released into the GI tract during the digestive process

Subsequently, drugs and metabolites can be reabsorbed into the body from the intestine and retained in the portal and systemic circulation (‘enterohepatic recycling’)

Drugs such as steroid hormones and digoxin are largely excreted in bile

True

false

Defined as the amount of time it takes for the plasma concentration of a drug to be reduced by 50%

most drugs are eliminated by first-order kinetics (amount of drug that is metabolized and excreted in a given unit of time is directly proportional to the concentration of drug in the systemic circulation at that time)

first order: T1/2 = 0.693 x V/clearance

A increase in drug clearance or decrease in V tends to prolong t1/2

T1/2 must be considered in designing dosing regimen

age

obesity

Cyp p450 inhibition

Cyp P 450 induction

renal failure

7 transmembrane helix G-protein coupled receptor

located on ganglia of PNS, CNS & autonomic effector organs innervated    

           by postganglionic parasympathetic nerves

five subtypes; M1-M5

Ligand gated ion channels

located in the peripheral autonomic ganglia, CNS, adrenal medulla,

             skeletal muscle, neuromuscular junction

Ligand gated ion channels

located in the peripheral autonomic ganglia, CNS, adrenal medulla,

             skeletal muscle, neuromuscular junction

2 subtypes [muscle type (NM), neuronal type (NN]

- located on ganglia of PNS, CNS & autonomic effector organs innervated    

           by postganglionic parasympathetic nerves

7 transmembrane helix G-protein coupled receptor

modulation of sleep

wakefulness

- learning, and memory

suppression of pain at the spinal cord level

epilepsy

TRUE

FALSE

Choline esters (includes ACh, and synthetic esters)

Naturally occurring Alkaloids

Muscarinic agonist are used clinically in the diagnosis of asthma and as miotic agents

     (agents that cause pupil constriction).

Common adverse effects of muscarinic agonist including diarrhea, nausea, diaphoresis, urinary urgency, constipation

Carbachol

bethanechol

Pilocarpine

cevimeline

has both muscarinic and nicotinic activity

resistant to cholinesterases, thus extends duration of action

use systematically 

Pharmacological action: miosis (pupillary constriction) and decrease elevated intraocular pressure (IOP)

üAdverse Effects: corneal clouding, retinal detachment, sweating, flushing, headache, abdominal cramps

exhibits muscarinic activity

hydrolyzed by cholinesterases

Pharmacological action: cause rapid miosis and potent stimulator od secretion (sweat, tear, saliva)

Therapeutic use: as a miotic agents (open angle glaucoma) and a sialogue (saliva inducing agent) used to treat xerostomia (dryness of the mouth)

Adverse Effects: sweating, nausea, rhinitis, headache, dizziness, abnormal vision, urinary frequency

An active drug may be converted into an inactive drug

An active drug may be converted to an active or toxic metabolite

An inactive prodrug may be converted into an active drug

A drug that cannot undergo excretion may stay in the body and cause side effects

Major organ of drug metabolism for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids and proteins) and drugs

Site of the “First-pass Effect”

Drugs are metabolized by the liver after they enter systemic circulation

Dosing regimens may need to be adjusted to account for metabolism by the liver of some drugs administered orally

Drugs that are inactivated after their first pass through the liver can be administered orally and intravenously

TRUE

FALSE

Are anabolic reactions (e.g., oxidation, reduction or hydrolysis) and the products can be inactivated or more chemically reactive

Convert lipophilic drugs into more polar compounds by introducing or unmasking a polar functional group such as hydroxyl (-OH) or amine (-NH2) groups

May increase, decrease or leave unaltered a drug’s pharmacological activity

Phase I reactions most frequently associated with drug metabolism are catalyzed by the cytochrome (CYP) P450 system (also known as microsomal mixed function oxidases)

all phase I reactions will require further modifications (e.g., under Phase II reactions) prior to excretion

True

False

The extensive overlapping substrate specificities by CYPs is a major underlying reason for the predominance of drug-drug interactions

Most active CYPs for drug metabolism are those in the CYP2C, 2D and 3A subfamilies

CYP3A4, the most abundantly expressed in the liver, accounts for the metabolism of over 50% of clinically used drugs

Together, the CYP-450-mediated reactions account for more than 95% of oxidative bio-transformations

Drug oxidation by the CYP-450 system requires: drug, p450 enzyme, molecular oxygen, NAD and NADH

Plasma cholinesterase (e.g., suxamethonium)

Alcohol dehydrogenase (e.g., ethanol, in addition to CYP2E1)

Xanthine oxidase (e.g., 6-mercaptopurine)

Monoamine oxidase (e.g., norepinephrine, serotonin)

sulfate conjugation (e.g., salicylic acid)

synthetic reactions and involve conjugation (i.e., attachment of a substituent group) which results in inactive products

Substrates are coupled by transfer enzymes to endogenous metabolites (e.g., glucuronic acid, sulfuric acid, acetic acids, amino acids and glutathione) in reactions that often involve high-energy intermediates

All Phase II reactions occur in the cytosol of the cell with the exception of glucuronidation which takes place in the luminal side of the ER

The catalytic rates of Phase II reactions are significantly slower than for Phase I reactions

In most cases, the conjugation process makes the drug more polar and pharmacologically active

Pharmacogenomics

Race and Ethnicity

Age and Gender

Diet and Environment

Disease

Xenobiotics can influence the extent of drug metabolism by activating transcription and expression of genes encoding drug-metabolizing enzymes

Induction or inhibition always increase incidental (a side effect of the drug)

Drugs, environmental pollutants and industrial chemicals can enter hepatocytes and bind to different nuclear receptors: pregnane X receptor (PXR), constitutively active androstane receptor (CAR), aryl hydrocarbon receptor (AhR)

consequences of CYP450 induction include: increase its own metabolism, increase the metabolism of a co-administered drug, production of toxic levels of reactive drug metabolites

Inhibitors of CYP-450 differ in their selectivity towards different isoforms of the enzyme and are classified by their mechanism of action such as competitive and noncompetitive inhibitors

Decreased metabolism of drugs that are metabolized by the inhibited enzyme

Increase metabolism of drugs that are metabolized by the inhibited enzyme

Increase in plasma levels of  drugs that are normally inhibited by enzyme

Prolongation of the presence of active drug in the body

Decrease in plasma levels of  drugs that are normally inhibited by enzyme

TRUE

FALSE

Bind to and inhibit acetylcholinesterase (AChE), preventing  hydrolysis of ACh

This increases the concentration of endogenously released ACh in the synaptic cleft. The accumulated ACh subsequently activates nearby cholinergic receptors

Agents in this class are also referred to as indirectly acting ACh receptor antagonists because they generally do not activate receptors directly

few AChE inhibitors have a direct action on cholinergic receptors. eg neostigmine, a quaternary carbamate, not only blocks AChE but also binds to and activates nAChRs at the neuromuscular junction (NMJ)

increasing transmission at the neuromuscular junction (NMJ)

increasing parasympathetic tone

increasing central cholinergic activity (e.g., to treat symptoms of AD)

increasing sympathetic tone

Increase the activity of endogenous ACh - use Myasthenia gravis and Eaton-Lambert syndrome

Potentiate parasympathetic actions: Eye (topical application to cornea decrease IOP) and GI (Increase in smooth muscle motility  and tone, secretion of  gastric acid)

Reverse anticholinergic drug poisoning counteract CNS effects anticholinergic toxicity

Increase central cholinergic activity. Use Cognitive impairment associated with multiple sclerosis and schizophrenia

edrophonium

neostigmine

pyridostigmine

donepezil

isoflurophate

Atropine

scopolamine

Ipratropium

Oxybutynin

Ambenonium

Act by binding directly to the agonist site, causing inhibition of all muscarinic function

Are used to produce a parasympatholytic effect in target organs. By blocking normal cholinergic tone, these compounds allow sympathetic responses to predominate

üClinically beneficially (Respiratory tract, urinary tract, GI, eye and heart)

Little or no blockade of nicotinic receptors, so have little or no action at NMJ or autonomic ganglia

Atropine

Ipratropium

Tiotropium

Benztropine

Oxybutynin

Blurred vision

Confusion

Mydriasis

Urinary retention

Diarrhea